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

To learn about the safety and effects of low-dose sirolimus in participants with RUNX1-FPD.

Study Overview

• Status: Recruiting
• Conditions: Familial Platelet Disorder; Hematopoietic
• Intervention / Treatment: Drug: Sirolimus

Detailed 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

• Study Type: Interventional
• Enrollment (Estimated): 6
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Courtney DiNardo, MD; Phone Number: (713) 794-1141; Email: cdinardo@mdanderson.org

Study Locations

• United States
  • Texas
    • Houston, Texas, United States, 77030
      • Recruiting
      • MD Anderson Cancer Center
      • Contact: Courtney DiNardo, MD; Phone Number: 713-794-1141; Email: cdinardo@mdanderson.org
      • Principal Investigator: Courtney DiNardo, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Arm 1; Participants will visit the study clinic 2 times during Week 1, one (1) time during Weeks 2-4, and then 1 time every 2 weeks after that (Weeks 6, 8, 10, and so on) until Week 22 (Month 6). Then participants will have a follow-up visit at Week 24 and again at Week 52 (Month 12). Participants will take sirolimus by mouth every day, at about the same time each day. Swallow the tablet(s) whole with a full glass of water (about 1 cup). Do not crush or chew the tablet(s). Participants may take sirolimus with or without food.

Drug: Sirolimus; Given by PO

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety and adverse events (AEs)	Incidence of Adverse Events, Graded According to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version (v) 5.0	Through study completion; an average of 1 year

Collaborators and Investigators

• Sponsor: M.D. Anderson Cancer Center
• Investigators: Principal Investigator: Courtney DiNardo, MD, M.D. Anderson Cancer Center

Publications and helpful links

Helpful Links

• MD Anderson Cancer Center

Study record dates

Study Major Dates

• Study Start (Actual): June 20, 2024
• Primary Completion (Estimated): June 11, 2026
• Study Completion (Estimated): June 11, 2028

Study Registration Dates

• First Submitted: February 8, 2024
• First Submitted That Met QC Criteria: February 8, 2024
• First Posted (Actual): February 15, 2024

Study Record Updates

• Last Update Posted (Actual): April 15, 2026
• Last Update Submitted That Met QC Criteria: April 10, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Hematologic Diseases; Blood Platelet Disorders; Organic Chemicals; Macrolides; Lactones; Sirolimus
• Other Study ID Numbers: 2023-0918; NCI-2024-01333 (Other Identifier: NCI-CTRP Clinical Registry)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No