BMS-986253 in Myelodysplastic Syndromes

Myelodysplastic Syndromes Clinical Trial

Official title: A Phase I/II Trial of BMS-986253 in Myelodysplastic Syndromes

Status Active, not recruiting

Clinical Trial Summary

Background: The myelodysplastic syndromes (MDS) are a group of bone marrow neoplasms. MDS mostly affect elderly people. The drugs used to treat MDS are not always effective, and the only curative treatment is stem cell transplant. Researchers want to see if a new drug can be used to treat MDS. Objective: To learn if BMS-986253 is a safe and effective treatment for MDS. Eligibility: Adults aged 18 and older with MDS. Design: Participants will be screened with a medical history, medication review, and physical exam. They will answer questions about how well they are able to take care of themselves. Their temperature, blood pressure, breathing rate, and heart rate will be monitored. They will have an electrocardiogram to see how well their heart is working. They will give blood and urine samples. They may have a bone marrow biopsy. Participants will be assigned to a specific group. They will receive either BMS-986253 alone or in combination with DNA methyltransferase inhibitors (DNMTi). Treatment will be given in 28-day cycles. Participants will get BMS-986253 as an infusion on days 1 and 15 of each cycle. Some participants also will take oral DNMTi on days 2-6 of each cycle. They will receive treatment until their disease gets worse or they have bad side effects. At study visits, some screening tests will be repeated. Some of the samples that are collected will be used for genetic testing. About 30 days after treatment ends, participants will have a follow-up visit to see how they are doing. After that, follow up will occur via phone every 3-6 months until the study ends. NIH will cover the costs for some travel expenses....

Clinical Trial Description

Background: The myelodysplastic syndromes (MDS) are a group of clonal bone marrow neoplasms characterized by ineffective hematopoiesis, cytopenia, and high risk for transformation to acute myeloid leukemia (AML). MDS is primarily a disease of the elderly, with about 80% of participants being older than 65-years of age; with 10,000 new diagnoses per year in the U.S. The only curative treatment for participants with MDS is allogeneic hematopoietic stem cell transplantation (HSCT) and only a small portion of participants are eligible. Depending on risk stratification, the median survival of high- and low-risk MDS participants is 1.5 to 5.9 years, respectively. DNA methyltransferase inhibitors (DNMTi) are the standard of care therapy for high-risk MDS. However, less than half of participants respond to DNMTi, and even the best responses are transient and non-curative. More effective and less toxic therapies are needed. Interleukin-8 (IL-8) is a proinflammatory chemokine from the CXC family and a potent chemoattractant of granulocytes and related cells to the site of inflammation. IL-8 is uniquely upregulated and found at high levels in both the peripheral blood and bone marrow aspirates of MDS participants. In purified MDS/AML long-term/short term stem cells and granulocyte-macrophage progenitor cells both IL-8 and the IL-8 receptor, CXCR2, are overexpressed. Preclinical data showed that CXCR2 inhibition led to significantly reduce proliferation of leukemic cell lines. In addition, MDS CD34+ cell cultures treated with neutralizing anti-IL-8 showed improvement in erythroid colony formation. BMS-986253 is a fully human IgG1 neutralizing antibody that showed a favorable safety profile in participants with advanced solid tumors. Concomitant treatment with DNMTi and BMS-986253 may improve treatment responses in participants with MDS by attenuating chemoattraction of myeloid derived suppressor cells to the bone marrow, indirectly disinhibiting NK- and T-cell responses against MDS stem cells, reducing neoangiogenesis, and improving cytopenia. Objectives: Primary objectives: Phase I: To determine the optimal biological dose (OBD) and RP2D of BMS-986253 with or without DNMTi (decitabine and cedazuridine) therapy in MDS participants, and to describe the safety and tolerability of BMS-986253. Phase II: To determine ORR to BMS-986253 with or without DNMTi (decitabine and cedazuridine) therapy in MDS, measured according to the proposed revised IWG 2018 response criteria. Eligibility: Participants must have histologically or cytologically confirmed MDS according to 2016 WHO criteria and - have higher risk (HR) MDS (R-IPSS >= 3.5) and received a minimum of 2 and maximum of 8 cycles of DNMTi for Phase I (and a maximum of 4 cycles for Phase 2), or - have lower risk (LR) MDS(R-IPSS <3.5) and at least one cytopenia (for both Phases I and II). Age >=18 years ECOG performance status <=2 (KPS >= 60%) Design: This study consists of two phases: Phase I: safety evaluation with determination of OBD of BMS-986253 with or without DNMTi (decitabine and cedazuridine), and Phase II: efficacy evaluation of BMS-986253 with or without DNMTi (decitabine and cedazuridine) In both Phase I and II, participants will be enrolled into two cohorts: A) Higher-risk cohort (HR-MDS), including high-risk and higher intermediate-risk disease, defined as those with R-IPSS >= 3.5: treatment with BMS-986253 in combination with DNMTi (decitabine and cedazuridine) B) Lower-risk cohort (LR-MDS), including low-risk and lower intermediate-risk disease participants, defined as those with R-IPSS <3.5: treatment with BMS-986253 given as monotherapy For Phase I, the safety endpoint will be DLT by D28 with the objective of defining the OBD and RP2D for BMS-986253. In addition, follow up for safety will be assessed 100 days after the end of the treatment cycle. For Phase II, the primary endpoint will be overall response rate after 6 cycles, reported separately by cohort. ;

Related Conditions & MeSH terms

• Myelodysplastic Syndromes
• Preleukemia
• Syndrome

• NCT number: NCT05148234
• Study type: Interventional
• Source: National Institutes of Health Clinical Center (CC)
• Status: Active, not recruiting
• Phase: Phase 1/Phase 2
• Start date: November 29, 2022
• Completion date: July 31, 2025