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BMS-986253 in Myelodysplastic Syndromes

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT05148234
Recruitment Status : Recruiting
First Posted : December 8, 2021
Last Update Posted : September 29, 2022
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )

Brief 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....


Condition or disease Intervention/treatment Phase
Myelodysplastic Syndromes Drug: decitabine and cedazuridine Drug: BMS-986253 Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 200 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I/II Trial of BMS-986253 in Myelodysplastic Syndromes
Estimated Study Start Date : October 4, 2022
Estimated Primary Completion Date : January 31, 2025
Estimated Study Completion Date : January 31, 2025

Resource links provided by the National Library of Medicine

Drug Information available for: Decitabine

Arm Intervention/treatment
Experimental: escalating dose of treatment for HR-MDS
escalating doses of BMS-986253 + DNMTi
Drug: decitabine and cedazuridine
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

Drug: BMS-986253
IV infusion, 200 mg/Vial (20 mg/mL) or 1000 mg/vial (100mg/mL)

Experimental: escalating doses of treatment for LR-MDS
escalating doses of BMS-986253
Drug: BMS-986253
IV infusion, 200 mg/Vial (20 mg/mL) or 1000 mg/vial (100mg/mL)

Experimental: phase II dose of BMS-986253 for HR-MD
phase II dose of BMS-986253 + DNMTi
Drug: decitabine and cedazuridine
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

Drug: BMS-986253
IV infusion, 200 mg/Vial (20 mg/mL) or 1000 mg/vial (100mg/mL)

Experimental: phase II dose of BMS-986253 for LR-MDS
phase II dose of BMS-986253
Drug: BMS-986253
IV infusion, 200 mg/Vial (20 mg/mL) or 1000 mg/vial (100mg/mL)




Primary Outcome Measures :
  1. Phase II: To determine efficacy as measured by overall response rate, separately by cohort. [ Time Frame: 6 months ]
    Overall response rate (ORR= CR + PR + [marrow CR + HI]) of BMS-986253 with and without DNMTi after 6 cycles of therapy

  2. Phase I: To determine MTD for BMS-986253 and RP2D, separately by cohort. [ Time Frame: 6 months ]
    MTD of BMS-986253 with and without DNMTi, as determined by DLT occurring by C1D28


Secondary Outcome Measures :
  1. Phase 1: To describe pharmacokinetic properties of BMS-986253 in MDS patients by cohort. [ Time Frame: 1 year ]
    Pharmacokinetic properties of BMS-986253 with and without DNMTi: AUC, half-life, and steady state concentration

  2. Phase II: To evaluate safety and tolerability of BMS-986253 in MDS patients by cohort. [ Time Frame: 1 year ]
    Safety as measured by incidence of AEs and SAEs, and AEs leading to discontinuation, death, and laboratory abnormalities.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria
  • 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 fromthe 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05148234


Contacts
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Contact: Christine T McGowan (240) 474-3584 christina.mcgowan@nih.gov
Contact: Steven Z Pavletic, M.D. (240) 760-6174 sp326h@nih.gov

Locations
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United States, Maryland
National Institutes of Health Clinical Center Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact National Cancer Institute Referral Office    888-624-1937      
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Steven Z Pavletic, M.D. National Cancer Institute (NCI)
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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT05148234    
Other Study ID Numbers: 10000356
000356-C
First Posted: December 8, 2021    Key Record Dates
Last Update Posted: September 29, 2022
Last Verified: September 8, 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: .All IPD recorded in the medical record will be shared with intramural investigators upon request. @@@@@@In addition, all large scale genomic sequencing data will be shared with subscribers to dbGaP.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Time Frame: Clinical data available during the study and indefinitely.@@@@@@Genomic data are available once genomic data are uploaded per protocol GDS plan for as long as database is active.
Access Criteria: Clinical data will be made available via subscription to BTRIS and with the permission of the study PI. @@@@@@Genomic data are made available via dbGaP through requests to the data custodians.

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) ):
heterogenous clonal diseases neoplasms
Interleukin-8
DNA methyltransferase inhibitors
cytopenias
Allogeneic Hematopoietic Stem Cell Transplantation
Additional relevant MeSH terms:
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Preleukemia
Myelodysplastic Syndromes
Syndrome
Disease
Pathologic Processes
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Neoplasms
Decitabine
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Enzyme Inhibitors