Imatinib to Increase RUNX1 Activity in Participants With Germline RUNX1 Deficiency

NCT06090669 | Recruiting Phase 1 FDA Drug

• 2 other identifiers: 10001542001542-C
• Study Type: interventional
• Target: 75
• Locations: 1 country
• Sites: 1

Brief Summary

Background: Runt-related transcription factor 1 (RUNX1) gene regulates the formation of blood cells. People with mutations of this gene may bleed or bruise easily; they are also at higher risk of getting cancers of the blood, bone marrow, and lymph nodes. Objective: The purpose of the study includes determining which dose of imatinib is best for people with pathogenic or likely pathogenic RUNX1 mutations without blood cancers, and to determine whether there are any changes in platelet function and inflammatory markers. Eligibility: Adults aged 18 and older with RUNX1 mutations. Healthy people without this mutation, including family members of affected participants, are also needed. Design: Participants with the RUNX1 mutation will be screened. They will have a physical exam with blood tests. They will have a test of their heart function. They may need a new bone marrow biopsy if they haven't had one in the past year. Imatinib is a tablet taken by mouth once a day, every day, at home. Affected participants in different parts of the study will take imatinib for either 28 days or up to 84 days. They will fill out questionnaires about how they are feeling. For the first part of the study, participants will have blood tests every 2 weeks, either at home or at the NIH, while they are taking the imatinib. They will have a follow up visit, at home or at the NIH, when they are done taking imatinib on Day 28. Participants on the second part of the study will come to NIH on days 1 and days 84. They will have blood tests every 2 weeks (at home or the NIH) while they are taking imatinib. They may opt to have a bone marrow biopsy repeated after they finish their course of imatinib. Participants will have a follow-up visit (at home or the NIH) 30 days after they stop taking imatinib. Participants who do not have the RUNX1 mutation will have 1 clinic visit. They will have blood tests. They will fill out questionnaires. They may opt to have a bone marrow biopsy.

Conditions

Inherited Bone Marrow Failure Syndrome; Familial Platelet Disorder With Predisposition to Myeloid Malignancies

Keywords

predisposition to hematologic malignancies; germline mutations; IBMFS

Outcome Measures

Primary Outcomes (2)

• Determine the dose of imatinib for dose expansion in participants with pathogenic or likely pathogenic germline RUNX1 mutations during the dose escalation phase

  Safety will be evaluated by the number of DLTs identified at each dose level. The number of DLTs at each dose level will be reported and used to determine the RP2D.

  Arm 1 for 1 month and Arm 2 for 3 months

• Determine the safety of imatinib in participants with pathogenic or likely pathogenic germline RUNX1 mutations during the dose expansion phase

  Safety will be evaluated by the number of DLTs identified at each dose level.

  Arm 1 for 1 month and Arm 2 for 3 months

Secondary Outcomes (4)

• Pharmacokinetics of imatinib in the RUNX1 population in the dose expansion phase

  Measured at baseline (Day 1) and Day 84 for Arm 2

• Improvement in platelet dense granule structure by electron microscopy as compared to baseline in the dose expansion phase

  Measured at baseline (Day 1- both arms) and Day 84 for Arm 2

• Change in platelet qualitative defects

  Measured at baseline (Day 1- both arms) and Day 28 for Arm 1 and Day 84 for Arm 2

• Safety of imatinib in the dose escalation phase

  Assessed from Day 1 of study drug through 28 days after the first dose.

Study Arms (3)

Dose Escalation

EXPERIMENTAL

Escalating doses of imatinib to determine the MTD

Drug: imatinib; Device: TruSight Oncology

Dose Expansion

EXPERIMENTAL

Imatinib at the MTD

Drug: imatinib; Device: TruSight Oncology

No Treatment

NO INTERVENTION

Collection of blood or marrow only. No treatment.

Interventions

imatinib DRUG

Imatinib at 300-400 mg PO QD based on arm assignment/dose level

Dose Escalation; Dose Expansion

TruSight Oncology DEVICE

Assay sequencing platform to identify pathogenic genetic mutations in DNA and RNA

Dose Escalation; Dose Expansion

Eligibility Criteria

• Age: 18 Years - 120 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Affected participants must have a confirmed pathogenic or likely pathogenic germline RUNX1 variant by history. ClinGen expert variant curation panel criteria for pathogenicity will be utilized.
• Affected participants must have a history of clinically significant bleeding as defined by history of abnormal ISTH-BAT score, use of anti-bleeding medications (e.g., amicar), history of platelet transfusion, abnormal PFA screen, abnormal TEG, abnormal platelet aggregation or abnormal platelet electron microscopy.
• Bone marrow morphology, flow cytometry and cytogenetics confirmed by the NIH Department of Laboratory Medicine (DLM) at least within 12 months of initiating imatinib.
• TSO500 performed by NCI Lab of Pathology within 12 months of initiating imatinib.
• Substantial GI malabsorption is not suspected.
• Participants with human immunodeficiency virus (HIV) on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial if their HAART medications do not interact with imatinib.
• Participants with evidence of chronic hepatitis B virus (HBV) infection, on suppressive therapy with undetectable HBV viral load are eligible for this trial. Suppressive therapy medication may not interact with imatinib.
• Participants with a distant history of hepatitis C virus (HCV) infection must have been treated and cured. Participants with active HCV infection who are currently on treatment, with undetectable HCV viral load are eligible. If unknown HCV is detected upon screening- these participants will not be eligible for the study.
• Unaffected family members or healthy volunteers without RUNX1 mutation by pedigree or molecular testing Only participants who are related to the proband need to provide a molecular test.
• The last dosage of any platelet inhibiting medications was at least 2 weeks prior to enrollment and research sample acquisition.
• Age \>=18 years.
• ECOG performance status \<=2 (Karnofsky \>=60%).
• Participants must have adequate organ and marrow function as defined below:
• leukocytes \>= 3,000/mcL
• absolute neutrophil count \>= 1,500/mcL

You may not qualify if:

• Participants who are receiving any other investigational agents.
• Participants who received prior hematologic malignancy directed therapy
• Participants receiving medication that would affect platelet number or function (e.g., aspirin and anti-platelet medications
• Participants without access to medical care at home.
• Pregnancy (confirmed with beta-HCG serum or urine pregnancy test performed in females of childbearing potential at screening).
• Participants with the following pathogenic/likely pathogenic abl mutations on baseline Illumina TSO500 testing of any detectable VAF within 12 months of receiving the first dose of imatinib
• Abl mutations resistant to imatinib (T315I, F317L/V/C, T315A, V299L, Y253H, E255V/K, F359V/I/C)
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to imatinib or other agents used in study.
• Concomitant medications that include the following:
• Participants requiring medications which are inhibitors or inducers of CYP3A4 metabolism, as these may change imatinib plasma levels.
• Uncontrolled intercurrent illness evaluated by history, physical exam, and chemistries or situations that would limit compliance with study requirements, interpretation of results or that could increase risk to the participant
• Participants with the following cardiac conditions: symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia.

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892, United States

RECRUITING

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Congenital Bone Marrow Failure Syndromes

Interventions

Imatinib Mesylate

Condition Hierarchy (Ancestors)

Bone Marrow Failure Disorders; Bone Marrow Diseases; Hematologic Diseases; Hemic and Lymphatic Diseases; Infant, Newborn, Diseases; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Intervention Hierarchy (Ancestors)

Benzamides; Amides; Organic Chemicals; Benzoates; Acids, Carbocyclic; Carboxylic Acids; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Piperazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Pyrimidines

Study Officials

• Lea C Cunningham, M.D.

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Rebecca B Alexander

CONTACT

(240) 781-4037; rebecca.alexander@nih.gov

Lea C Cunningham, M.D.

CONTACT

(301) 642-1633; lea.cunningham@nih.gov

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 17, 2023
• First Posted: October 19, 2023
• Study Start: December 19, 2023
• Primary Completion (Estimated): October 30, 2026
• Study Completion (Estimated): October 30, 2027
• Last Updated: April 21, 2026

Record last verified: 2026-04-17

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: Data from this study may be requested from other researchers at least 1 year after the completion of the primary endpoint. Genomic data are available once genomic data are uploaded per protocol GDS plan for as long as database is active. @@@@@@
• Access Criteria: Data from this study may be requested by contacting the PI. Genomic data are made available via dbGaP through requests to the data custodians.@@@@@@

Locations

US (1)