BMS-986253 in Myelodysplastic Syndromes

Study Overview
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Brief Summary
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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....

Detailed Description
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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.

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

Conditions
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Myelodysplastic Syndromes

Intervention / Treatment
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* Drug: decitabine and cedazuridine
* Drug: BMS-986253


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: Participants must have histologically or cytologically confirmed MDS according to 2016 WHO criteria And: have HR-MDS (R-IPSS >= 3.5) and received a minimum of 2 and maximum of 8 prior cycles for phase I and 4 for phase II of DNMTi therapy, or have LR-MDS (R-IPSS <3.5), and, at least one cytopenia: granulocytes < 1.0 x 10^9/L and/or hemoglobin < 110 g/L with signs/symptoms of symptomatic anemia or transfusion-dependency platelets < 100 x 10^9/L Age >=18 years --Because no dosing or adverse event data are currently available on the use of BMS-986253 as monotherapy or in combination with DNMTi in participants <18 years of age, children are excluded from this study, but will be eligible for future pediatric trials. ECOG performance status <=2 (Karnofsky >=60%). Life expectancy greater than 6 months. Participants must have adequate organ function as defined below: --total bilirubin <=1.5 X institutional upper limit of normal OR <=3 X institutional upper limit of normal in participants with Gilbert s syndrome (*except for participants with increased bilirubin levels attributed to intramedullary hemolysis, which will be allowable) AST(SGOT)/ALT(SGPT) <=3 X institutional upper limit of normal OR <=5 X institutional upper limit of normal if related to disease specific cause creatinine clearance (by Cockcroft-Gault) >=60 mL/min/1.73 m^2 for participants with creatinine levels above institutional normal. The effects of BMS-986253 on the developing human fetus are unknown. For this reason and because DNMTi as well as other therapeutic agents used in this trial are known to be teratogenic, women of child-bearing potential (WOCBP) and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and up to 6 months after study completion and last dose of DNMTi. Ability of subject to understand and the willingness to sign a written informed consent document. EXCLUSION CRITERIA: For phase I: Participants with HR-MDS (R-IPSS >=3.5) that have not yet received or received less than 2 cycles of DNMTi therapy. Participants with LR-MDS (R-IPSS <3.5) with the following characteristics that have not yet received or are still deriving benefit from the following standard of care therapies: Hgb <10 g/dL, Epo level <500 mU/mL: Erythropoietin-stimulating agents (ESAs) MDS with del5q: Lenalidomide MDS with ringed sideroblasts (MDS-RS) with SF3B1 mutation: Luspatercept Participants with platelet transfusion-refractory thrombocytopenia, with inability to keep platelet threshold above 10K/mcL with transfusions or those with ongoing or uncontrolled hemorrhagic complications. Participants with clinically significant neutropenia, ANC<100, with frequent hospitalizations for infection (average >1 hospitalization per month in past 6 months) Participants who are receiving or have received any other investigational agents within 28 days before start of study treatment. History of allergic reactions attributed to compounds of similar chemical or biologic composition to DNMTi or other agents used in study. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. Pregnant women or women presently breast-feeding their children are excluded due to unknown risks to a developing fetus or infant. Any significant disease that, in the opinion of the investigator, may impair the participant s tolerance of study treatment. Active or uncontrolled autoimmune diseases requiring treatment. Chronic hepatitis B or C infection, because potential immune impairment caused by these disorders may diminish the effectiveness of this immunologic therapy. HIV-positive participants are ineligible because of the potential for decreased immune response. Presence of any other malignancy (except basal and squamous cell carcinoma of the skin, or stable chronic cancers on hormone or targeted therapy) for which participant received systemic anticancer treatment within 24 months prior to enrollment. Prior history of allogeneic hematopoietic stem cell transplantation.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: escalating dose of treatment for HR-MDS<br>escalating doses of BMS-986253 + DNMTi | Drug: decitabine and cedazuridine<br>* FDA-approved DNMTi PO decitabine and cedazuridine according to guidelines Abbreviated Title: BMS-986253 in MDS 34 Version Date: 9/08/2021 outlined in FDA product label. SOC DNMTi will<br>Drug: BMS-986253<br>* IV infusion, 200 mg/Vial (20 mg/mL) or 1000 mg/vial (100mg/mL)<br>|
| Experimental: escalating doses of treatment for LR-MDS<br>escalating doses of BMS-986253 | Drug: BMS-986253<br>* IV infusion, 200 mg/Vial (20 mg/mL) or 1000 mg/vial (100mg/mL)<br>|
| Experimental: phase II dose of BMS-986253 for HR-MD<br>phase II dose of BMS-986253 + DNMTi | Drug: decitabine and cedazuridine<br>* FDA-approved DNMTi PO decitabine and cedazuridine according to guidelines Abbreviated Title: BMS-986253 in MDS 34 Version Date: 9/08/2021 outlined in FDA product label. SOC DNMTi will<br>Drug: BMS-986253<br>* IV infusion, 200 mg/Vial (20 mg/mL) or 1000 mg/vial (100mg/mL)<br>|
| Experimental: phase II dose of BMS-986253 for LR-MDS<br>phase II dose of BMS-986253 | Drug: BMS-986253<br>* IV infusion, 200 mg/Vial (20 mg/mL) or 1000 mg/vial (100mg/mL)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase II: To determine efficacy as measured by overall response rate, separately by cohort. | Overall response rate (ORR= CR + PR + [marrow CR + HI]) of BMS-986253 with and without DNMTi after 6 cycles of therapy | 6 months | 
| Phase I: To determine MTD for BMS-986253 and RP2D, separately by cohort. | MTD of BMS-986253 with and without DNMTi, as determined by DLT occurring by C1D28 | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1: To describe pharmacokinetic properties of BMS-986253 in MDS patients by cohort. | Pharmacokinetic properties of BMS-986253 with and without DNMTi: AUC, half-life, and steady state concentration | 1 year | 
| Phase II: To evaluate safety and tolerability of BMS-986253 in MDS patients by cohort. | Safety as measured by incidence of AEs and SAEs, and AEs leading to discontinuation, death, and laboratory abnormalities. | 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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heterogenous clonal diseases neoplasms, Interleukin-8, DNA methyltransferase inhibitors, cytopenias, Allogeneic Hematopoietic Stem Cell Transplantation