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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.

National Cancer Institute (NCI)

Anemia

Anti-Infective Agents

Thalidomide

Immunosuppressive Agents

Immunologic Factors

Anti-Bacterial Agents

Angiogenesis Inhibitors

Growth Inhibitors

Didier Bouscary, MD, Ph-D

The GFM previously conducted a dose-escalating phase II trial of thalidomide in MDS with a minimum dose of 200mg/d and a maximum dose 800mg/d. Responses were evaluated according to IWG criteria at week 16 and thalidomide continued up to week 56 in responders. 82% patients received at least 8 weeks of treatment and were evaluable. 59% had hematological improvement, mainly on the erythroid lineage (Increase of Hemoglobin). Most responses were observed at low doses and between 4 and 8 weeks.

The objectives of this trial (Thal-SMD-20) are to evaluate the efficacy and tolerance of lower doses thalidomide in low risk MDS patients with transfusion-dependant anemia.

Thalidomide:

First part of the trial: 82 patients at 200mg/day given at bedtime x 12 weeks, decreased to 100mg/day if grade 1 or 2 side. Stopped temporally for 1 week if grade 3 or 4 side effects. Then reintroduced at the same dose. If side effects again, definitively stopped.

Responses evaluated at 12 weeks according to IWG criteria for the erythroid lineage

At week 12:

* If no Hematological improvement (HI): increased to 300mg/day for 8 weeks and then eventually to 400mg/day for 8 weeks more, if no HI.
* If Hematological improvement (HI): continued at the same dose.

Second part of the trial: 30 patients treated at 50mg/day x 12 weeks. Responses evaluated at 12 weeks according to IWG criteria for the erythroid lineage

At week 12:

* If no Hematological improvement (HI): increased to 100mg/day for 8 weeks and then eventually to 200mg/day for 8 weeks more, if no HI.
* If Hematological improvement (HI): continued at the same dose.

Thalidomide at Low Dose for the Treatment of Patient With Myelodysplastic Syndromes - THAL-SMD-200

Thalidomide for the Treatment of Cytopenias of Patients With Low Risk Myelodysplastic Syndromes

Groupe Francophone des Myelodysplasies

Pancytopenia

Hematinics

Micronutrients

Epoetin Alfa

Deferasirox

Iron

Chelating Agents

Iron Chelating Agents

Patients will receive erythropoietin 40,000 units/week. If after 4 weeks erythroid improvement is inadequate, dose will be escalated to 60,000 units/week. If after 12 weeks of treatment, erythroid improvement in inadequate, patients will be switched to the combination arm. At any time when erythroid response is achieved, erythropoietin treatment will be stopped until end of study.

Patients will receive deferasirox dispersible tablet (DT) 10 mg/kg/day or deferasirox film-coated tablet (FCT) 7 mg/kg/day in combination with erythropoietin 40,000 units/week. If after 4 weeks erythroid improvement is inadequate, erythropoietin dose will be escalated to 60,000 units/week. If after 12 weeks of treatment, erythroid improvement in inadequate, patients will be discontinued from the study. At any time when erythroid response is achieved, erythropoietin treatment will be stopped until end of study. Patients will continue deferasirox treatment.

provided as dispersible tablets for oral use in 125 and 250, 500 mg

Deferasirox DFX, DT

Erythropoietin alpha

provided as film-coated tablet for oral use in 90, 180, 360 mg strengths

Deferasirox DFX, FCT

Novartis Pharmaceuticals

The primary purpose of this trial was is to assess the effect of treatment with deferasirox combined with erythropoietin vs. erythropoietin alone on erythropoiesis in patients with low- and int-1-risk myelodysplastic syndrome. The addition of deferasirox to erythropoietin can lead to a potential synergism with the reduction of reactive oxygen species, through both the NF-kB pathway and the control of free toxic iron. This may create a better environment in the bone marrow for a better response with erythropoietin.

This study was designed to test in a prospective way the combination of deferasirox with erythropoietin in terms of their effect on hematopoiesis.

This study did not meet the original enrollment objective of 60 patients and was terminated without extending enrollment past original planned LPFV of 31-Oct-2016.

Combination Study of Deferasirox and Erythropoietin in Patients With Low- and Int-1-risk Myelodysplastic Syndrome.

An Open-label, Phase II, Randomized, Pilot Study to Assess the Effect in Term of Erythroid Improvement of Deferasirox Combined With Erythropoietin Compared to Erythropoietin Alone in Patients With low-and Int-1-risk Myelodysplastic Syndrome.

Difference in percentage of patients achieving an erythroid response within 12 weeks of treatment between the two arms according to modified IWG 2006 criteria increase in hemoglobin (Hb) ≥ 1.5 g/dL. Erythroid response is defined as the increase in Hb from baseline ≥ 1.5 g/dL. Patients achieving erythroid response at least once within 12 weeks were considered responders

Hematological response criteria defined as: Erythroid response: hemoglobin (Hb) increase from baseline \>= 1.5 g/dL (baseline \< 11 g/dL), neutrophil response: increase from baseline \>= 100% and increase \> 0.5 × 10\^9/L (baseline \<1 × 10\^9/L), platelet response: increase from baseline \>= 30 × 10\^9/L (baseline \<100 × 10\^9/L) according to modified IWG 2006 criteria

Percentage of participants achieving an hematologic improvement defined as: neutrophil improvement: increase from baseline \>0.5 × 10\^9/L (baseline = 1.0 × 10\^9/L ), platelet improvement: increase from baseline ≥ 30 × 10\^9/L (baseline = 100 × 10\^9/L), hemoglobin improvement: Hb increase from baseline ≥ 1 g/dL (baseline\<11 g/dL)

Absolute change in hemoglobin values for patients showing improvement: Hemoglobin improvement Hb increase from baseline ≥ 1 g/dL (baseline\<11 g/dL)

Absolute change in platelets and neutrophil levels for participants showing improvement: neutrophil improvement: increase from baseline \>0.5 × 10\^9/L (baseline = 1.0 × 10\^9/L ), platelet improvement: increase from baseline ≥ 30 × 10\^9/L (baseline = 100 × 10\^9/L)

Erythroid response: hemoglobin increase from baseline \> = 1.5 g/dL (baseline \<11 g/dL)

Erythroid response: hemoglobin increase from baseline \> = 1.5 g/dL (baseline \<11 g/dL). Percentages are based on N. Confidence intervals are calculated using Clopper-Pearson method. Hemoglobin value is at time of first response

Absolute change in serum ferritin from baseline

This analysis included patients randomized either to EPO or DFX+EPO at baseline as well as patients who did not have erythroid response at week 12 in the EPO group and switched to combination therapy.

This analysis included patients randomized either to EPO or DFX+EPO at baseline as well as patients who did not have erythroid response at week 12 in the EPO group and switched to combination therapy. The time-course of Hb and its absolute changes from baseline was summarized by descriptive statistics by visit and erythroid response. Patients randomized to EPO and not switching after 12 weeks to EPO+DFX would consist of only responders.

There was no washout period during the study before switch of treatment. Therefore effects (including AEs) from long lasting treatment like EPO can potentially still be observed after the switch, e.g. from EPO+DFX to DFX alone. Thus the resulting includes both treatments (DFX-EPO category). The same applies for staring EPO alone and switching to EPO plus DFX.

Patients receiving EPO during the first 12 weeks and no switching to EPO+DFX arm

EPO A

Patients receiving EPO+DFX from week 1 and continuing with EPO+DFX after 12 weeks or with DFX alone after 12 weeks

EPO+DFX DT

Patients receiving EPO alone and switched to EPO+DFX after 12 weeks of treatment

EPO+DFX FCT

Switched to DFX+EPO After 12 Weeks

Starting dose was erythropoietin 40,000 units/week. If after 4 weeks erythroid improvement was inadequate, dose was escalated to 60,000 units/week. If after 12 weeks of treatment, erythroid improvement was inadequate, participants were switched to the combination arm. At any time when erythroid response was achieved, erythropoietin treatment was stopped until end of study.

Erythropoietin Alpha

Starting dose was deferasirox dispersible tablet (DT) 10 mg/kg/day or deferasirox film-coated tablet FCT) 7 mg/kg/day in combination with erythropoietin 40,000 units/week. If after 4 weeks erythroid improvement was inadequate, erythropoietin dose was escalated to 60,000 units/week. If after 12 weeks of treatment, erythroid improvement was inadequate, participants were discontinued from the study. At any time when erythroid response was achieved, erythropoietin treatment was stopped study and Deferasirox treatment was continued until end of study

Deferasirox + Erythropoietin Alpha

Total

Age, Continuous

Sex: Female, Male

Caucasian

Asian

Race/Ethnicity, Customized

Study Director

Difference in Percentage of Patients Achieving Erythroid Response Within 12 Weeks, by Treatment Group (Full Analysis Set)

Absolute Change From Baseline to Post-baseline Value for Hemoglobin(g/dL)(Full Analysis Set)

Hematologic improvement

Neutropil improvement

Platelet improvement

Hemoglobin improvement

Number of patients who met criteria varied across parameters

Summary of Hematologic Improvement in Patients Randomized to EPO+DFX and EPO Alone, Within 24 Weeks of Treatment (Full Analysis Set)

Absolute Change in Hemoglobin Values up to 24 Weeks

Platelets

Neutrophils

Absolute Change in Platelets and Neutrophil Levels up to 24 Weeks

Patients randomized to EPO alone with inadequate response at 12 weeks who had been switched over to combination EPO+DFX

EPO+DFX (12 Weeks)

Summary of Erythroid Response in Participants Randomized to EPO Alone at Baseline and Switched to EPO+DFX After 12 Weeks of Treatment (Full Analysis Set)

Patients who were in EPO alone group and were not switched to EPO+DFX after 12 weeks,

EPO (24 Weeks)

Summary of Erythroid Response Within 24 Weeks in Participants Randomized to EPO at Baseline and Not Switched to EPO+DFX After 12 Weeks of Treatment (Full Analysis Set)

Responders - Week 5

Responders - Week 9

Responders - Week 13

Responders - Week 17

Responders - Week 21

Non-responders - Week 5

Non-responders - Week 9

Non-responders - Week 13

Number of patients analyzed varied by visit

Absolute Change in Serum Ferritin up to 24 Weeks for Erythropoietin Alpha Arm (Full Analysis Set)

Responders - Week 13|

Non-responders - Week 9|

Non-responders - Week 13|

Non-responders - Week 17

Non-responders - Week 21

Absolute Change in Serum Ferritin up to 24 Weeks for Deferasirox + Erythropoietin Alpha Arm (Full Analysis Set)

EPO+DFX at 12

Absolute Change in Serum Ferritin up to 24 Weeks for EPO+DFX at 12 Weeks Arm (Full Analysis Set)

Absolute Change in Hemoglobin (Hb) From Baseline for Erythropoietin Alpha Arm (Full Analysis Set)

Absolute Change in Hemoglobin (Hb) From Baseline for Deferasirox + Erythropoietin Alpha Arm (Full Analysis Set)

Responders - Week 9|

Responders - Week 17|

Non-responders - Week 17|

This analysis included patients randomized either to EPO or DFX+EPO at baseline as well as patients who did not have erythroid response at week 12 in the EPO group and switched to combination therapy. The time-course of Hb and its absolute changes from baseline was summarized by descriptive statistics by visit and erythroid response. Patients randomized to EPO and not switching after 12 weeks to EPO+DFX would consist of only responders

EPO+DFX at 12 Weeks

Absolute Change in Hemoglobin (Hb) From Baseline for EPO+DFX at 12 Weeks Arm (Full Analysis Set)

Overall Study

Leukemia

Leukemia, Myeloid

Leukemia, Myeloid, Acute

Myeloid Leukemia

Acute Myeloid Leukemia

Acute Non Lymphoblastic Leukemia

Acute Graft Versus Host Disease

Participants with myelodysplastic syndromes and associated malignancies

Participants (controls) without MDS or associated malignancies, contributing bone marrow

Rebecca Alexander

Kathy McGraw, Ph.D.

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

Background:

Myelodysplastic syndromes (MDS) occur when the cells that make blood cells are abnormal. There are limited treatment options for MDS. Researchers want to learn more through this natural history study so they can develop better treatments.

Objective:

To study the natural course of MDS and MDS/myeloproliferative neoplasms (MPN) and collect biological samples that can help researchers understand the disease.

Eligibility:

People with suspected or confirmed MDS or MDS/MPN. Healthy donors are also needed. They can be people who are scheduled to donate bone marrow at NIH for a relative, or they may be providing bone marrow in another study.

Design:

Participants will be screened with a medical history.

Participants will have a physical exam. They will give blood and urine samples. They will discuss their symptoms, medications, and ability to perform their normal activities. They will complete surveys about how they are feeling.

Participants will have a bone marrow biopsy. A needle will be inserted through a small cut. Bone marrow will be removed. A small piece of bone may be removed.

Participants may have an optional skin biopsy.

Participants may give optional saliva and stool samples. They may collect these samples at home and mail them to NIH.

Participants may undergo optional apheresis. One or two needles or intravenous (IV) lines will be placed in their arm, neck, or groin veins. Blood will be removed. A machine will separate out the white cells. The rest of the blood will be returned to the participant.

Participants will be contacted for follow-up once a year for up to 20 years.

Healthy donors will have marrow collected for this study during their scheduled procedure with no follow-up.

Background:

* Myelodysplastic syndromes (MDS) are heterogenous 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 treatments 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 in an effort to develop novel therapeutic strategies and to alter the natural history of the disease.
* Chronic inflammation is central to disease pathology, as evidenced by pro-inflammatory cytokines in the bone marrow milieu, transcriptional upregulation of inflammatory genes, and dysregulation of innate immune signaling pathways.
* We hypothesize the chronic inflammation drives MDS pathogenesis and may be exploited therapeutically. Further, we anticipate the correlatives proposed here to be used not only to uncover critical disease driving pathways, but also to potentially reveal disease and treatment response biomarkers, as well to better refine both diagnosis and prognosis.

Objectives:

- To characterize the natural history of myelodysplastic syndromes (MDS) and to assess overall and progression free survival

Eligibility:

Participants with MDS

* Any gender, any age
* Histologically or cytologically suspected or confirmed MDS, MDS/MPN, (MDS/MPN- RS-T, MDS/MPN-U, CMML, aCML) or sAML with antecedent MDS or MDS/MPN

OR

* diagnosis with a precursor condition that is associated with a risk of progression to MDS.
* Any amount of prior therapy and may be currently receiving MDS-directed therapy.
* Must have an identified primary oncologist, hematologist or generalist outside NIH who agrees to manage care and any diagnostic findings provided by this study.

Controls

* Any gender and must be eligible for marrow donation per clinical center requirements.
* No history of hematological malignancies listed as inclusion criteria for the group of participants with MDS or current autoimmune disease
* Control marrow volunteers must be scheduled for bone marrow harvest for clinical application, or if evaluated for malignancy, have a bone marrow aspirate scheduled to rule out bone marrow involvement at which time additional samples will be taken as controls for the research purposes of this study.

Design:

* This is a natural history and biospecimen acquisition protocol for participants with Myelodysplastic Syndromes (MDS).
* In addition, we will perform a comprehensive research analysis based on the hypothesis that chronic inflammation in MDS arising from a variety of contributors results in hematopoietic differentiation and maturation blocks leading to dysplasia, cytopenias, and disease progression, and that these may be exploited for novel therapeutic targeting strategies.
* This is a single site (Clinical Center) study that will accrue 1,000 MDS participants and 100 marrow controls (transplant donor or non-involved malignancy) volunteers over a 20-year study accrual duration.
* Diagnostic testing will be performed as is routine for these participants in addition to planned research correlative analyses. Follow-up will occur approximately annually to assess status and survival.

Comprehensive Molecular and Clinical Evaluation of Pediatric and Adult MDS

.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.

report the overall survival and progression status of participants

report the number of participants that have provided at least one of the biospecimens described in the protocol

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
BMS-986253 in Myelodysplastic Syndromes	NCT05148234	Myelodysplastic...	decitabine and ... BMS-986253	18 Years -	National Institutes of Health Clinical Center (CC)
Thalidomide at Low Dose for the Treatment of Patient With Myelodysplastic Syndromes - THAL-SMD-200	NCT00455910	Myelodysplastic...	Thalidomide	18 Years -	Groupe Francophone des Myelodysplasies
Combination Study of Deferasirox and Erythropoietin in Patients With Low- and Int-1-risk Myelodysplastic Syndrome.	NCT01868477	Low and Int 1-r...	Deferasirox DFX... Erythropoietin ... Deferasirox DFX...	18 Years -	Novartis
Comprehensive Molecular and Clinical Evaluation of Pediatric and Adult MDS	NCT05350748	Myelodysplastic...		1 Day - 120 Years	National Institutes of Health Clinical Center (CC)

Spots Global Cancer Trial Database for cytopenias

Every month we try and update this database with for cytopenias cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Spots Global Cancer Trial Database for cytopenias

Every month we try and update this database with for cytopenias cancer trials from around the world to help patients and their families find trials that might be right for them. We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Every month we try and update this database with for cytopenias cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.