Sirolimus for Improving Hematopoietic Function in Patients with RUNX1 Familial Platelet Disorder
This phase II trial tests the safety and effectiveness of sirolimus for improving hematapoietic function in patients with RUNX1 familial platelet disorder. High doses of sirolimus are often used to prevent organ transplant rejection. Administered at lower doses, sirolimus may enhance immune system function and/or stimulate the bone marrow to make more platelets.
Inclusion Criteria
- 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 (P)/likely pathogenic (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 bone marrow sample at time of screening and at the end of treatment with sirolimus
- Platelet count of ≥ 50,000/µL
- Estimated glomerular filtration rate based on Modification of Diet in Renal Disease (MDRD) calculation, > 30 mL/min/1.73m^2
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 3 × upper limit of normal (ULN)
- Total bilirubin < 1.5 × ULN
- 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, bacillus Calmette-Guerin (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
Additional locations may be listed on ClinicalTrials.gov for NCT06261060.
Locations matching your search criteria
United States
Texas
Houston
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 increases in platelet counts during and after treatment with low-dose sirolimus.
II. Evaluate changes in somatic mutation variant allele frequency (VAF).
III. Monitor the rate of somatic mutation acquisition (ie, mutation burden).
IV. Assess change in platelet aggregation score.
V. Measure the change from baseline in bleeding score (International Society on Thrombosis and Haemostasis Bleeding Assessment Tool [ISTH-BAT]).
VI. Evaluate change in mTORC1 downstream signaling (pS6/EBP).
EXPLORATORY OBJECTIVES:
I. Measure rescue of elevated cytokine profiles.
II. Evaluate reversal of myeloid skewing using flow cytometry.
III. Determine changes in bone marrow (eg, megakaryocytic atypia and cellularity).
IV. Assess changes in patient-reported outcomes measures (eg, European Organization for Research and Treatment of Cancer [EORTC] and Patient Reported Outcomes Common Terminology Criteria for Adverse Events [PRO-CTCAE]).
V. Describe the pharmacokinetics of sirolimus in patients with RUNX1-FPD.
VI. Determine the correlation between sirolimus trough levels and each endpoint.
OUTLINE:
Patients receive sirolimus orally (PO) once daily (QD) for 6 months in the absence of disease progression or unacceptable toxicity. Patients also undergo bone marrow biopsy at screening and end of treatment and undergo blood sample collection throughout the trial. Patients may also optionally undergo bone marrow biopsy during follow up.
After completion of study treatment, patients are followed up at 24 and 52 weeks.
Trial PhasePhase II
Trial Typetreatment
Lead OrganizationM D Anderson Cancer Center
Principal InvestigatorCourtney DiNardo
- Primary ID2023-0918
- Secondary IDsNCI-2024-01333
- ClinicalTrials.gov IDNCT06261060