Symptoms and General Pathology

All Conditions

Neoplasms

Blood and Lymph Conditions

Rare Diseases

Syndrome

Leukemia

Leukemia, Myeloid

Leukemia, Myeloid, Acute

Preleukemia

Myelodysplastic Syndromes

Bone Marrow Diseases

Hematologic Diseases

Myeloid Leukemia

Acute Myeloid Leukemia

Acute Non Lymphoblastic Leukemia

Acute Graft Versus Host Disease

Healthy volunteers who will donate blood, and/or bone marrow and may donate other samples

Healthy volunteers who will donate stool samples only

Rebecca Alexander

Kathy McGraw, Ph.D.

For more information at the NIH Clinical Center contact National Cancer Institute Referral Office

Background:

Myelodysplastic syndromes (MDS) are disorders of blood stem cells that can develop into blood cancers. Treatment options are limited. To find better treatments, researchers need to better understand how MDS develops. To do that, they must be able to compare biospecimens from people with the disease to those of healthy people.

Objective:

This study will create a database of biospecimens collected from healthy volunteers.

Eligibility:

Healthy people aged 18 and older.

Design:

Participants will be screened. They will have a physical exam with blood and urine tests.

Up to 5 types of samples will be collected on 1 or more days within 1 month of screening:

Blood: Blood will be drawn by inserting a needle into a vein.

Saliva: Participants will scrape the insides of their cheeks with a brush.

Stool: Participants will be given a container to collect stool at home. They will use a prepaid envelope to mail in the sample.

Bone marrow: A sample of the soft tissue inside the bones will be drawn out. The area to be biopsied, usually the lower back, will be numbed. A needle will be inserted through a small cut to remove the sample. Participants' pain will be monitored; additional numbing medicine may be used.

Skin: A piece of skin about 1/6 of an inch across will be cut away. Stitches may be used to close the wound. Participants will return to the clinic to have the stitches removed.

Participants do not have to provide all of the samples listed. They will give each sample only once.

Background:

* Myelodysplastic syndromes (MDS) are heterogeneous stem cell disorders characterized by ineffective hematopoiesis resulting in cellular dysplasia, peripheral cytopenias, and increased risk for transformation to acute myeloid leukemia (AML).
* There are limited treatment options, all of which have unimpressive response rates and limited response durations, with the only potential cure being hematopoietic stem cell transplant (HSCT). Unfortunately, as a disease of the elderly (average age of diagnosis \>65 years), most participants are not eligible for HSCT due to advanced age and other comorbidities.
* It is critical we further elucidate the processes that lead to disease manifestation to develop novel therapeutic strategies and alter the natural history of the disease.
* In order to understand the biology of the disease, it is critical to have control biospecimens from healthy individuals to delineate the mechanisms driving disease pathogenesis.

Objective:

-To create a database of analyzed biospecimens collected from healthy volunteers.

Eligibility:

* Age \>= 18 years old
* Healthy volunteers as confirmed by clinical evaluation

Design:

* This is a trial to analyze samples from healthy volunteers collected at NIH Clinical Center.

  --Participants = will be asked to provide blood, and/or bone marrow, and other samples (skin biopsy samples, saliva, stool samples).
* The total protocol accrual goal is 1,000 participants. Enrollment is expected to take place over approximately 20-50 years.

Collection of Blood, Bone Marrow, Skin, Saliva, and Stool Samples From Healthy Volunteers Used for Comparative Analysis of Myeloid Malignancies

.All large scale genomic sequencing data will be shared with subscribers to dbGaP.@@@@@@All collected IPD will be shared via request to the principal investigator.

Collection of biospecimens from healthy volunteers.

National Cancer Institute (NCI)

Cytopenia

Precancerous Conditions

Antineoplastic Agents

All Drugs and Chemicals

Decitabine

Decitabine and cedazuridine drug combination

Antimetabolites

Enzyme Inhibitors

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

decitabine and cedazuridine

IV infusion, 200 mg/Vial (20 mg/mL) or 1000 mg/vial (100mg/mL)

BMS-986253

Steven Z Pavletic, M.D.

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....

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.

BMS-986253 in Myelodysplastic Syndromes

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

.All collected IPD will be shared. @@@@@@In addition, all large scale genomic sequencing data will be shared with subscribers to dbGaP.

Overall response rate (ORR= CR + PR + \[marrow CR + HI\]) of BMS-986253 with and without DNMTi after 6 cycles of therapy

MTD of BMS-986253 with and without DNMTi, as determined by DLT occurring by C1D28

Pharmacokinetic properties of BMS-986253 with and without DNMTi: AUC, half-life, and steady state concentration

Safety as measured by incidence of AEs and SAEs, and AEs leading to discontinuation, death, and laboratory abnormalities.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Collection of Blood, Bone Marrow, Skin, Saliva, and Stool Samples From Healthy Volunteers Used for Comparative Analysis of Myeloid Malignancies	NCT05588154	Myelodysplastic...		18 Years -	National Institutes of Health Clinical Center (CC)
BMS-986253 in Myelodysplastic Syndromes	NCT05148234	Myelodysplastic...	decitabine and ... BMS-986253	18 Years -	National Institutes of Health Clinical Center (CC)

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