Conditions: Myelodysplastic Syndromes
Keywords: heterogenous clonal diseases neoplasms Interleukin-8 DNA methyltransferase inhibitors cytopenias Allogeneic Hematopoietic Stem Cell Transplantation
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 2
Healthy volunteers: no

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 HuMax-interleukin 8 (IL-8) 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 deoxyribonucleic acid (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.

National Institutes of Health (NIH) will cover the costs for some travel expenses....

Detailed 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 United States (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.

Deoxyribonucleic acid (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 chemokine (C-X-C motif) 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/Acute myeloid leukemia (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 cluster of differentiation 34 (CD34+) cell cultures treated with neutralizing anti-IL-8 showed improvement in erythroid colony formation.

BMS-986253 is a fully human Immunoglobulin G1 (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 natural killer (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 recommended phase 2 dose (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 overall response rate (ORR) to BMS-986253 with or without DNMTi (decitabine and cedazuridine) therapy in MDS, measured according to the proposed revised International Working Group (IWG) 2018 response criteria.

Eligibility:

Participants must have histologically or cytologically confirmed MDS according to 2016 World Health Organization (WHO) criteria and

* have higher risk (HR) MDS Revised International Prognostic Scoring System (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

Eastern Cooperative Oncology Group (ECOG) performance status \<=2 (KPS \>= 60%)

Design:

This study consists of two phases:

Phase I: safety evaluation with determination of optimal biological dose (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 dose limiting-toxicity (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.

Arms:
arm 1: Escalating doses of Human Humax (HuMax)-interleukin 8 (IL-8) (BMS-986253) + deoxyribonucleic acid (DNA) methyltransferase inhibitors (DNMTi) for higher risk (HR) myelodysplastic syndromes (MDS) participants. arm 2: Escalating doses of Human Humax (HuMax)-interleukin 8 (IL-8) (BMS-986253) for lower risk (LR) myelodysplastic syndromes (MDS) participants. arm 3: Phase II dose of Human Humax (HuMax)-interleukin 8 (IL-8) (BMS-986253) + deoxyribonucleic acid (DNA) methyltransferase inhibitors (DNMTi) for higher risk (HR) myelodysplastic syndromes (MDS) participants. arm 4: Phase II dose of Human Humax (HuMax)-interleukin 8 (IL-8) (BMS-986253) for lower risk (LR) myelodysplastic syndromes (MDS) participants.

Interventions: intervention 1: Deoxyribonucleic acid (DNA) methyltransferase inhibitors (DNMTi) Decitabine intervention 2: Deoxyribonucleic acid (DNA) methyltransferase inhibitors (DNMTi) Cedazuridine intervention 3: BMS-986253 intervention 4: Bone Marrow Biopsy intervention 5: Bone Marrow Aspiration intervention 6: ECG
Intervention descriptions: intervention 1: For Higher Risk (HR) Myelodysplastic Syndromes (MDS) cohort, the study drug of BMS-986253 will be given in combination with standard of care (SOC) Food and Drug Administration (FDA)-approved DNMTi by mouth (PO) decitabine and cedazuridine according to guidelines outlined in FDA product label. Standard of care (SOC) DNMTi will be administered via oral route once daily starting Day (D)2 of each treatment cycle through D6. intervention 2: For Higher Risk (HR) Myelodysplastic Syndromes (MDS) cohort, the study drug of BMS-986253 will be given in combination with standard of care (SOC) Food and Drug Administration (FDA)-approved DNMTi by mouth (PO) decitabine and cedazuridine according to guidelines outlined in FDA product label. Standard of care (SOC) DNMTi will be administered via oral route once daily starting Day (D)2 of each treatment cycle through D6. intervention 3: Intravenous (IV) infusion, 200 mg/Vial (20 mg/mL) or 1000 mg/vial (100mg/mL). Abbreviated Title: Human Humax (HuMax)-interleukin 8 (IL-8) (BMS-986253) in Myelodysplastic Syndromes 34 Version Date: 9/08/2021 outlined in Food and Drug Administration (FDA) product label. intervention 4: Bone marrow biopsy: required at screening/baseline, Phase I post cycle (C)

1(C1Day(D)28 +/- 3 days) and Phase II post cycle 2 (C2D28 +/- 3 days) and post cycle 6 (C6D28 +/- 3days); and if needed clinically in the setting of aplasia or concern for disease progression. intervention 5: Bone marrow aspiration: required at screening/baseline, Phase I post cycle (C)

1(C1Day(D)28 +/- 3 days) and Phase II post cycle 2 (C2D28 +/- 3 days) and post cycle 6 (C6D28 +/- 3days); and if needed clinically in the setting of aplasia or concern for disease progression. intervention 6: 12-lead electrocardiogram (ECGs) will be performed at baseline only for safety.

Protocol document:
Prot_SAP_003.pdf: 
Abbreviated Title: BMS-986253 in MDS
1
Version Date:  3/24/2025
Abbreviated Title:  BMS-986253 in MDS 
NIH Protocol #:  000356
Version Date:  3/24/2025
NCT Number:  NCT05148234
Title:   A Phase I/II Trial of BMS-986253 in Myelodysplastic Syndromes
  NCI Principal Investigator:
Alain Mina, MD
Immune Deficiency Cellular Therapy Program (IDCTP)
Center for Cancer Research (CCR)
National Cancer Institute (NCI)
National Institutes of Health (NIH)
Building 10, Room 6N119A
9000 Rockville Pike
Bethesda, MD 20892
Phone: 240-858-7625
Email:  alain.mina@nih.gov
 
Drug Name:
BMS-986253
DNMTi
(decitabine and cedazuridine)
IND Number:
157591
Sponsor:
Center for Cancer Research
Manufacturer:
BMS
Otsuka Pharmaceutical Co. Ltd
Supplier:
BMS
CC Pharmacy


Abbreviated Title: BMS-986253 in MDS
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Version Date:  3/24/2025
PRÉCIS
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[1], and 


Abbreviated Title: BMS-986253 in MDS
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Version Date:  3/24/2025
o
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
o
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.


Abbreviated Title: BMS-986253 in MDS
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TABLE OF CONTENTS 
PRÉCIS...........................................................................................................................................2
TABLE OF CONTENTS ................................................................................................................4
STATEMENT OF COMPLIANCE ................................................................................................7
1
INTRODUCTION ...................................................................................................................7
1.1
Study Objectives............................................................................................................7
1.2
Background and Rationale ............................................................................................8
2
ELIGIBILITY ASSESSMENT AND ENROLLMENT .......................................................19
2.1
Eligibility Criteria........................................................................................................19
2.2
Screening Evaluation...................................................................................................21
2.3
Participant Registration and Status Update Procedures ..............................................22
2.4
Baseline Evaluation.....................................................................................................23
3
STUDY IMPLEMENTATION .............................................................................................24
3.1
Study Design ...............................................................................................................24
3.2
Drug Administration....................................................................................................28
3.3
Dose Modifications .....................................................................................................31
3.4
Evaluations During the Treatment ..............................................................................31
3.5
On Study Assessments/Evaluations ............................................................................34
3.6
Study Calendar ............................................................................................................37
3.7
Cost and Compensation...............................................................................................39
3.8
Criteria for Removal from Protocol Therapy and Off Study Criteria .........................39
4
CONCOMITANT MEDICATIONS/MEASURES...............................................................40
4.1
Allowed Concomitant Medications/Supportive Measures:.........................................40
4.2
Drug interactions:........................................................................................................41
4.3
Contraindicated agents: ...............................................................................................41
5
CORRELATIVE STUDIES FOR RESEARCH ...................................................................41
5.1
Biospecimen Collection ..............................................................................................41
5.2
Sample Storage, Tracking and Disposition .................................................................45
5.3
Samples for Genetic/Genomic Analysis......................................................................48
6
DATA COLLECTION AND EVALUATION .....................................................................49
6.1
Data Collection............................................................................................................49
6.2
Data Sharing Plans ......................................................................................................50


Abbreviated Title: BMS-986253 in MDS
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6.3
Response Criteria ........................................................................................................51
6.4
Toxicity Criteria ..........................................................................................................54
7
NIH REPORTING REQUIREMENTS / DATA AND SAFETY MONITORING PLAN...54
7.1
Definitions...................................................................................................................54
7.2
OHSRP Office of Compliance and Training / IRB Reporting....................................54
7.3
NCI Clinical Director Reporting .................................................................................55
7.4
NIH Required Data and Safety Monitoring Plan ........................................................55
8
SPONSOR PROTOCOL/SAFETY REPORTING................................................................55
8.1
Definitions...................................................................................................................55
8.2
Assessment of Safety Events.......................................................................................57
8.3
Reporting of Serious Adverse Events .........................................................................57
8.4
Waiver of expedited reporting to CCR........................................................................58
8.5
Safety Reporting Criteria to the Pharmaceutical Collaborator....................................58
8.6
Reporting Pregnancy ...................................................................................................60
8.7
Regulatory Reporting for Studies Conducted Under CCR-Sponsored IND ...............61
8.8
Sponsor Protocol Deviation Reporting........................................................................61
9
CLINICAL MONITORING..................................................................................................61
10
STATISTICAL CONSIDERATIONS ..................................................................................62
10.1
Objectives and Endpoints............................................................................................62
10.2
Sample Size Determination.........................................................................................65
10.3
Populations for Analyses.............................................................................................67
10.4
Statistical Analyses......................................................................................................67
11
COLLABORATIVE AGREEMENTS..................................................................................69
11.1
Cooperative Research and Development Agreement (CRADA)................................69
12
HUMAN SUBJECTS PROTECTIONS................................................................................69
12.1
Rationale For Subject Selection ..................................................................................69
12.2
Participation of Children .............................................................................................69
12.3
Risk/Benefit Assessment.............................................................................................69
12.4
Consent Process and Documentation ..........................................................................71
13
REGULATORY AND OPERATIONAL CONSIDERATIONS..........................................72
13.1
Study Discontinuation and Closure.............................................................................72
13.2
Quality Assurance and Quality Control ......................................................................73


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13.3
Conflict of Interest Policy ...........................................................................................73
13.4
Confidentiality and Privacy.........................................................................................73
14
PHARMACEUTICAL AND INVESTIGATIONAL INFORMATION...............................74
14.1
BMS-986253  (IND # 157591) ...................................................................................74
14.2
DNMTi (decitabine and cedazuridine)........................................................................76
15
REFERENCES ......................................................................................................................78
16
LIST OF ABBREVIATIONS................................................................................................88
17
APPENDICES .......................................................................................................................90
17.1
Appendix A:  Performance Status Criteria..................................................................90
17.2
Appendix B:  2016 WHO classification for Myelodysplastic Syndrome ...................91
17.3
Appendix C:  Revised International Prognostic Scoring System (IPSS-R) for 
Myelodysplastic Syndromes......................................................................................................92
17.4
Appendix D:  The 2006 International Working Group response criteria with modified 
definitions for hematologic improvement by the 2018 International Working Group response 
criteria.[85] ................................................................................................................................93
17.5
Appendix E:  Blood and Marrow Processing Core Protocols.....................................96
17.6
Appendix F:  Clinical Data Elements for CRF Entry in Clinical Database ................98
17.7
Appendix G:  Diagnosis and Management of HLH..................................................100
17.8
Appendix H:  Women of Childbearing Potential Definitions and Methods of 
Contraception.............................................................................Error! Bookmark not defined.


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STATEMENT OF COMPLIANCE 
The trial will be carried out in accordance with International Council on Harmonisation Good 
Clinical Practice (ICH GCP) and the following: 
• United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 
CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812) 
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are 
responsible for the conduct, management, or oversight of NIH-funded clinical trials have 
completed Human Subjects Protection and ICH GCP Training.
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the Institutional Review Board (IRB) for review and approval.  Approval of both 
the protocol and the consent form must be obtained before any participant is enrolled.  Any 
amendment to the protocol will require review and approval by the IRB before the changes are 
implemented to the study.  In addition, all changes to the consent form will be IRB-approved; an 
IRB determination will be made regarding whether a new consent needs to be obtained from 
participants who provided consent, using a previously approved consent form.
1
INTRODUCTION
1.1
STUDY OBJECTIVES
1.1.1
Primary Objective
1.1.1.1
Phase I
•
To determine the optimal biological dose (OBD) and recommended phase 2 dose 
(RP2D) of BMS-986253 in combination with and without DNMTi in participants 
with high- and low-risk myelodysplastic syndromes (MDS), respectively; and to 
describe the safety and tolerability of BMS-986253 in participants with MDS. 
OBD will be the lowest tolerated dose leading to maximal suppression of serum 
free IL-8 levels*.
*Maximal suppression of serum free IL-8 levels will be monitored for a goal of 
achieving IL-8 levels below the lower limit of detection of the assay in real time 
as outlined in Section 5.1.3.2 [ultrasensitive immunoassay based on Quanterix 
Simoa technology (lower limit of quantification = 0.86 pg/mL) by Myriad-RBM] 
1.1.1.2
Phase II
•
To determine the overall response rate (ORR) to BMS-986253 in combination 
with and without DNMTi in participants with high- and low-risk MDS 
respectively, measured according to the proposed revised International Working 
Group (IWG) 2018 response criteria.


Abbreviated Title: BMS-986253 in MDS
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1.1.2
Secondary Objectives
1.1.2.1
Phase I
•
To describe pharmacokinetic properties of BMS-986253 with or without DNMTi 
in MDS participants.
1.1.2.2
Phase II
•
To evaluate safety and tolerability of BMS-986253 with or without DNMTi in 
MDS participants, as well as clinical outcomes including overall improvement 
rate (OIR), transfusion-independence (TI), cytogenetic response rate, time to best 
response (CR, PR, marrow CR + HI, HI) , disease free survival (DFS: definition: 
time to relapse for participants who achieve CR), progression-free survival (PFS; 
definition: disease progression or death from MDS), leukemia-free survival (LFS; 
definition: progression to AML or death from any cause), and overall survival 
(OS: definition: death from any cause).
1.1.3
Exploratory Objectives
•
To evaluate changes in serum cytokine levels pre- and post-treatment with BMS-
986253.
•
To evaluate the cell composition in the peripheral blood and bone marrow 
microenvironment before and after treatment with BMS-986253.
•
To evaluate changes in the transcriptome and proteome in response to treatment 
with BMS-986253.
•
To determine the degree of bone marrow myeloid-derived suppressor cell 
(MDSC) infiltration.
•
To describe changes in genetic clonal diversity during treatment with BMS-
986253 in combination with DNMTi.
•
To assess cell-autonomous effects on the MDS clone by measuring biomarkers in 
the Akt pathway (i.e. pS743) in MDS blasts.
•
To evaluate cell-autonomous and microenvironment dependent activity of BMS-
986253 using ex vivo culture of participant-derived hematopoietic stem and 
progenitor cells.
•
To assess quality of life improvement by participant reported outcomes using the 
EORTC QLQC30 score.
1.2
BACKGROUND AND RATIONALE
1.2.1
Myelodysplastic syndromes
The myelodysplastic syndromes (MDS) are a group of heterogenous clonal neoplasms of 
hematopoietic stem cells, characterized by dysplastic changes in at least one myeloid lineage, 
recurrent genetic aberrations, presence of up to 20% myeloblasts in the bone marrow, and high 
risk of evolution to acute myelogenous leukemia (AML).[1] Myelodysplasia results in 
ineffective hematopoiesis with consequential peripheral blood cytopenia(s). Anemia is the most 


Abbreviated Title: BMS-986253 in MDS
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common clinical presentation of MDS, but other cytopenias are also often present. Cytopenia, 
together with ineffective maturation of neutrophils and platelets, often result in severe and/or 
recurrent infections and/or bleeding episodes, respectively. In general, it is estimated that up to 
1/3 of participants with MDS will die from cytopenia-related complications, up to 1/3 have 
disease progression into a secondary AML with poor prognosis, and the remaining 1/3 may die 
from causes unrelated to their MDS.[2, 3]
MDS is a disease of the elderly, with a median age at diagnosis of approximately 75 years, with 
~80% of participants being ≥65 years.[4] Based on cancer registry data, about 10,000 new MDS 
cases are diagnosed per year in the United States,[5, 6] but the number is probably 
underestimated[7] and may be as high as >40,000 based on Medicare claims analyses.[8] There 
is a slight predominance of males.[4]
Most MDS participants (~90%) have sporadic disease and the remainder are therapy-related 
MDS (t-MDS), the latter often presenting in participants younger than 60 years of age. In the last 
decade, familial related myeloid neoplasia in persons with germ-line mutations (i.e. RUNX1, 
GATA2, DDX41, CEPBA, ANKRD26, ETV6) is recognized as a predisposing condition for earlier 
acquisition of additional MDS-related mutations and MDS development.[9] Additionally, MDS 
can also develop from the rare inherited bone marrow failure disorders, such as Fanconi and 
Diamond-Blackfan anemia, which can present in childhood and adolescence.[10]
A conceptual model of MDS evolution[11] presumes an initiating somatic driver mutation in the 
hematopoietic stem cell with subsequent formation of the mutant stem cell clone. The most 
commonly affected genes involve RNA splicing, DNA methylation, histone modification, 
transcription regulators, DNA-repair control, signaling and cohesin complex. Six genes are 
commonly affected and have been reported to be mutant in at least 10% of participants: SF3B1, 
TET2, SRSF2, DNMT3A, ASXL1, and RUNX1.[12] In the second phase, the mutant clone 
expands and when it reaches approximately 4% of the total hematopoiesis, clonal hematopoiesis 
of indeterminate potential (CHIP) arises. The duration of the first phase and potential of further 
progression to the third phase (MDS or clonal cytopenia of undetermined significance [CCUS] – 
cytopenia with presence of a clonal population without morphologic evidence of dysplastic 
changes) seems to be related to the genes affected by mutations and the size of the clonal 
population.[13] Most participants with CHIP and mutations in DNMT3A, TET2, or ASXL1 will 
slowly progress to the third phase, while those harboring spliceosome gene mutations (i.e. 
SF3B1, SRSF2, U2AF1) will usually progress faster into MDS.[13] The spliceosome gene 
mutations are collectively present in more than 50% of the participants with MDS and are 
mutually exclusive.[14, 15] They are most commonly present in MDS participants when 
compared to the participants with other malignancies. In the third phase, clonal predominance of 
the mutant clone is established with further acquisitions of additional mutations (median of 
3).[16, 17] The fourth phase is initiated with the selection of a clone that usually harbors  AML-
driving mutations (i.e. FLT3, PTPN11, WT1, IDH1, NPM1, IDH2 and NRAS) leading to 
progression into secondary AML (s-AML) with ≥20% blasts in the bone marrow (Figure 1).
According to World Health Organization (WHO) 2016 classification of myeloid neoplasms and 
acute leukemia,[1] based on the number of lineages affected by dysplastic changes, the 
percentage of blasts in bone marrow, the existence of ring sideroblasts and genetic changes, 
several different MDS-related entities can be discriminated (Figure 1) with defined diagnostic 
criteria. Apart from that, MDS precursor conditions, such as CHIP and CCUS, are defined 
(Figure 1) by expert panels through a consensus process.[18-21]


Abbreviated Title: BMS-986253 in MDS
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Figure 1. Spectrum from non-malignant states to MDS and aggressive secondary AML with 
current treatment options.
The prognosis of MDS depends on disease- and participant-related characteristics. The disease-
specific factors with major influence on the prognosis of participants with MDS are the number 
and depth of cytopenias, the percentage of bone marrow blasts and the cytogenetic aberrations. 
These factors are incorporated in Revised International Prognostic Scoring System (R-IPSS) - 
currently the most relevant prognostic index that stratifies MDS participants in the 5 prognostic 
groups predicting OS and time-to-progression to AML.[22] For the purposes of clinical practice, 
an R-IPSS score of 3.5 is accepted as a cutoff for stratifying the participants into “higher-risk” 
MDS (HR-MDS) versus “lower-risk” MDS (LR-MDS) with corresponding median OS of 1.5 
versus 5.9 years, respectively (see Appendix C).[23] About 1/3 of participants with MDS will be 
classified as HR-MDS. Apart from classic cytogenetics already incorporated into R-IPSS, 
somatic mutations can also be independent prognostic factors, such as TP53 mutations, which 
are associated with poor prognosis.[24] Participant-specific factors also play important 
prognostic roles. Older age was found to be an independent negative risk factor on OS, 
particularly in participants with LR-MDS.[25] The time-dependent MDS-specific comorbidity 
index (MDS-CI) showed good predictive value for non-leukemic death and survival in LR-MDS 
participants (see Appendix E).[26] For HR-MDS, comorbidities are usually the limiting factor 
for more intensive treatment including HSCT, and therefore, represents an indirect factor 
predictive of poor outcome due to increased treatment-related mortality.[27]
1.2.2
Interleukin 8 (IL-8) in MDS
A defining feature of MDS is aberrant and/or chronic inflammation, and recent work has 
solidified the notion that cytokine mis-regulation is a hallmark of the disease. IL-8 (CXCL8) is a 
proinflammatory chemokine from the CXC family and a potent chemoattractant of granulocytes 
and related cells to the site of inflammation.[28] Its non-constitutive production is triggered by 
inflammatory stimuli such as tumor necrosis factor alpha (TNFα) and interleukin-1b (IL-1b).[29] 
The main activity of IL-8 is mediated by its two specific cell surface G protein-coupled 
receptors, CXCR1 and CXCR2.[30] The latter one is likely responsible for the proangiogenic 
effect of IL-8, independent of vascular endothelial growth factor (VEGF).[31, 32] Based on the 
research in prostatic cancer,[33] signaling through CXCR1 could play an important role in 
tumorigenesis by increasing proliferation of malignant cells.


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In cancer cells, the effect of IL-8 is autocrine and paracrine, promoting type 3 endothelial-to-
mesenchymal transition (EMT) and cancer stem cell renewal shown across different solid 
cancers[34-36] and AML.[37] EMT is the process in which epithelial cells are transformed to 
into mesenchymal cells[38] and is associated with tumor invasion, metastasis and chemotherapy 
resistance.[39] There is emerging evidence that EMT transcription factors, such as Twist1, 
Snail1/2 and ZEB  play an important role in myeloid malignancies by promoting proliferation, 
cell renewal/stemness and therapy-resistance,[39] including progression of MDS to AML.[40-
42]
Dysregulated immune pathways play an important role in the pathogenesis of MDS. Cytokine 
profiles in peripheral blood and bone marrow identified the chemokines IL-8 and CXCL10 as 
showing a strong correlation with the MDS phenotype, and IL-8 was unique among 19 other 
cytokines in showing upregulation in both peripheral blood and bone marrow aspirates.[43] 
Moudra et al.[44] measured cytokine levels before and after lenalidomide treatment and DNMTi, 
and found that IL-8, IL-27, CXCL10, and MCP1 were elevated in the bone marrow of all groups 
of MDS participants. Surprisingly, the levels increased with DNMTi therapy, but the IL-8 
expression was much higher in DNMTi non-responders than responders. The latter observation 
suggests that IL-8 overexpression may play a role in DNMTi treatment resistance. In participants 
with MDS and concurrent autoimmune disorders (AD) IL-8 expression levels are even more 
pronounced than in those without AD. AD were identified in a third of MDS participants in one 
study,[45] and together with the R-IPSS,[22] concurrent AD is an independent adverse 
prognostic factor for overall survival (OS). Relapsed/refractory AML participants also have high 
levels of IL-8.[46, 47] In the preclinical experiments done in Laboratory of Receptor Biology 
and Gene Expression (NCI/CCR),[46] heterozygous U2AF1 mutation was found to be necessary 
and sufficient for elevated IL-8 secretion, supporting an association between the genotype and 
phenotype. IL-8 levels were found to be upregulated by ~20 times of baseline levels in isogenic 
cell lines with heterozygous U2AF1 mutation. The same effect was visible in the human cancer 
cell lines corrected by clustered regularly interspaced short palindromic repeats (CRISPR) and in 
the NKM1-cell line derived from a participant with AML harboring a U2AF1 mutation.[46] The 
underlying mechanism for elevated levels of cytokines is not well-understood, but there is some 
inclination that a history of infection or autoimmune disease is associated with increased risk of 
MDS.[48, 49]
Both IL-8 and CXCR2 are overexpressed in purified MDS/AML long-term/short-term stem cells 
and granulocyte-macrophage progenitor cells.[37] In vitro inhibition of CXCR2 leads to a 
significant reduction in the proliferation of several leukemic cell lines and primary AML/MDS 
cells through cell cycle arrest. Moreover, in vivo inhibition of CXCR2 led to significant 
improvement in survival of U937 xenografted NOD scid gamma (NSG) mice. In addition, IL-8 
knockdown results in decreased proliferation and colony forming ability along with increased 
apoptosis of HL60, NB4, and THP1 AML cell lines.[47] Anemia is one of the hallmarks of MDS 
and lower levels of hemoglobin, i.e. worsening anemia, increase R-IPSS and adverse 
prognosis.[22] MDS CD34+ cell cultures treated with neutralizing IL-8 antibody showed 
improvement in erythroid colony formation.[50] Also, higher CXCR2 gene expression levels in 
MDS participants were demonstrated to correlate with lower hemoglobin levels and with 
increased transfusion requirements.[37] 
The indirect mechanism of action is not well studied at present - partly due to the lack of MDS 
models in humanized mice, but also due to the fact that mice do not secrete IL-8 or an IL-8 


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homolog, as the gene encoding IL-8 has been lost from the rat/mouse (muroid rodent) 
lineage.[51] Nevertheless, there is a reason to postulate a role for IL-8 in creating a 
microenvironment conducive to MDS development. IL-8 enhances endothelial cell proliferation 
and capillary tube organization[52] and higher microvascular density (MVD) has been found in 
the bone marrow of participants with MDS in comparison to normal controls, a finding that 
seems to be VEGF-independent.[53] Although both AML cells and stromal cells secrete IL-8, 
the bone marrow stromal cells are the main source of IL-8. IL-8 produced by stromal cells 
protects AML cells against apoptosis in co-culture experiments in vitro.[47, 54] Similarly, 
endothelial cells in AML participants secrete IL-8, which increases expansion of the AML blasts. 
This also leads to resistance to the chemotherapy agent cytarabine, which is the front-line 
therapy for AML and sometimes for high-risk MDS with excess blasts. Nevertheless, a small 
molecule inhibitor of IL-8 inhibited AML cell growth in tissue culture.[55] Moreover, Dr. 
Larson’s lab has shown in a lung xenograft model that tumorigenic cells lines containing splicing 
factor mutations (U2AF1 – S34F) show reduced nodule formation in NOG mice when treated 
with IL-8 neutralizing Ab compared to mice treated with control IgG. [46] 
Several preclinical studies have reported findings supporting IL-8’s direct role as a 
chemoattractant for MDSCs. [56-58] Increased chemotaxis of both granulocytic and monocytic 
MDSCs were seen in response to recombinant IL-8 and IL-8 derived from cancer cell lines.[58]  
Further, a neutralizing anti-IL-8 antibody could potentially be used in combination with recently 
developed MDS chimeric antigen receptor T-cell (CAR-T) therapies.[59] Specifically, MDSCs 
(LIN–HLA-DR–CD33+), which are a cell population that is distinct from the neoplastic clone, 
accumulate in the bone marrow of MDS participants and impair hematopoiesis, and are derived 
from myeloid progenitors.[60] MDSCs repress T-cell immunity through multiple metabolic 
pathways,[61] and their reduction could be therapeutically beneficial.[62] A comprehensive 
proteomics profiling study[63] identified IL-8 as the central molecule in the network of more 
than 150 dysregulated proteins in the bone marrow of participants with AML, suggesting IL-8 is 
a promising therapeutic target. All the above studies suggest a paracrine interaction between 
MDS/AML cells and the microenvironment, mediated largely by IL-8.
Inflammatory cytokines are also controlled at the post-transcriptional level. [46, 64] Moreover, 
translational regulation is a hallmark of hematopoiesis[65, 66] and is mis-regulated in CD123+ 
progenitor cells from MDS participants.[67] In line with this observation, germline mutations in 
the translation machinery (RPS19, RPS26, RPS17, RPL5, RPL11) manifest as defects in 
myelopoiesis, and the MDS del(5q) subtype results in haploinsufficiency of RPS14.[68] Yet 
somatic mutations in the translation machinery are largely absent in the disease, and there is little 
understanding of the relationship between driver mutations in MDS and subsequent translational 
misregulation. In the preclinical experiments done in Laboratory of Receptor Biology and Gene 
Expression (NCI/CCR), a heterozygous U2AF1 mutation was found to lead to widespread 
changes in translation such that mutant cells showed a ‘non-oncogene addiction’ to the ribosome 
biogenesis machinery.[69] These data indicate an unanticipated functional connection between a 
splicing factor mutation and the ribosome biogenesis machinery.
The preceding observations necessitate clinical correlates which specifically interrogate post-
transcriptional regulation in MDS. Although there has been exhaustive DNA and RNA 
sequencing in MDS, there has been little if any quantitative measurements of translational 
regulation. Indeed, despite the fact that measurements of translational activity are technically 
feasible and reveal widespread regulation across healthy human tissues,[70] the only extant 


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ribosome footprinting analyses remotely relevant to MDS have been carried out in T-ALL cell 
lines[71] or in CLL primary cells cultured ex vivo.[72] 
1.2.3
Current treatment options for the participants with MDS
Currently, the only curative treatment modality for the participants with MDS is allogeneic 
hematopoietic stem cell transplantation (HSCT). Since HSCT is associated with high incidence 
of mortality and morbidity, only a small portion of fit participants are eligible to undergo a 
transplant.[73, 74] There is an estimate that only 6 of 100 MDS participants will receive HSCT 
(2 will be cured, 3 will relapse and 1 will die from the HSCT-related complications).[3]
DNMTi, 5-azacitidine (AZA) and decitabine (DAC), are the standard of care therapies in HR-
MDS. However, less than a half of participants respond to DNMTi, and even the best responses 
are transient, non-durable, and non-curative.[75] Although the benefit on OS was significant in 
the AZA registration trial, [75] in real-life practice the impact on OS is not reproducible and 
prolongs OS for just a few months.[76].[77] Numerous combination therapies with DNMTi have 
been explored in treatment of MDS/AML. The BCL-2-inhibitor, venetoclax, in combination with 
DNMTi has emerged as a promising therapeutic combination with good safety and efficacy in 
AML,[78] though remains under clinical investigation in MDS.[79-81] Two presentations on 
early data from ongoing clinical trials of venetoclax in combination with DNMTi were presented 
at this past year’s 2020 American Society of Hematology conference: (a) a Phase 1b trial by 
Garcia et al. that explored use of venetoclax plus azacitidine in 57 high-risk MDS participants, 
and reported an ORR of 77% with a 13 month median follow-up, and high rates of grade 3 AEs 
in 97% of participants, including febrile neutropenia in 46% and neutropenia and 
thrombocytopenia in 51% and 30%, respectively;[80] and (b) a Phase 1b trial of venetoclax plus 
azacitidine by Zeidan et al for treatment of MDS in the relapsed/refractory setting; Of the 38 
participants enrolled, with a median follow up of 6.8 months, there was a clinical response of CR 
+ mCR in 40%, and HI in 25%. Common grade 3-4 AEs included neutropenia and 
thrombocytopenia in 50% and 42% of participants, respectively.[81] While reported efficacy is 
promising for this combination, the side effect profile and complications due to cytopenias 
appear significant based on these preliminarily data and this regimen may require further 
optimization in the MDS setting.  
LR-MDS is generally not an indication for HSCT, although some participants may be 
eligible.[73, 74] At the time of diagnosis, participants with LR-MDS have several treatment 
options based on the characteristics of the disease. The primary objective in the treatment 
approach to participants with LR-MDS is to preserve quality of life and improve cytopenia.[82] 
Erythropoiesis stimulating agents (ESA) are indicated in participants with LR-MDS and anemia, 
with a ~70% overall response rate (ORR) in participants with endogenous erythropoietin (EPO) 
levels < 500 mU/L, but ORR is < 10% in those with EPO > 500 mU/L.[83] The duration of 
response is up to ~24 months. As a second line treatment after ESA failure for participants with 
MDS with ring sideroblasts, an ORR of 38% is reported in the luspatercept registration trial.[84] 
According to International Working Group (IWG) 2018 Response Criteria,[85] 28% of 
participants remained transfusion-independent for 48 weeks. The 5q syndrome is the subtype of 
MDS with isolated 5q deletion without other cytogenetic abnormalities accounting for about 
15% of all MDS cases.[86] Due to the specific haploinsufficiency in 5q syndrome, treatment 
with lenalidomide targets selectively aberrant signaling pathways[87] and even complete 
cytogenetic remission can be induced with a median time to progression of 2-3 years.[88] After 


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the progression, usually there is an emergence of clone with additionally acquired mutations with 
an adverse prognostic significance (i.e. TP53 or RUNX1). Lenalidomide was also evaluated via a 
randomized phase III trial in treatment of non-del5q LR-MDS participants who were ineligible 
or refractory to ESAs, which resulted in a 26.9% RBC transfusion independence (RBC-TI) rate 
and improved HRQoL as measured by EORTC QLQ-C30.[89] While not considered standard of 
care for LR-MDS, DNMTis have been explored in this setting, including a randomized phase 2 
trial evaluating low-dose decitabine vs azacitidine in this participant population with reported 
ORR between 40-70%, which are now being confirmed in a larger trial.[90] A meta-analysis 
explored azacitidine efficacy in LR-MDS with a reported RBC-TI rate of 38.9%.[91] A recent 
phase II trial of imetelstat, a telomerase inhibitor, in 53 RBC-transfusion dependent LR-MDS 
participants reported 8- and 24-week RBC-TI rates of 42% and 29%, respectively, that were 
durable for a median of 87 weeks.[92] Participants with hypoplastic MDS are candidates for 
immunosuppressive therapy with cyclosporine with or without anti-thymocyte gamma globulin 
(ATG, only for younger fit participants).[93] A substantial number of participants with LR-
MDS, other than those mentioned above will be candidates for a “watch-and-wait” approach 
with supportive transfusion treatment or administration of granulocyte stimulating colony factor 
(G-CSF) agents when required. Most such participants will eventually develop regular 
dependence on red-cell transfusions and be at great risk of parenchymal iron overload and related 
organ toxicity.[94]
1.2.4
BMS-986253
1.2.4.1
Background and safety
BMS-986253 (HuMax-Immune) is a fully human IgG1 kappa neutralizing monoclonal antibody 
against IL-8. It binds the IL-8 epitope on both IL-8 isoforms (72 and 78 amino acids), important 
for CXCR1/2 binding, and prevents IL-8 from binding to its corresponding receptors. Since 
BMS-986253 cannot bind receptor-bound IL-8, it shows no antibody dependent cell-mediated 
cytotoxicity (ADCC) or complement-dependent cytotoxicity (CDC). It shows no cross-reactivity 
with other human tissues or chemokines.[95]
BMS-986253 has been tested in a single dose PK study in monkeys at 20 and 160 mg/kg. The 
dosing was clinically tolerable in the monkeys. A reduction of serum IL-8 to below the lower 
limit of detection was seen for the total follow-up period of 6 weeks. A larger multiple dose 
toxicokinetic study in cynomolgus monkeys at doses 20, 80 and 160 mg/kg/week for 12 weeks 
has been completed and showed no safety issues.
A phase I/II clinical trial[96] designed to evaluate safety and efficacy in palmoplantar pustulosis 
(PPP), a rare chronic inflammatory skin disorder, enrolled 31 participants. For PPP, BMS-
986253 showed efficacy in reducing disease activity. The antibody was well-tolerated, with no 
serious adverse events (SAE) attributed to treatment. The most frequently reported mild or 
moderate adverse events included nausea, nasopharyngitis, and headache. Moreover, no 
antihuman antibodies developed after administration of BMS-986253.[96] In the phase I trial of 
BMS-986253 in advanced solid tumors as monotherapy,[97] 11/15 subjects achieved the best 
response of stable disease (4 subjects had progressive disease). Reduction of serum IL-8 levels 
were observed across all dose levels (4, 8, 16 and 32 mg/kg every 2 weeks) without reaching a 
dose-limiting toxicity (DLT) or defining maximum tolerated dose (MTD). Treatment with BMS-
986253 reversed EMT process measured by the EMT markers and inhibited IL-8 induced 
peripheral blood cells migration isolated from subjects post-treatment. The most common 


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adverse events (AE), regardless of causality, were constipation (n=5), nausea (n=4) and anemia 
(n=4). Six subjects (40%) had grade 3 AEs with increased ALP (n=2) and anemia (n=2) being 
the most common. Treatment-related AEs occurred in one-third of the subjects and were all 
grade 1 and 2 (anemia and fatigue as the most common). Four subjects experienced SAE non-
related to the treatment (grade 3 pain, abdominal infection, fall, decreased ALP, hyponatremia 
[n=5]; grade 2 pulmonary embolism [n=1]). The pharmacokinetic (PK) analysis showed an 
approximate linear correlation between increasing dose and exposure for the dose range of 4 
mg/kg to 32 mg/kg.[97]
In the currently ongoing clinical trial phase 1/2 (CA027-002, ClinicalTrials.gov NCT03400332), 
testing various flat doses of BMS-986253 in combination with nivolumab, treatment-related AEs 
were observed in 140/144 participants with solid cancer at the time of the preliminary analysis 
(data cutoff date of 16-Jan-2023). No DLTs were observed, and no safety signals were identified. 
The most common treatment-related AEs in combination with nivolumab were fatigue (n=53), 
malignant neoplasm progression (n=44), nausea and anemia (n=35), and decreased appetite 
(n=33), dyspnea and diarrhea (n=29), constipation (n = 27), pyrexia (n = 24), abdominal pain (n 
= 19), asthenia and weight decreased (n = 18), urinary tract infection, pneumonia, vomiting, 
hyponatremia, and arthralgia (n = 17), pruritus (n = 16), and cough (n = 15). Other Grade 5 AEs 
include sepsis, respiratory failure, cardiac death, death, pneumonia, pneumonia aspiration, 
neoplasm malignant, neoplasm progression, arterial rupture, and cardiac arrest (n = 1).Based on 
preliminary clinical data from that trial BMS-986253 does not appear to significantly increase 
the rate of nivolumab-induced AEs.[95]
Based on currently available clinical data from prior trials including 158 participants,[95-97] 
only 3 participants had infusion reactions. One participant received 8 mg/kg BMS-986253 
monotherapy and experienced a grade 1 infusion reaction on Cycle 1 Day 1, which did not recur 
with subsequent infusions. Two participants treated with 2,400 mg BMS-986253 Q2W + 480 mg 
nivolumab Q4W experienced infusion reactions: one grade 2 infusion reaction on Cycle 1, Day 
15 and continued to receive subsequent infusion of study therapy and tolerated well, and one 
experienced a grade 4 infusion reaction on Cycle 2, Day 15 that led to drug discontinuation.
Of note, there has been a higher-than-expected incidence of hemophagocytic 
lymphohistiocytosis (HLH) in participants receiving ipilimumab + nivolumab + blinded study 
drug (BMS-986253 or placebo) in Part 2 of Study CA027-002. As of 31 Jan 2023, 159 
participants were treated in Part 1 with the nivolumab + BMS-986253 doublet, across different 
dose levels and/or schedules of BMS-986253. No dose-dependent toxicities were identified. In 
Part 1C, 15 participants were treated with BMS-986253 (3600 mg Q2W) in combination with 
nivolumab (1 mg/kg Q3W) and ipilimumab (3 mg/kg Q3W) to evaluate safety and preliminary 
anti-tumor activity of the triplet regimen. Part 2 was a randomized, double-blind evaluation of 
BMS-986253 (3600 mg Q2W) in combination with nivolumab (1 mg/kg Q3W) and ipilimumab 
(3 mg/kg Q3W) (Cohort 2A) vs nivolumab and ipilimumab plus placebo (Cohort 2B) in 
participants with melanoma that have progressed on anti-PD-(L)1 therapy with the objectives of 
comparing anti-tumor activity and assessing the safety of the triplet combination of BMS-986253 
with nivolumab and ipilimumab. As of 27 Jan 2023, 57 participants across 18 sites in eight 
countries have been treated in the blinded part 2. To date, 3 HLH cases have been reported in 
Part 2, 2 of which were fatal. In Part 2, as of the data cutoff date of 10-Jan-2023, 54 participants 
with advanced/metastatic solid tumors have been treated with BMS-986253 3,600 mg or placebo 
Q2W in combination with nivolumab 1 mg/kg Q3W and ipilimumab 3 mg/kg Q3W.


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The sponsor’s safety monitoring team determined that the rate of HLH reported is higher than 
anticipated and elected to unblind the treatment assignment for the 3 participants to evaluate a 
potential contribution of BMS-986253. The randomization of the 3 participants with HLH was 
divided between the two arms. Of the 2 HLH cases with a fatal outcome, 1 occurred in each arm 
(2A and 2B). Overall, the incidence rates of HLH reported in the 2 arms were not considered 
meaningfully different. There were no HLH cases reported in participants treated with BMS-
986253 in the following cohorts:
BMS-986253 monotherapy in phase 1 Study CA027-001 (n=15), BMS-986253 + nivolumab 
inCA027-002 Part 1A/B (n=144), nivolumab + ipilimumab + BMS-986253 in CA027-002 Part 
1C (n=15), nor in participants (n=122) in 8 investigator sponsored research studies evaluating 
BMS-986253 in combination with nivolumab and other drugs in oncology indications.
In summary, it was determined that a contributory factor of BMS-986253 for the reported cases 
of HLH cannot be ascertained. The basis for the higher-than-expected frequency of HLH in the 
study cannot yet be determined and the evaluation is further confounded by the presence of 
significant comorbidities in the affected participants, including sepsis, possible gastrointestinal 
perforation, and viral infection (i.e., a recent COVID-19 infection in one participant, and 
evidence of EBV in 2 participants), all of which can present with an overlapping symptom 
complex and/or may contribute to the development of HLH. In addition, HLH case reports are a 
well described complication of immune checkpoint inhibitor monotherapy (pembrolizumab or 
nivolumab alone) or nivolumab/ipilimumab combinations. [98] 
Because BMS-986253 is scheduled for intravenous (IV) administration, extravasation at the site 
of infusion may induce reactions such as edema, redness, itching, and tenderness. To date, no 
injection-site reactions have been reported. 
1.2.4.2
Dosing
In a previous trial that enrolled non-cancer subjects noted above,[96] BMS-986253 was given as 
a single IV dose first at escalating dose levels ranging from 0.15 to 8 mg/kg. Subsequently, the 
same participants were treated with 4 weekly doses of 0.15 to 4 mg/kg. In the trial with advanced 
solid cancers as monotherapy,[97] BMS-986253 was given as a single IV dose first at escalating 
dose levels ranging from 4 to 32 mg/kg. Subsequently, the same participants were treated with 
the antibody every 2 weeks until progression with the same dose. In a currently ongoing trial that 
enrolled advanced cancer participants in combination with nivolumab at a dose of 480 mg every 
4 weeks,[95] BMS-986253 is given as a single IV flat dose escalating from 600 to 2400 mg 
every 4 weeks and as a single IV flat dose escalating from 1200 to 2400 mg every 2 weeks. The 
last dosing regimen of 2400 mg every 2 weeks showed the best profile in terms of the deepest 
and most durable reduction of serum IL-8 levels among dose groups (Figure 2). Based on this, 
exploratory PK/PD modeling on serum IL-8 suggested that higher dose of BMS-986253 may 
further improve serum IL-8 suppression. Ongoing studies are currently testing higher dosing of 
3600 mg every 2 weeks [Personal communication with BMS].


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Figure 2. Flat dosing regimens and serum IL-8 levels in subjects treated with BMS-986253 in 
combination with nivolumab.
1.2.4.3
Pharmacokinetic and pharmacodynamic data
After single dose administration, the peak BMS-986253 serum concentration occurs at around 1 
hour. Maximum plasma concentrations are dose-dependent, but plasma clearance rates are dose-
independent. The half-life of the antibody is approximately 11.3 days. The pharmacodynamics 
effect was evaluated by measuring the IL-8 levels in wound fluid. In the three highest dose levels 
tested, there appeared to be a dose-dependent reduction in the IL-8 concentration in the wound 
fluid (2, 4, and 8 mg/kg).[96] In the phase 1 dose escalation study as monotherapy,[97] a 
sustained reduction in serum IL-8 > 50% was detected in 6 of 15 participants by assessing 
changes in serum IL-8 measured in samples obtained pre- and post-dose. Of the 6 participants 
exhibiting a sustained reduction in serum IL-8, four were from the 6-participant cohort dosed at 
32 mg/kg, and one of each was from the 4- and 16-mg/kg 3-participant cohorts. In the ongoing 
phase 1/2a trial in advanced cancers in combination with nivolumab,[95]  Single Molecule Array 
(SIMOA) technology is being used to detect serum free IL-8 (IL-8 that is not bound to 
therapeutic antibody). The serum free IL-8 results (as of the data cut-off date 16-Jan-2020) for 76 
participants who were treated with varying doses of BMS-986253 in combination with 
nivolumab 480 mg Q4W and all participants displayed a rapid decrease in free serum IL-8 
(Cycle 1 Day 2). The data suggest that BMS-986253 decreases free serum IL-8 in a dose- and 
frequency-dependent manner and that the 2,400 mg Q2W dosing provides the deepest and most 
durable suppression of free serum IL-8, with modeling suggesting that higher dose of BMS-
986253 may further improve serum IL-8 suppression.


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1.2.5
Rationale for Myeloid Malignancy Program Investigation
In general, long term treatment outcomes for MDS participants are dismal. It is estimated that of 
every 100 MDS participants, four will be long-time survivors, with the rest of succumbing to 
either  MDS- or treatment-related complications (67) or MDS-unrelated complications (29).[3] 
There has been no progress in populations based studies in survival of MDS participants during 
last 2 decades.[77] Novel approaches are needed which do not rely exclusively on cytotoxic 
therapy and/or intervene earlier in the course of the disease. Current clinical trials for participants 
with MDS enroll less than 5% of MDS participants.[76] With better understanding of complex 
MDS pathophysiology, trials using combination treatments are emerging, especially for those 
ineligible for the HSCT, therefore representing an unmet need.[11]  
Since immune disturbance in MDS is common pathologic finding,[101] and MDSCs have be 
found to induce myelodysplasia,[60] with evidence of VEGF-independent neoangiogenesis and 
overexpression of EMT transcription factors as important processes in the evolution of 
MDS,[53] there is a reasonable evidence that by blocking IL-8-mediated processes with IL-8 
neutralization, a positive, disease-modifying therapeutic effect could be achieved. Preclinical in 
vitro work has also shown that blockade of the IL-8 receptor, CXCR2, led to significant 
reduction in the proliferation of several leukemic cell lines and primary AML/MDS cells. [37]
In the preclinical experiments done in Laboratory of Receptor Biology and Gene Expression 
(NCI/CCR), a heterozygous U2AF1 mutation was found to lead to widespread changes in 
translation such that mutant cells showed a ‘non-oncogene addiction’ to the ribosome biogenesis 
machinery.[69] These data indicate an unanticipated functional connection between a splicing 
factor mutation and the ribosome biogenesis machinery. The preceding observations necessitate 
clinical correlates which specifically interrogate post-transcriptional regulation in MDS. 
Although there has been exhaustive DNA and RNA sequencing in MDS, there has been little if 
any quantitative measurements of translational regulation and this trial will allow a novel insight 
in the pathophysiology if MDS in synergy with the ongoing basic laboratory NCI/CCR research. 
A new Clinical and Translational Correlates Facility was recently funded by the FY20 Directors 
Challenge Innovation Award and is physically housed initially within NHLBI space (PI 
Christopher Hourigan et al). This facility will create the ability to perform standardized research 
correlates proposed on this study and across the growing NIH Myeloid Malignancies Clinical 
Trials portfolio. Work from intramural investigators has recently demonstrated that high-
sensitivity genomic measurements outperform conventional clinical assessments for myeloid 
malignancy participants in predicting relapse and survival following HSCT and suggest that 
additional intervention on high-risk subjects can improve clinical outcomes.[102] This sets the 
stage for a “precision medicine” approach where personalized assessments of clonal disease 
burden can be used not only to judge the success of therapy, but also as a target for intervention.
In this trial we hypothesize that the addition of BMS-986253 to treatment with DNMTi is safe in 
adult MDS participants. Based on the presented data on IL-8 in MDS, we also hypothesize that 
IL8 suppression with BMS-986253 will enhance efficacy of DNMTi therapy in adult HR-MDS 
participants and will be also effective for cytopenia-improvement as monotherapy in LR-MDS 
participants.


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2
ELIGIBILITY ASSESSMENT AND ENROLLMENT 
2.1
ELIGIBILITY CRITERIA
2.1.1
Inclusion Criteria
1. Participants must have histologically or cytologically confirmed MDS according to 2016 
WHO criteria[1]
a.
And:
2. 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
3. have LR-MDS (R-IPSS <3.5),  
a.
and, at least one cytopenia:
i. granulocytes < 1.0 x 109/L and/or
ii. hemoglobin < 110 g/L with signs/symptoms of symptomatic anemia or 
transfusion-dependency
iii. platelets < 100 x 109/L
2.1.1.1
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.
2.1.1.2
ECOG performance status ≤2 (Karnofsky ≥60%, see Appendix A).
2.1.1.3
Life expectancy greater than 6 months.
2.1.1.4
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
≥60 mL/min/1.73 m2 for participants with
       (by Cockcroft-Gault)                   creatinine levels above institutional normal.
2.1.1.5
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; 


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abstinence) prior to study entry, for the duration of study participation, and up to 6 
months after study completion and last dose of DNMTi.
2.1.1.6
Ability of subject to understand and the willingness to sign a written informed consent 
document.
2.1.2
Exclusion Criteria
2.1.2.1
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.
2.1.2.2
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
2.1.2.3
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.
2.1.2.4
Participants with clinically significant neutropenia, ANC<100, with frequent 
hospitalizations for infection (average >1 hospitalization per month in past 6 months)
2.1.2.5
Participants who are receiving or have received any other investigational agents within 
28 days before start of study treatment.
2.1.2.6
History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to DNMTi or other agents used in study.
2.1.2.7
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.
2.1.2.8
Pregnant women or women presently breast-feeding their children are excluded due to 
unknown risks to a developing fetus or infant.
2.1.2.9
Any significant disease that, in the opinion of the investigator, may impair the 
participant’s tolerance of study treatment.
2.1.2.10 Active or uncontrolled autoimmune diseases requiring treatment.
2.1.2.11 Chronic hepatitis B or C infection, because potential immune impairment caused by 
these disorders may diminish the effectiveness of this immunologic therapy.
2.1.2.12 HIV-positive participants are ineligible because of the potential for decreased immune 
response.
2.1.2.13 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.
2.1.2.14 Prior history of allogeneic hematopoietic stem cell transplantation.


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2.1.3
Recruitment Strategies
This protocol will be advertised on NIH websites (clinicaltrials.gov, future Myeloid Malignancy 
Program Web Site) and on NIH social media platforms. 
2.2
SCREENING EVALUATION
2.2.1
Screening activities performed prior to obtaining informed consent
Minimal risk activities that may be performed before the subject has signed a consent include the 
following: 
•
Email, written, in person or telephone communications with prospective subjects 
•
Review of existing medical records to include H&P, laboratory studies, etc.  
•
Review of existing MRI, x-ray, or CT images
•
Review of existing photographs or videos
•
Review of existing pathology specimens/reports from a specimen obtained for diagnostic 
purposes
2.2.2
Screening activities performed after a consent for screening has been signed
The following activities will be performed only after the subject has signed the consent for this 
study for screening. Assessments performed at outside facilities or on another NIH protocol 
within the timeframes listed below may be abstracted and used to determine eligibility once a 
participant has signed the consent for this study. Note:  Given the standard nature of the planned 
clinical laboratories, interlaboratory variability is not a concern and participants may have 
clinical labs drawn locally, with results sent to the NIH study team (e.g., via fax).
Screening tests are valid for 30 days prior to enrollment unless otherwise specified. 
•
Medical history
•
Physical examination
•
Laboratory evaluations
•
ECG
If protocol therapy is started > 8 days of these eligibility screening evaluations, the medical 
history, physical examination, laboratory evaluations, and ECG must be repeated prior to starting 
protocol therapy (i.e., repeated at Baseline/prior to C1D1; see Section 2.4).
2.2.2.1
Histologic confirmation: All participants are required to have histologically confirmed 
MDS. Pathology reports from outside institutions confirming the diagnosis will be 
acceptable for eligibility purposes with required secondary NIH pathology review.
2.2.2.2
History and physical examination: Complete history and physical examination 
(including height, weight, vital signs, and performance score).
2.2.2.3
Laboratory Evaluation: Laboratory data are to be obtained:
•
Hematological Profile: CBC with differential
•
Biochemical Profile: total bilirubin, BUN, albumin, calcium, creatinine, 
SGOT [AST], SGPT[ALT], phosphorous, magnesium, potassium, sodium, 


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LDH, uric acid, ferritin, endogenous erythropoietin, vitamin B12, folate, 
copper, zinc, ANA, thyroid function studies (TSH, Free T4) 
•
Infectious serologies including HIV, HBV, HCV
•
SARS-CoV2 testing per clinical center guidelines
•
Urine and/or serum pregnancy test for female participants of childbearing 
potential (within 24 hours prior to start of therapy)
2.2.2.4
Cardiac Evaluation: Electrocardiogram (ECG) will be obtained.
2.2.2.5
Bone Marrow aspirate and biopsy - (May be performed during baseline evaluation) 
must be done within 30 days prior to treatment initiation
2.3
PARTICIPANT REGISTRATION AND STATUS UPDATE PROCEDURES
Registration and status updates (e.g., when a participant is taken off protocol therapy and when a 
participant is taken off-study) will take place per CCR SOP ADCR-2, CCR Participant 
Registration & Status Updates found at: 
https://ccrod.cancer.gov/confluence/pages/viewpage.action?pageId=73203825.
2.3.1
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical trial but are 
not subsequently assigned to the study intervention or entered in the study. A minimal set of 
screen failure information is required to ensure transparent reporting of screen failure 
participants, to meet the Consolidated Standards of Reporting Trials (CONSORT) publishing 
requirements and to respond to queries from regulatory authorities. Minimal information 
includes demography, screen failure reason, eligibility criteria, and any serious adverse event 
(SAE).
Individuals who do not meet the criteria for participation in this trial (screen failure) because of 
any specific inclusion/exclusion criteria by discretion of PI may be rescreened.
2.3.2
Treatment Assignment (for Phase I and II)
Cohorts in phase I:
Number
Name
Description
1
“Lower-risk” MDS: 
eligible lower-risk phase I 
participants
Participants with confirmed MDS and R-IPSS score < 3.5 
(low and lower intermediate-risk) that are eligible for phase 
I.
2
 “Higher-risk” MDS: 
eligible higher-risk phase I 
participants
Participants with confirmed MDS and R-IPSS score ≥3.5 
(high and higher intermediate-risk) that are eligible for 
phase I.
Cohorts in Phase II:
Number
Name
Description


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3
“Lower-risk” MDS
Participants with confirmed MDS and R-IPSS score < 3.5 
(low and lower intermediate-risk)
4
 “Higher-risk” MDS
Participants with confirmed MDS and R-IPSS score ≥3.5 
(high and higher intermediate-risk)
Arms    
Number
Name
Description
1
escalating doses of 
treatment for LR-MDS
escalating doses of BMS-986253
2
escalating dose of 
treatment for HR-MDS
escalating doses of BMS-986253 + DNMTi (decitabine and 
cedazuridine)
3
phase II dose of BMS-
986253 for LR-MDS*
phase II dose of BMS-986253
4
phase II dose of BMS-
986253 for HR-MD
phase II dose of BMS-986253 + DNMTi (decitabine and 
cedazuridine)
*Poor-risk genomic features, such as bi-allelic TP53 mutation, can escalate a participant from 
LR-MDS cohort #3 to HR-MDS cohort #4 for phase II, per PI discretion.
Arm Assignment
Participants in cohort 1 are assigned to arm 1; Cohort 2 assigned to arm 2; Cohort 3 are assigned 
to arm 3, and cohort 4 are assigned to arm 4.
2.4
BASELINE EVALUATION
To be performed within 8 days prior to initiating study treatment.
Medical Assessment:
•
History and physical examination including vital signs (blood pressure, pulse, respiratory 
rate, oxygen saturation)
•
Height and weight
•
Performance status determination (see Appendix A for ECOG)
•
ECG
•
Concomitant medications assessment
•
Questionnaires/assessments: 
Note:  These apply to English speaking participants only. 
o
Rockwood/CFS and MDS-CI Questionnaire 
o
European Organization for Research and Treatment of Cancer (EORTC) quality 
of life questionnaire = EORTC QLQC30 score 
o
Psychosocial Assessment 
Laboratory Assessments:


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•
Complete blood count plus differential, platelet count, and reticulocyte count
•
Serum chemistries (Na, K, Cl, CO2, glucose, BUN, creatinine, albumin, calcium, 
magnesium, phosphorus, alkaline phosphatase, ALT, AST, total bilirubin, LDH, TSH, 
erythropoietin), CRP
•
Blood type and screen (as clinically indicated)
•
Urinalysis
•
 Research blood per section 5.1 Blood sample for T-cells, B-cells, and NK cells [TBNK] 
(CD3, CD4, CD8, CD19 clinical panel)
•
Bone Marrow aspirate and biopsy - (May be performed during screening evaluation) 
must be done within 30 days prior to treatment initiation.
o
Morphology, flow cytometry, cytogenetics, and molecular tests, and research 
collection (See Section 5.1)
•
Next Generation Sequencing- panel of myeloid genes from the peripheral blood and/or 
marrow. (May be performed during screening evaluation) must be done within 30 days 
prior to treatment initiation.
•
Peripheral blood flow cytometry (if peripheral blood blasts present, will trend at end of 
each treatment cycle until clearance)
To be performed within 24 hours prior to initiating study treatment:
•
Serum beta-HCG for females of childbearing potential (FCBP): A female of childbearing 
potential is a sexually mature woman who:
o
Has not undergone a hysterectomy, tubal ligation, or bilateral oophorectomy
o
Has not been naturally postmenopausal for at least 24 consecutive months (i.e., 
has had menses at any time in the preceding 24 consecutive months).
In addition, male and female participants should be willing to practice effective birth control 
prior to study entry, during the study, and for six months following the last study treatment, 
unless they have had a prior vasectomy, hysterectomy, or bilateral oophorectomy.
An extension up to 72 hours prior to the start of study treatment is permissible in situations 
where results cannot be obtained within the standard 24-hour window.
3
STUDY IMPLEMENTATION
3.1
STUDY DESIGN
This study consists of two phases:
•
Phase I: determination of OBD of BMS-986253 with and without DNMTi for HR- and 
LR-MDS cohorts, respectively, and 
•
Phase II: examining the efficacy of BMS-986253 with and without DNMTi for HR- and 
LR-MDS cohorts, respectively
In the Phase I, subjects will be enrolled to start treatment with BMS-986253 after a minimum of 
2 cycles and up to initiation of an 8th cycle of DNMTi. 
The safety endpoint will be DLT on D28. In addition, follow up for safety will be assessed 100 
days after the last dose of treatment. 


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OBD will be the lowest tolerated dose level showing optimal biological activity, defined as 
maximal suppression of serum free IL-8 levels.
Participants enrolled on phase I will be treated at the corresponding BMS-986253 dose level 
until occurrence of disease progression, death, or unacceptable toxicity or until response 
assessment on C7D1 (maximum 6 cycles) if no evidence of clinical response. The participants 
will be followed up for overall, event- and progression-free survival until the study closure. The 
study will be closed when all enrolled participants have been followed up for at least 8 years or 
have died.
Both Phase I and II portions of study will enroll two cohorts: 
A) HR-MDS: subjects with higher-risk MDS that will be treated with BMS-986253 in 
combination with DNMTi.
B) LR-MDS: subjects with lower-risk MDS that will be treated with BMS-986253 given as 
monotherapy. 
In the Phase II portion, the treatment naïve subjects (or up to 4 cycles of prior DNMTi) will start 
treatment with BMS-986253 from the first cycle and the efficacy will be assessed until any off-
treatment criteria are met (Section 3.8). BMS-986253 will be administered on days 1 and 15 of 
each cycle, and participants will remain on therapy until disease progression, death, or 
unacceptable toxicity or taken off therapy if no evidence of clinical response after 6 cycles 
(C7D1). The participants will be followed up for overall, event- and progression-free survival 
until the study closure. The study will be closed when all enrolled participants have been 
followed up for at least 5 years or have died.
Study treatment schema
**In the HR-MDS Cohort, DNMTi therapy (marked by the orange line) may start prior to study enrollment. As 
stated in the eligibility sections (see Section 2.1.1): For HR-MDS cohort, participants are eligible if they have 
received a minimum of 2 cycles of DNMTi therapy and up to a maximum of 8 prior cycles for phase I, and up to 
maximum 4 cycles of DNMTi therapy for phase II. 


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◊Once enrolled on study, DNMTi administration will be aligned to start on D2 of the on-protocol treatment cycles 
with oral decitabine and cedazuridine, to be taken once daily for 5 total days (D2-6).
*EOT will occur at disease progression, death, unacceptable toxicity OR if no clinical response is seen by 
completion of 6 cycles of therapy.
3.1.1
Dose Limiting Toxicity (DLT)
DLT is defined as any of the following:
•
Any grade ≥ 3 non-hematologic toxicity that is possibly, probably, or definitely related to 
study drug, except transient (≤ 48 hour) grade 3 fatigue, nausea, local reactions, flu-like 
symptoms, fever, headache, infusion reactions, or laboratory abnormalities that are not 
associated with organ pathology.
•
In the absence of active MDS, hematologic DLTs for each arm include:
o
LR-MDS arm: any grade ≥4 decrease in ANC or PLTs lasting more than 7 days. 
o
HR-MDS arm:  any grade ≥4 decrease ANC or PLTs lasting more than 28 days. 
o
If the bone marrow at the end of cycle 1 of therapy is hypoplastic (< 5% 
cellularity), adjustments to treatment schedule will be allowed to delay next cycle 
for up to 2 weeks after count recovery or if toxicity resolves to Grade 2 or below.
•
Liver Injury (DILI) as defined by a positive Hy’s Law 
(https://www.fda.gov/media/116737/download):
o
AT (ALT or AST) elevation > 3 times upper limit of normal (ULN), AND
o
Total bilirubin > 2 times ULN, without initial findings of cholestasis (elevated 
serum alkaline phosphatase), AND
o
No other immediately apparent possible causes of AT elevation and 
hyperbilirubinemia, including, but not limited to, viral hepatitis, pre-existing 
chronic or acute liver disease, or the administration of other drug(s) known to be 
hepatotoxic. 
•
The following toxicities are not considered dose-limiting in MDS participants: 
o
Grade 3 or 4 febrile neutropenia 
o
Grade 3 or 4 infection only if a direct complication of cytopenias due to active 
underlying MDS
o
Grade 3 or 4 hypotension explained by sepsis 
o
Grade 3 or 4 hemorrhage/bleeding 
o
Other expected direct complication of cytopenia due to active myeloid 
malignancy 
•
Any adverse reaction that leads to dose reduction or withdrawal.
3.1.2
Dose Escalation
Participants will receive BMS-986253 A safety lead-in will be performed. The safety lead-in will 
be 28 days in length and consist of 2 doses of BMS-986253 (on days 1 and 15) with a safety 
evaluation through day 28. Dose escalation will proceed in cohorts of 3–6 participants. The MTD 
is the dose level at which no more than 1 of up to 6 participants experience DLT during one 
cycle (28 days) of treatment, and the dose below that at which at least 2 (of ≤6) participants have 
DLT as a result of the drug. If a participant did not experience DLT and did not finish treatment, 
he or she will not be evaluable for toxicity and will be replaced in the dose level. Participants 
will be taken off treatment if unacceptable toxicity occurs and is attributed to all therapeutic 


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agents (see section 3.8). These patients will also be evaluated for safety and efficacy (see Section 
7.4.1 and 8).
Dose Escalation Schedule
Dose Level
Dose of BMS-986253
Level -1
600 mg IV Q2W over 60 minutes
Level 1
1200 mg IV Q2W over 60 minutesa
Level 2
2400 mg IV Q2W over 120 minutesb
Level 3
3600 mg IV Q2W over 120 minutes b
a 60 minute duration will be used for pts weighing > 35 kg. For pts weighing < 35 kg the infusion 
duration should be 120 minutes.
b 120 minute duration will be used for pts weighing > 35 kg. For pts weighing < 35 kg the 
infusion duration should be 180 minutes.
Dose escalation will follow the rules outlined in the Table below.
Number of Participants 
with DLT
at a Given Dose Level
Escalation Decision Rule
0 out of 3
Enter up to 3 participants at the next dose level
> 2
Dose escalation will be stopped. This dose level will be 
declared the maximally administered dose (highest dose 
administered). Up to 3 additional participants will be 
entered at the next lowest dose level if only 3 participants 
were treated previously at that dose.
1 out of 3
Enter up to 3 more participants at this dose level.
•
If 0 of these 3 participants experience DLT, proceed 
to the next dose level.
•
If 1 or more of this group develop DLT, then dose 
escalation is stopped, and this dose is declared the 
maximally administered dose. Up to 3 additional 
participants will be entered at the next lowest dose 
level if only 3 participants were treated previously at 
that dose.
<1 out of 6 at highest dose 
level below the maximally 
administered dose that 
exhibits optimal biologic 
activity 
This is the OBD and is generally the recommended phase 
2 dose. At least 6 participants must be entered at the 
recommended phase 2 dose.


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The report including the supporting safety data and delineation of each criteria met, with the 
dose-escalation decisions will be provided to the Sponsor (OSROSafety@nih.gov) before 
additional participants will be enrolled into the study. The Dose Escalation Determination form 
on the sponsor website: 
https://ccrod.cancer.gov/confluence/display/CCRCRO/Forms+and+Instructions  may be used for 
this purpose.
Documentation of dose escalation determinations including the criteria met must be provided to 
the Sponsor prior to dose administration at the next dose level. An OSRO Dose Escalation 
Determination template form is available for recording of dose escalation related PI 
determinations or another format may be used but all equivalent information and PI signature is 
required. 
The completed form or equivalent documentation should be kept in the site study files, sent to 
the Sponsor and available for review by the OSRO Clinical Site Monitors.
3.2
DRUG ADMINISTRATION
3.2.1
BMS-986253
Product Name  
BMS-986253-01 Injection, 100mg/mL (1000 mg/vial OR 1200 
mg/vial)
Product description and 
Packaging 
Packaging: Vials are labeled with a one panel clinical label. 
Individual vials are packaged into a labeled carton. Vials should 
remain in the original carton until use.
Vials: 20 cc Type I Glass Vial; with 20 mm seal
Appearance: 
1000 mg/vial and 1200 mg/vial – Colorless to slightly yellow liquid 
(NGT Y5); Clear to opalescent (NGT 18 NTU); Light (Few) 
particulates (consistent in appearance to proteinaceous particles) 
may be present.
Product Ingredients
 Each vial contains 1000 mg or 1200 mg of BMS-986253
3.2.1.1
 Drug Product Preparation
Handling: As with all injectable drugs, care should be taken when handling and preparing BMS-
986253. BMS-986253 should be prepared using local regulation/guidelines regarding 
engineering (e.g., a biological safety cabinet, laminar or vertical flow hood) and the 
administrative controls required for the preparation and administration of hazardous compounds 
(if so determined), to include standard procedures for the safe handling of sterile products 
applying aseptic techniques. Gloves are required. If BMS-986253 solution comes in contact with 
the skin or mucosa, immediately and thoroughly wash with soap and water. For additional 
information, please refer to the Safety Data Sheet (SDS).
Preparation: 


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•
Withdraw the required volume of BMS-986253 and transfer into an intravenous 
container.
•
Dilute BMS-986253 (1000 mg/vial or 1200 mg/vial) with either 0.9% Sodium 
Chloride Injection, or 5% Dextrose Injection to prepare an infusion with a final 
concentration ranging from 10 mg/mL to 16mg/mL (see table 3.1.2-1 below). 
BMS-986253 is compatible in polyolefin, PVC/non-PVC, DEHP/non- DEHP 
containers.
•
Mix diluted solution by gentle inversion. Do not shake.
•
Discard partially used vials or empty vials of BMS-986253.
•
If using Close System Transfer Device (CSTD) for preparation and/or 
administration of BMS-986253 please check below list of compatible CSTD 
devices. Please reach out to us at pharmacyservices@bms.com for compatibility 
information on any other CSTDs.
 
3.2.1.2
Recommended Storage and Use Conditions
The product does not contain a preservative. After preparation, store the BMS-986253 infusion 
either:
•
at room temperature for no more than 4 hours from the time of preparation. (This 
includes room temperature storage of the infusion in the IV container and time for 
administration of the infusion.)
or
•
under refrigeration at 2°C to 8°C (36°F to 46°F) for no more than 24 hours from the time 
of infusion preparation (including the maximum 4 hour RT storage period).
Do not freeze.
3.2.1.3
Dosage and administration
Administration: Visually inspect drug product solution for particulate matter and discoloration 
prior to administration. Discard the vial if the solution is cloudy, discolored, or contains 
extraneous particulate matter other than a few translucent-to-white, proteinaceous particles. Do 
not shake the vial.
BMS 986253 is to be administered as an IV infusion and not by IV push or bolus injection.
BMS-986253 infusion should be administered over protocol specified administration time 
through an intravenous line containing a sterile, non-pyrogenic, low protein binding 
polyethersulfone (PES) or Nylon in-line filter (pore size of 0.2). Do not co-administer other 
Drug Product 
Compatible CSTDs
BMS-986253, 1000 mg/vial 
BD (Phaseal), ICU Medical 
(Chemolock and Chemoclave), 
B.Braun (OnGuard/Tevadaptor) 
and Equashield, Carefusion 
(Texium/SmartSite) 


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drugs (outside of the ones listed in this protocol) through the same intravenous line. Flush the 
intravenous line “above” the in-line filter at end of infusion with appropriate diluent.
Dose level
Infusion 
total volume
Concentration
Rate duration
600 mg
50 mL
12 mg/mL
60 min
1200 mg
100 mL 
12 mg/mL
60 mina
2400 mg
200 mL
12 mg/mL
120 minb
3600 mg
250 mL
14.4 mg/mL
120 minb
a 60 minute duration will be used for pts weighing > 35 kg. For pts weighing < 35 kg the infusion 
duration should be 120 minutes.
b 120 minute duration will be used for pts weighing > 35 kg. For pts weighing < 35 kg the infusion 
duration should be 180 minutes.
BMS-986253 should be dosed per subject assignment and as outlined in the study drug dosing 
section of the clinical protocol (See section 3.1.2).
See BMS-986253 guidance document for specific instructions on dosing solution preparation 
and infusion duration.
See section 3.2.1.4.1 for Safety monitoring guidelines during first infusion of BMS-986253.
3.2.1.4
Infusion reactions
While rare, infusion reactions can occur with infusion of BMS-986253. Most infusion reactions 
if they occur are mild with symptoms ranging from local skin erythema, skin rash, flushing, 
headache, nausea, fevers, chills or shaking, itching, they can present as more severe reactions 
including hypotension, wheezing, dyspnea or hypoxemia, angioedema, facial swelling, dizziness 
or presyncope, which can be fatal if untreated. The onset and timing for these reactions include 
during or after the infusion on the day of infusion or the day after infusion, with resolution 
commonly 48 hours after onset of symptoms. 
Monitoring for these symptoms of infusion reaction and prompt recognition with appropriate 
interventions is imperative and will be required on this protocol. 
Management should be according to best medical judgment and up-to-date guidelines (for 
example by NCCN, available at 
https://www.nccn.org/professionals/physician_gls/pdf/immunotherapy.pdf, ESMO[103]).
3.2.1.4.1 Safety Monitoring Guidelines for infusion of BMS-986253:
Vital signs, including blood pressure, heart rate, temperature, respiratory rate and SpO2 must be 
taken at the following intervals:
•
For first hour of infusion: every 15 minutes.
•
For second hour of infusion: every 30 minutes. 
•
Through one hour post-completion of infusion: every 30 minutes. 


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If participants experience any signs or symptoms of hypersensitivity, which include dyspnea, 
stridor, scratchy throat, throat or facial swelling, changes in vital signs including hypoxia 
hypotension, lethargy/confusion or change in mental status, immediate medical attention is 
needed with appropriate management per NIH Clinical Center Anaphylaxis Treatment 
Medication Guidelines (http://intranet.cc.nih.gov/pharm/pdf/ATM_GUIDELINES.pdf).
3.2.2
DNA methyltransferase inhibitors (DNMTi)
For HR-MDS cohort, the study drug of BMS-986253 will be given in combination with standard 
of care (SOC) FDA-approved DNMTi PO decitabine and cedazuridine according to guidelines 
outlined in FDA product label. SOC DNMTi will be administered via oral route once daily 
starting D2 of each treatment cycle through D6. [75][104][105]
3.3
DOSE MODIFICATIONS
No dose modifications are allowed for BMS-986253. Dose modifications for toxicity related to 
the DNMTi used will be done according to standard of care per the FDA product label 
recommendations. 
3.4
EVALUATIONS DURING THE TREATMENT
All evaluation days, for flexibility around participant schedules, can be performed up to +/-3 
days. If a participant visit is delayed greater than 3 days due to weather, medical issues, or etc., 
the next evaluation will occur when possible and the 2 week cycle will reset from that point (the 
next dose will be 2 weeks +/-3 days from the previous dose). 
Phase I and Phase II, C1, C(1+x) and beyond (until off treatment criteria are met):
•
Day 1 – all lab checks and medical evaluation will be done pre-dose:
o
History and Physical Exam 
o
Vital signs 
o
CBC with differential, platelet count, and reticulocyte count 
o
Serum chemistry panel (includes sodium, chloride, potassium, CO2, BUN, 
Creatinine, glucose, AST/ALT, Alkaline phosphatase, total bilirubin, direct 
bilirubin, albumin, total protein, magnesium, phosphorous, calcium, LDH, uric 
acid), CRP
o
Blood type and screen (as clinically indicated)
o
TBNK (CD3, CD4, CD8, CD19 clinical panel)
o
Urinalysis 
o
Serum beta-HCG for females of childbearing potential (FCBP) (within 24 hours 
of Day 1) 
o
Blood samples for pharmacokinetics (PK) and pharmacodynamics (PD)  (see 
section 5.1) 
o
For Phase I participants only
o
Transfusion dependency assessment
o
Concomitant medications assessment
o
BMS-986253 administration
•
Day 2:
o
Vital signs (only for Cycle 1)


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o
Clinician assessment (only for Cycle 1)
o
Blood samples for 24-hour PK/PD timepoint (see Section 5.1)
o
Start oral decitabine and cedazuridine (Day 1 of 5 of DNMTi)
•
Days 3-6:
o
DNMTi administration of oral decitabine and cedazuridine (HR-MDS cohorts). 
 
•
Day 8:
o
Weekly Labs (only for Cycle 1) CBC/diff, reticulocyte count, chemistries (as 
above and included CRP)
•
Day 15 – all lab checks and medical evaluation will be done pre-dose:
o
History and Physical Exam 
o
Vital signs 
o
CBC with differential, platelet count, and reticulocyte count 
o
Blood type and screen (as clinically indicated) 
o
Serum chemistry panel (includes sodium, chloride, potassium, CO2, BUN, 
Creatinine, glucose, AST/ALT, Alkaline phosphatase, total bilirubin, direct 
bilirubin, albumin, total protein, magnesium, phosphorous, calcium, LDH, uric 
acid), CRP
o
TBNK (CD3, CD4, CD8, CD19 clinical panel)
o
Urinalysis 
o
Serum beta-HCG for females of childbearing potential (FCBP) (within 24 hours 
of Day 1) 
o
Blood samples for pharmacokinetics (PK) and pharmacodynamics (PD) (see 
section 5.1) 
o
For Phase I participants only
o
Concomitant medications assessment
o
BMS-986253 administration
•
Days 16 
o
Vital signs (only for Cycle 1)
o
Clinician assessment (only for Cycle 1)
o
Blood samples for 24-hour PK timepoint (see Section 5.1)
•
Day 22:
o
Weekly Labs (only for Cycle 1) CBC/diff, reticulocyte count, chemistries (as 
above including CRP)
•
Day 28 
o
Bone marrow evaluation (aspiration and biopsy) per protocol or per clinical 
necessity. 
▪
Morphology, flow cytometry, cytogenetics, molecular tests, and research - 
see section 5.1) 
▪
Per protocol, bone marrow biopsy after initiation of therapy required:
•
Phase I post cycle 1(C1D28 +/- 3 days)  


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•
Phase II post cycle 2 (C2D28 +/- 3 days)
•
Phase II post cycle 6 (C6D28 +/- 3 days)
•
With development of treatment-related aplasia or concern for 
disease progression
▪
All other BMB are optional and per PI or LAI discretion.
o
Peripheral blood flow cytometry (if peripheral blood blasts present, will trend at 
end of each treatment cycle until clearance)
o
Research blood per section 5.1
AT DISEASE PROGRESSION
If participant has disease progression on treatment while being evaluated at the NIH the 
following tests will be done within 7 days after diagnosis of progression.
•
Research Blood per section 5.1 
•
TBNK (CD3, CD4, CD8, CD19 clinical panel)
•
Adverse event and transfusion requirement assessment
•
Mandatory Bone Marrow Biopsy and aspirate
•
Peripheral blood flow cytometry (if evidence of peripheral blood blasts and NGS myeloid 
mutation panel)
•
CBC with differential, platelet count, and reticulocyte count
•
Blood type and screen (as clinically indicated) 
•
Serum chemistry panel (includes sodium, chloride, potassium, CO2, BUN, Creatinine, 
glucose, AST/ALT, Alkaline phosphatase, total bilirubin, direct bilirubin, albumin, total 
protein, magnesium, phosphorous, calcium; also need LDH, uric acid, CRP)
•
PT/INR, PTT and fibrinogen
END OF TREATMENT VISIT
Will be done 30 ± 7 days from the end of the last cycle on therapy.
•
History & Physical Exam 
•
Vital signs 
•
Serum beta-HCG for females of childbearing potential (FCBP) Urinalysis
•
CBC with differential, platelet count, and reticulocyte count
•
Fibrinogen
•
Blood type and screen (as clinically indicated) 
•
Serum chemistry panel (includes sodium, chloride, potassium, CO2, BUN, Creatinine, 
glucose, AST/ALT, Alkaline phosphatase, total bilirubin, direct bilirubin, albumin, total 
protein, magnesium, phosphorous, calcium; also need LDH, uric acid, CRP)
•
Concomitant medications assessment
•
Adverse event and transfusion dependency assessment
•
Research blood collection only if bone marrow performed (see section 5.1)
•
TBNK (CD3, CD4, CD8, CD19 clinical panel)
•
EORTC (see section 3.5.3)
•
Psychosocial Assessment (see section 3.5.3)


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FOLLOW-UP 
After the End of Treatment visit, follow up will occur via phone call every 3 months (+/- 1 
month) for first 24 months, then every 6 months (+/- 3 months)  at least 5 years post enrollment. . 
Outside medical records will be requested along with the phone call for the first follow-up visit 
only. 
•
Overall survival, event- and progression-free survival status 
Adverse events assessment (only at first follow-up visit)
END OF STUDY
•
Overall survival, event- and progression-free survival status will be assessed via phone 
call.
3.5
ON STUDY ASSESSMENTS/EVALUATIONS
The timepoints for assessments are listed in Section 0, Study Calendar.  Unless otherwise 
indicated, assessments on dosing days must be performed prior to the administration of study 
therapy. For screening procedure details, refer to section 2.2.  Baseline evaluations do not need 
to be repeated if already performed at screening within 8 days prior to initiation of study therapy. 
3.5.1
Safety Assessments and Other Assessments
•
Physical exam - review of organ systems, weight, and vital signs (i.e., temperature, pulse, 
respirations, blood pressure). Height will only be required prior to treatment no later than 
cycle 1 day 1. After initiation of study drug, symptom-directed physical examinations 
will be performed as clinically indicated in the investigator’s judgment.
•
Medical history – performed during long term follow up in order to assess safety and 
efficacy. 
•
Concomitant medications – a record of all medications including herbal supplements but 
not including study therapy that a participant has taken during the study will be recorded 
in order to assess confounding factors in safety and efficacy assessments
•
Adverse events – participant reported adverse events will be collected throughout the 
study in order to assess safety.
•
ECOG performance status:  an assessment of activities of daily living 
•
Bone marrow biopsy and aspiration:  required at screening/baseline, Phase I post cycle 
1(C1D28 +/- 3 days) and Phase II post cycle 2 (C2D28 +/- 3 days) and post cycle 6 
(C6D28 +/- 3days); and if needed clinically in the setting of aplasia or concern for 
disease progression
•
Electrocardiogram 12-lead ECGs will be performed at baseline only for safety
•
Blood chemistries - Sodium (Na), Potassium (K), Chloride (Cl), Total CO2 (bicarbonate), 
Creatinine, Glucose, Urea nitrogen (BUN), Albumin, Calcium total, Magnesium total 
(Mg), Inorganic Phosphorus, Alkaline Phosphatase, ALT/GPT, AST/GOT, Total 
Bilirubin, Direct Bilirubin, Total Protein will be performed to assess organ function


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•
CBC with differential includes Neutrophils, Lymphocytes, Monocytes, Eosinophils, 
Basophils, WBC, RBC, Hemoglobin, Hematocrit, RBC Indices, MCV, RDW, Platelet. 
•
TBNK for research
•
Other blood test: amylase lipase, creatine kinase, ACTH, TSH, free T4, PT, PTT, INR, 
ESR and CRP will be performed per study calendar to assess organ function
•
Urinalysis for safety
•
Serum or urine pregnancy test – performed prior to administration of study therapy in 
women of childbearing potential and women < 12 months since the onset of menopause 
to ensure participant is not pregnant
3.5.2
Efficacy Assessments
•
Cytogenetic response rate
•
Time to best response (CR, PR, marrow CR+HI, HI)
•
Disease free survival (definition: time to relapse for participants who achieve CR)
•
Progression free survival (definition: disease progression or death from MDS)
•
Leukemia free survival (definition: progression to AML or death from any cause)
•
Overall survival (definition: death from any cause)
•
Transfusion-dependence and independence, for RBC and platelets
3.5.3
Questionnaires 
3.5.3.1
Participant questionnaires are only offered in English and are therefore not required in 
non-English speaking participants that may be enrolled on the protocol.
3.5.3.1.1 Rockwood Frailty Index
The Rockwood Clinical Frailty Score (CFS) was developed as a deployable tool to be used by 
clinicians to assess level of vulnerability. It uses clinical descriptors and pictographs to divide 
participants into 9 levels of vulnerability ranging from 1 (very fit) to 9 (terminally ill). [106] This 
9-point scale uses a visual chart to assess frailty classifications; someone with a score of ≥5 is 
classified as frail. The CFS was validated in a sample of 2305 older Canadian participants who 
remained alive 5 years after the Canadian Study of Health and Aging (CSHA-2). [107] CFS will 
be completed at baseline only in a clinical setting. A member of the study team will observe the 
participants physical activity and ability and score them.
3.5.3.1.2 MDS-CI
MDS-specific comorbidity index (MDS-CI) is a scoring system for MDS participants to be used 
by clinicians using a time-dependent index to predict the effects of comorbidities on treatment 
outcomes. [108] Five comorbidities independently predictive for non-leukemic death (cardiac, 
hepatic, pulmonary, renal, solid tumor) were assigned a score proportional to the regression 
coefficient of the multivariable Cox’s proportional hazards model, the MDS-CI score was 
calculated as the sum of these weighted scores, and grouped into three risk groups – low, 
intermediate, and high risk. The MDS-CI was validated in a sample of 840 MDS participants 
from Pavia, Italy and a validation cohort of 504 participants in Dusseldorf, Germany. [26] MDS-
CI will be completed at baseline only. A member of the study team will assess clinical 
information and score by completing the standard form. 


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3.5.3.1.3 European Organization for Research and Treatment of Cancer (EORTC) quality of life 
questionnaire = EORTC QLQC30 score 
The European Organization for Research and Treatment of Caner (EORTC) Quality of Life 
Questionnaire is a participant self-report questionnaire used to assess participants’ health-related 
quality of life in the oncology field. [109] This questionnaire incorporates nine multi-item scales, 
three symptom scales, a global health scale, and a quality-of-life scale. This questionnaire was 
validated across three language-cultural groups as well as against different questionnaires. [110] 
EORTC QLQ‐C30 has been the most frequently used participant-reported outcome 
(PRO)/quality of life questionnaire in published MDS studies to-date and has commonly been a 
contributory measure of PRO to drug-approval processes for MDS. [111] EORTC-QLQC will be 
completed using self-administered form by participant at baseline, C3D28 (+/- 1 day), C6D28 
(+/- 1 day), C9D28 (+/- 1 day), C12D28 (+/- 1 day), C24 (+/-1 day), and end of treatment.
3.5.3.1.4 NIH MDS Adult Psychosocial Assessment
The psychosocial assessment is a self-report form that was originally developed for the NIH 
gastrointestinal stromal tumor (GIST) Clinic[112] in order to identify specific psychosocial areas 
of concern and symptoms not covered in the Patient-Reported Outcomes Measurement 
Information System (PROMIS) and other standardized measures. It contains items covering 
demographic factors, perceived general health, psychosocial concerns, psychiatric history, self-
identified needs, and interest in a range of possible psychosocial services. It has now been 
adapted and is being used with patients at the NIH participating in the Medullary Thyroid Cancer 
(MTC) and RUNX1 natural history studies. Three versions of the interview were created; one for 
adult patients to complete on their own (age >18 years), another for parents of children to 
complete about their child, and a third, briefer interview for adolescent patients (ages 12-17 
years). This questionnaire will be provided to patients for completion at baseline, C12D28 (+/- 1 
day) , C24D28 (+/-1 day), and end of treatment


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3.6
STUDY CALENDAR
Phase I and II
All Cycles 
Procedure
Screening a
Baseline c
Day 
1f
Day 
2
Day 
15f
Day 
16
Day 
28
At Disease 
Progression 
m
End of 
treatment 
visitk
Post 
Therapy 
Follow-
upl
E
n
d 
o
f 
S
t
u
d
y
History and PE
X
X
X
Xg
X
Xg
X
Vital signst
X
X
X 
X 
X 
X 
X
Height and Weight
X
Xo
Performance Score
X
X
Labsn  
X
X
X
X
X 
X
Serum Pregnancy Test 
X
X e
X e
Xe
X
Urinalysis
X
X
X
X
ECG
X
X
Bone Marrow bx and 
aspirate (see section 5.1)
X
X d
Xj
X
Histologic Confirmation b
X
Correlative Research 
Studies (see section 5.1)
X
X
X
X
PK/PD (see section 5.1)i
X
X
X
X
NIH advanced Directive 
X
DNMTi Administrationh
X
BMS-986253 
Administrationq
X
X
Response Evaluationr
X
Follow-up by phone call
X
X
Transfusion Dependency 
Assessment
X
X
X
Adverse Event Assessment 
X
X
X
X
X
X
X
Xs
Concomitant Medications
X
X
X
X
X
Questionnairesp
Rockwood/CFS
MDS-CI
EORTC QLQC30 score
Psychosocial assessment
Xp
Xp
a.
Screening tests are valid for 30 days prior to enrollment unless otherwise specified.
b.
Any time prior to enrollment
c.
Within 8 days prior to initiating study treatment unless otherwise noted


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d.
May be performed during screening evaluation; must be done within 30 days prior to treatment initiation.
e.
To be performed within 24 hours prior to initiating study treatment:
f.
Pre-dose unless otherwise noted. 
g.
Clinician Assessment only (only for Cycle 1)
h.
Higher-Risk (HR) MDS Cohorts only, to initiate PO DNMTi on D2 (+/- 1 day per PI or LAI discretion), 
and continue daily dosing through D6 of each cycle
i.
PK sampling Cycle 1(day 1 and day 15) and cycle 2 (day 1 only) for Phase I participants only-See section 
5.1.3.1 for PK blood draw details. PD sampling for Phase I participants only - (baseline, C1D2, C1D15, 
C2D1, C2D2, C2D15, C3D1, C4D1 - see section 5.1.3.2 for blood draw details
j.
See section 5.1: bone marrow biopsy and aspiration required at screening/baseline, Phase I post cycle 
1(C1D28 +/- 3 days) and Phase II post cycle 2 (C2D28 +/- 3 days) and post cycle 6 (C6D28 +/- 3days); and 
if needed clinically in the setting of aplasia or concern for disease progression.  All other are optional and 
per PI discretion. 
k.
Will be done 30 ± 7days from the end of the last study cycle.
l.
Follow up will occur via phone call every 3 months (+/- 1 month) for first 24 months, then every 6 months 
(+/- 3 months)up to 5 years post enrollment. . Outside medical records will be requested along with the 
phone call for the first follow-up visit only. 
m.
Within 7 days
n.
See section 2.2.2, 2.4, and 3.4 for detailed lab collection instructions. For Cycle 1, patients will undergo 
weekly lab monitoring with CBC/diff, and chemistry (see section 3.4) on days 8 and 22.
o.
Weight only 
p.
Rockwood/CFS and MDS-CI to be completed at baseline only; EORTC-QLQC and Psychosocial 
assessment will be completed per section 3.5.3. Questionnaires required only in English speaking 
participants.
q.
See Safety monitoring guidelines during infusion (Section 3.2.1.4.1)
r.
Response assessment Phase I post cycle 1 and as clinically indicated and Phase 2 post cycle 2, post cycle 6, 
and as clinically indicated.
s.
Only at first follow up time point; See section 6.1
t.
See Section 3.2.1.4.1 for details on frequency of vital sign monitoring during first infusion of BMS-
986253. Vital signs required for D2 and D16 of Cycle 1 only.
* CFS: Clinical Frailty Scale; MDC-CI: MDS-Specific Comorbidity Index; EORTC-QLQC:  European 
Organization for Research and Treatment of Cancer (EORTC) quality of life questionnaire (QLQ)


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3.7
COST AND COMPENSATION 
3.7.1
Costs
NIH does not bill health insurance companies or participants for any research or related clinical 
care that participants receive at the NIH Clinical Center.  If some tests and procedures are 
performed outside the NIH Clinical Center, participants may have to pay for these costs.    
3.7.2
Compensation
Participants will not be compensated on this study.
3.7.3
Reimbursement 
The NCI will cover the costs of some expenses associated with protocol participation.  Some of 
these costs may be paid directly by the NIH and some may be reimbursed to the 
participant/guardian as appropriate.  The amount and form of these payments are determined by 
the NCI Travel and Lodging Reimbursement Policy.   
3.8
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA
Prior to removal from protocol therapy, effort must be made to have all subjects complete a 
safety visit approximately 100 days after the last dose of study therapy.
3.8.1
 Criteria for removal from protocol therapy
•
Progressive disease
•
Participant requests to be withdrawn from active therapy
•
Unacceptable toxicity as (section 3.3)
•
Lack of clinical response seen after 6 cycles of therapy (C7D1)
•
Completion of safety visit
•
Investigator discretion
•
Positive pregnancy test
3.8.2
Off-Study Criteria
•
Participant requests to be withdrawn from study
•
Death
•
Screen failure
•
Permanent loss of capacity to consent 
•
Completion of protocol-driven follow-up
•
Lost to follow-up
•
Investigator discretion
3.8.3
. Lost to Follow-up
A participant will be considered lost to follow-up if he or she fails to return for 3 scheduled visits 
and is unable to be contacted by the study site staff.
The following actions must be taken if a participant fails to return to the clinic for a required 
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•      The site will attempt to contact the participant and reschedule the missed visit within 30 
days and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain if the participant wishes to and/or should continue in the study.
•      Before a participant is deemed lost to follow-up, the investigator or designee will make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, 
if necessary, an IRB approved certified letter to the participant’s last known mailing 
address or local equivalent methods). These contact attempts should be documented in 
the participant’s medical record or study file.
•      Should the participant continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up.
4
CONCOMITANT MEDICATIONS/MEASURES
4.1
ALLOWED CONCOMITANT MEDICATIONS/SUPPORTIVE MEASURES: 
4.1.1
Antimicrobial Prophylaxis
•
Per standard of care supportive measures for participants with MDS, standard antimicrobial 
prophylaxis will be considered for neutropenic participants who exhibit ANC <1000 for ≥7 
days prior to study enrollment, either initiation of continuation of prior supportive therapy, 
including but not limited to:
o
antibacterial prophylaxis with levofloxacin 750 mg daily 
o
antiviral prophylaxis with acyclovir 800 mg twice daily
•
For participants with clinical indication administration of anti-Pneumocystis jiroveci 
pneumonia prophylactic therapy is allowed. 
•
For participants with history of fungal infection, or other clinical indication, continuation of 
antifungal prophylaxis will be allowed.
4.1.2
Hematologic support
•
Due to the hematologic abnormalities associated with MDS, management of hematologic 
toxicity in MDS participants will be at the discretion of the PI. 
•
Transfusions of red blood cells and platelets will be allowed per the appropriate participant-
specific hematologic parameters. 
•
Growth factor support with G-CSF, erythropoietin agonists, and/or thrombopoietin agonists 
will not be allowed while on trial.
4.1.3
Management of HLH:
Patients with HLH who have deteriorating organ function (eg, cardiovascular, pulmonary, renal, 
hepatic, or neurologic) should be managed immediately with stoppage of BMS-986253. 
Evidence of end-organ damage should prompt consideration of initiation of HLH-specific 
treatment.
Treatment options include:
1) Steroids:


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Dexamethasone is given intravenously or orally and tapered over the eight-week 
induction:
•
Weeks 1 and 2 – 10 mg/m2 daily
•
Weeks 3 and 4 – 5 mg/m2 daily
•
Weeks 5 and 6 – 2.5 mg/m2 daily
•
Week 7 – 1.25 mg/m2 daily
•
Week 8 – Taper dose to zero
2) HLH-94 Protocol: consists of eight weeks of induction therapy with etoposide (VP-16) 
and dexamethasone, with intrathecal therapy for those with CNS involvement.
•
Etoposide (VP-16) is given at a dose of 150 mg/m2 twice weekly for the first two 
weeks, and once weekly for weeks three through eight. [113] 
4.2
DRUG INTERACTIONS:
•
 There are no special warnings or precautions in term of drug interaction with BMS-986253. 
[95]
4.3
CONTRAINDICATED AGENTS:
•
No other antineoplastic, immunomodulatory, or immunosuppressive therapies, including 
corticosteroids (barring adrenal insufficiency supplementation dosing), should be given 
concomitantly while on trial. 
•
Growth factor support will not be allowed (see Section 4.1.2). 
5
CORRELATIVE STUDIES FOR RESEARCH
5.1
BIOSPECIMEN COLLECTION
5.1.1
Summary Table of Planned Correlative Tests/assays and Biospecimens Collection:
Test/assay
Volume 
(approx.)
Type of tubea
Collection 
Site/ Type of 
Specimen
Collection 
point 
Location of 
specimen 
analysis
Pharmacokinet
ics:
Antibody PK
5 mL
BPC 
Serum Free 
Simoa IL-8 
assay
5 mL
SST 
vacutainer 
tubes
-Serum 
samples 
should then be 
transferred to 
micronic tubes 
for shipping to 
bioanalytical 
lab.
- Peripheral 
blood
See section 
5.1.3 for PK 
and PD 
sampling 
schedules.
BPC 
Leukocyte 
Subsets:
3mL per tube
 
EDTA tube 
 
- PBMC
Baseline and 
D1 of each 
Fresh 
peripheral 
blood will be 
drawn, and 


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CD3, CD4, 
CD8, CD19,
CD4:CD8 
ratio, NK 
markers
(TBNK panel)
 
treatment 
cycle
lympho-
phenotyping 
will be 
performed 
using Clinical 
Center’s CLIA 
certified 
Immunophenot
yping (TBNK) 
panel and 
reported in the 
CRIS.
Next 
generation 
sequencing/ 
Myeloid 
molecular 
mutation 
panel:
TSO-500 
Panel
2 mL per tube
EDTA 
(lavender top) 
or ACD (yellow 
top)
 
- Bone marrow 
aspirate
(1) Baseline 
bone marrow
(2) Bone 
marrow 
C1D28 for 
Phase I
(3) Bone 
marrow 
C2D28 for 
Phase II
(3) Bone 
marrow 
C6D28 for 
Phase II
NCI 
Laboratory of 
Pathology
Flow 
Cytometry
 
3-5mL per 
tube
Sodium 
Heparin green 
top
 
- Bone marrow 
aspirate
Baseline and 
with every 
bone marrow 
evaluation per 
protocol
 
NCI, DLM
 
Clinical MDS 
FISH*
*only needed if 
cytogenetic 
analysis not 
possible
 
3 mL per tube 
if bone marrow
 
5 mL per tube 
if whole blood
 
Sodium 
Heparin green 
top
 
- Bone marrow 
aspirate
Baseline and 
with every 
bone marrow 
evaluation per 
protocol
Mayo send out 
test
 
Clinical 
Cytogenetics
 
6 mL
 
Sodium 
Heparin green 
top
 
- Bone Marrow 
Baseline and 
with every 
bone marrow 
evaluation per 
protocol
 
Mayo send out 
test
 


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Pathologic 
evaluation - 
Bone Marrow 
Biopsy 
 
 
Core biopsy
Per standard 
practice/slide 
preparation 
and inclusion 
of core biopsy
 
- Bone Marrow 
Biopsy
Baseline and 
with every 
bone marrow 
evaluation per 
protocol
 
DLM 
Peripheral 
Blood flow 
cytometry
2 mL 
EDTA tube
- Peripheral 
Blood
Baseline
If peripheral 
blood blasts 
present, will 
trend at end of 
each treatment 
cycle until 
clearance 
NCI, DLM
 
Research 
Sample
10 mL
EDTA tube
- Marrow 
aspirate
Baseline and 
with every 
bone marrow 
evaluation 
BPC 
Research: 
S100A8, 
S100A9
3 mL
EDTA tube
Bone marrow 
aspirate
Baseline and 
with every 
bone marrow 
evaluation 
1W-3888
Dr. Rosandra 
Kaplan 
laboratory
Research: 
Ribosome 
footprinting; 
Quantitative 
mass 
spectrometry
10 mL
EDTA tube
- Marrow 
aspirate
Baseline and 
with every 
bone marrow 
evaluation 
Dr. Daniel 
Larson 
laboratory
Blood
- Bone marrow 
aspirate
Research:
- Deep NGS 
Sequencing
- Singe cell 
sequencing 
-Somalogic
- Whole 
Genome 
Sequencing
12.5mL
2.5ml
2.5ml 
Paxgene, 10ml 
EDTA tube
2.5ml Paxgene 
tube
 
Blood 
(Baseline and 
with every 
bone marrow 
evaluation) 
Bone Marrow 
(Screening/ba
seline (Phase I 
and Phase II), 
C1D28 Phase 
I, C2D28 and 
C6D28 for 
Phase II)
BPC
a.
Please note that tubes and media may be substituted based on availability with the 
permission of the PI or laboratory investigator.


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5.1.2
Immune Monitoring
•
Cytokines analysis
o
Evaluation of serum levels of and changes in (pre- versus post-treatment) cytokines 
(IL-8, IFN-γ, IL-10, IL-12, IL-2, IL-4, TGF-ß, IL-6, CXCL1, IL-1α). 
•
Cytokines will be measured in peripheral blood samples as well as bone 
marrow. 
•
Cell subset analysis
o
Flow cytometry 
•
Monitoring of cellular subsets including lymphocyte subsets, MDSCs, NK 
cells, and Tregs
•
Flow cytometry will be conducted on both peripheral blood and bone 
marrow aspirate samples. 
o
TBNK peripheral blood panel
5.1.3
PK/PD Sampling Schedule (Phase I)
5.1.3.1
PK Sampling Schedule
5.1.3.1.1 Cycle 1 Day 1 (C1D1) and Day 15 (C1D15)
Time
Administration of
BMS-986253
PK
Before infusion, within 30 
minutes
X
Start of infusion
X
1 hour after end of infusion (+30
minutes/-5 minutes)
X
4 hours after end of infusion (+/-
45 minutes)
X
12 hours after end of infusion
(+/- 2 hours)
X
24 hours after infusion (+/- 4 
hours)
X
5.1.3.1.2 Cycle 2 Day 1 (C2D1) 
Time
Administration of 
BMS-986253
PK
Before infusion, within 30 
minutes
X
Start of infusion
X
At least 1 hour after end of
Infusion (between 1-2 hours after 
end of infusion)
X


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5.1.3.2
PD Sampling Schedule:
Free serum IL-8 levels will be assessed by ultrasensitive immunoassay based on Quanterix 
Simoa technology (lower limit of quantification = 0.86 pg/mL) by Myriad-RBM.
•
Baseline (pre-administration of BMS-986253,- 60 minutes)
•
C1D2 (24 hours after infusion, +/- 4 hours)
•
C1D15 (pre-administration of BMS-986253,- 60 minutes)
•
C2D1(pre-administration of BMS-986253,- 60 minutes)
•
C2D2(24 hours after infusion, +/- 4 hours)
•
C2D15(pre-administration of BMS-986253,- 60 minutes)
•
C3D1 (pre-administration of BMS-986253, - 60 minutes)
•
C4D1 (pre-administration of BMS-986253, - 60 minutes)
5.1.4
Disease Monitoring
•
Bone marrow evaluation for correlative studies will be done at each study time point 
when performed for clinical purposes including biopsy and aspirate: prior to initiation of 
treatment (baseline) and for interim assessment per the outlined study calendar (See 
Section 0).
o
Pathology review of aspirate and core biopsy with immunohistochemistry-defined 
immunophenotyping
o
Flow cytometric evaluation of cell subsets and immunophenotyping of 
myeloblasts, if present.
o
Cytogenetics
o
Fluorescence in situ hybridization (FISH)
o
Next generation sequencing/ molecular mutation analysis
•
None of the resulting information from correlative studies will be returned to the 
participant or used in clinical decision making unless performed in a CLIA-certified 
laboratory and ordered for a clinical indication.
•
Research samples of the bone marrow will also be collected and stored for further 
analyses, which may include (but not limited to):
o
Cytokine evaluation
o
Whole genome sequencing
o
Single cell sequencing
o
Ultra-deep NGS measurable residual disease mutational analysis
o
Quantitative mass spectrometry
o
Ribosome footprinting
o
Ex vivo culture and phenotypic analysis
•
All participants will receive a careful medical and clinical evaluation with particular 
focus on indicators of possible germline predisposition. Where appropriate, germline 
testing for mutations in genes predisposing to myeloid malignancy will be obtained. For 
positive cases, referral to clinical protocols at NIH and elsewhere will be made after 
discussion with individual participants about available treatment options.
5.2
SAMPLE STORAGE, TRACKING AND DISPOSITION
Samples will be ordered in CRIS and tracked through a Clinical Trial Data Management System. 


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Should a CRIS screen not be available, the CRIS downtime procedures will be followed. 
Samples will not be sent outside NIH without appropriate approvals and/or agreements, if 
required. 
5.2.1
Samples Managed by Dr. Larson Laboratory
Sample Data Collection
All samples sent to the Larson Laboratory will be barcoded, with data entered and stored in 
Labmatrix utilized by the BPC. This is a secure program, with access to Labmatrix limited to 
defined Larson lab personnel, who are issued individual user accounts. Installation of Labmatrix 
is limited to computers specified by Dr. Larson. These computers all have a password restricted 
login screen. 
Labmatrix creates a unique barcode ID for every sample and sample box, which cannot be traced 
back to participants without Labmatrix access. The data recorded for each sample includes the 
participant ID, name, trial name/protocol number, time drawn, cycle time point, dose, material 
type, as well as box and freezer location. Participant demographics associated with the clinical 
center participant number are provided in the system. For each sample, there are notes associated 
with the processing method (delay in sample processing, storage conditions on the ward, etc.).
Sample Storage and Destruction
Barcoded samples are stored in barcoded boxes in a locked freezer at either -20 or -80C 
according to stability requirements.  These freezers are located onsite in the Larson Lab in the 
Bethesda campus. Visitors to the laboratory are required to be accompanied by laboratory staff at 
all times. 
Access to stored clinical samples is restricted. Samples will be stored until requested by a 
researcher named on the protocol. All requests are monitored and tracked in Labmatrix. All 
researchers are required to sign a form stating that the samples are only to be used for research 
purposes associated with this trial (as per the IRB approved protocol) and that any unused 
samples must be returned to the BPC. It is the responsibility of the NCI Principal Investigator to 
ensure that the samples requested are being used in a manner consistent with IRB approval.
Following completion of this study, samples will remain in storage as detailed above. Access to 
these samples will only be granted following IRB approval of an additional protocol, granting 
the rights to use the material. 
If, at any time, a participant withdraws from the study and does not wish for their existing 
samples to be utilized, the individual must provide a written request. Following receipt of this 
request, the samples will be destroyed (or returned to the participant, if so requested). The PI will 
record any loss or unanticipated destruction of samples as a deviation. Reporting will be per the 
requirements of section 7.2.
Sample barcodes are linked to participant demographics and limited clinical information. This 
information will only be provided to investigators listed on this protocol, via registered use of the 
Labmatrix. It is critical that the sample remains linked to participant information such as race, 
age, dates of diagnosis and death, and histological information about the tumor, in order to 
correlate genotype with these variables.


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5.2.2
Samples Managed by Dr. Figg’s Blood Processing Core (BPC)
Blood and Bone Marrow Collection
Please e-mail NCIBloodcore@mail.nih.gov at least 24 hours before transporting samples (the 
Friday before is preferred).
For sample pickup, page 102-11964.
For immediate help, call 240-760-6180 (main blood processing core number) or, if no answer, 
240-760-6190 (main clinical pharmacology lab number).
For questions regarding sample processing, contact NCIBloodcore@mail.nih.gov
The samples will be processed, barcoded, and stored in Dr. Figg’s lab until requested by the 
investigator.
See Appendix E for processing instructions.
Sample Data Collection
All samples sent to the Blood Processing Core (BPC) will be barcoded, with data entered and 
stored in Labmatrix utilized by the BPC. This is a secure program, with access to Labmatrix 
limited to defined Figg lab personnel, who are issued individual user accounts. Installation of 
Labmatrix is limited to computers specified by Dr. Figg. These computers all have a password 
restricted login screen. 
Labmatrix creates a unique barcode ID for every sample and sample box, which cannot be traced 
back to participants without Labmatrix access. The data recorded for each sample includes the 
participant ID, name, trial name/protocol number, time drawn, cycle time point, dose, material 
type, as well as box and freezer location. Participant demographics associated with the clinical 
center participant number are provided in the system. For each sample, there are notes associated 
with the processing method (delay in sample processing, storage conditions on the ward, etc.).
Sample Storage and Destruction
Barcoded samples are stored in barcoded boxes in a locked freezer at either -20 or -80C 
according to stability requirements.  These freezers are located onsite in the BPC and offsite at 
NCI Frederick Central Repository Services in Frederick, MD. Visitors to the laboratory are 
required to be accompanied by laboratory staff at all times. 
Access to stored clinical samples is restricted. Samples will be stored until requested by a 
researcher named on the protocol. All requests are monitored and tracked in Labmatrix. All 
researchers are required to sign a form stating that the samples are only to be used for research 
purposes associated with this trial (as per the IRB approved protocol) and that any unused 
samples must be returned to the BPC. It is the responsibility of the NCI Principal Investigator to 
ensure that the samples requested are being used in a manner consistent with IRB approval.
Following completion of this study, samples will remain in storage as detailed above. Access to 
these samples will only be granted following IRB approval of an additional protocol, granting 
the rights to use the material. 
If, at any time, a participant withdraws from the study and does not wish for their existing 
samples to be utilized, the individual must provide a written request. Following receipt of this 
request, the samples will be destroyed (or returned to the participant, if so requested).. The PI 


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will record any loss or unanticipated destruction of samples as a deviation. Reporting will be per 
the requirements of section 7.2.
Sample barcodes are linked to participant demographics and limited clinical information. This 
information will only be provided to investigators listed on this protocol, via registered use of the 
Labmatrix. It is critical that the sample remains linked to participant information such as race, 
age, dates of diagnosis and death, and histological information about the tumor, in order to 
correlate genotype with these variables.
5.3
SAMPLES FOR GENETIC/GENOMIC ANALYSIS
5.3.1
Description of the scope of genetic/genomic analysis
•
Myeloid mutation molecular analysis – Next Generation Sequencing (NGS):
o
Bone marrow aspirate and peripheral blood samples will be sent for NGS as 
discussed in clinical monitoring section above.
▪
These will detect mutations and report respective variable allele frequency 
which will help support whether the mutations are somatic versus 
germline. With any concern for germline mutation, further testing will be 
supported for confirmation. 
▪
As NGS analysis is for clinical purposes and is being performed by a 
CLIA-certified clinical laboratory, NGS results may be added to the 
medical record and returned to the participant to help inform future 
therapy.
•
Research whole genome sequencing, Single cell sequencing, Ultra-deep NGS measurable 
residual disease mutational analysis.
•
Genetic Biomarkers:
o
IL-8 is a stimulator of angiogenesis, which acts through the receptors CXCR1 and 
CXCR2, the latter being the endothelial receptor. The IL-8 -251T > A 
polymorphism increases plasma IL-8 levels by  increasing IL-8 production[114] 
[96] Single nucleotide polymorphisms (SNPs) the IL-8/CXCR1/CXCR2 genes 
could alter treatment response or outcome by affecting the IL-8 signaling 
pathway. 
o
This will be assessed via WGS studies, and correlation between these genetic 
variants and toxicity and clinical endpoints will be explored. 
•
Germline-predisposition to MDS evaluation:
o
All participants will receive a careful medical and clinical evaluation with 
particular focus on indicators of possible germline predisposition. Where 
appropriate, especially for participants diagnosed with MDS under the age of 40 
years or with a strong family history, germline testing for mutations in genes 
predisposing to myeloid malignancy will be obtained via skin biopsy and 
culturing of fibroblasts. 
o
For positive cases, referral to clinical protocols at NIH and elsewhere will be 
made after discussion with individual participants about available treatment 
options.


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5.3.2
Description of how privacy and confidentiality of medical information/biological 
specimens will be maximized
NGS analysis will be both for clinical and research purposes. Results of NGS testing performed 
by a CLIA-certified clinical laboratory will be added to the medical record and returned to the 
participant to help inform future therapy. Research sequencing results will not be returned to 
participants, unless a potentially actionable clinically actionable gene variant is identified (see 
5.3.3). If a germline mutation is found upon further testing, participant will be referred to genetic 
counseling. PHI will be linked to the sample as this is an important part of disease management 
and prognostication and is standard. PHI will not be released to third parties. Research 
sequencing will be uploaded to public databases in compliance with NIH genomic data sharing 
policies.
5.3.3
Management of Results
Subjects will be contacted if a clinically actionable gene variant is discovered. Clinically 
actionable findings for the purpose of this study are defined as disorders appearing in the 
American College of Medical Genetics and Genomics recommendations for the return of 
incidental findings that is current at the time of primary analysis. (A list of current guidelines is 
maintained on the CCR intranet: 
https://ccrod.cancer.gov/confluence/display/CCRCRO/Incidental+Findings+Lists). Subjects 
will be contacted at this time with a request to provide a sample to be sent to a CLIA certified 
laboratory. If the research findings are verified in the CLIA certified lab, the subject will be 
offered the opportunity to come to NIH (at our expense) to have genetic education and 
counseling to explain this result. If the subject does not want to come to NIH, a referral to a 
local genetic healthcare provider will be provided (at their expense).
This is the only time during the course of the study that incidental findings will be returned. No 
interrogations regarding clinically actionable findings will be made after the primary analysis.
6
DATA COLLECTION AND EVALUATION 
6.1
DATA COLLECTION
The PI will be responsible for overseeing entry of data into a 21 CFR Part 11-compliant data 
capture system provided by the NCI CCR and ensuring data accuracy, consistency and 
timeliness. The principal investigator, associate investigators/research nurses and/or a contracted 
data manager will assist with the data management efforts. Primary and final analyzed data will 
have identifiers so that research data can be attributed to an individual human subject participant.
All adverse events, including clinically significant abnormal findings on laboratory evaluations, 
regardless of severity, will be followed until return to baseline or stabilization of event. 
Document AEs from the first study intervention, study day 1, through study day 100 after the 
subject received the last product administration, except for Grade 1 AEs, which will be collected 
and recorded for first 30 days on study only. After 100 days, only adverse events which are 
serious and related to the study investigational agent need to be recorded. 
An abnormal laboratory value will be recorded in the database as an AE only if the laboratory 
abnormality is characterized by any of the following:


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•
Results in discontinuation from the study
•
Is associated with clinical signs or symptoms 
•
Requires treatment or any other therapeutic intervention
•
Is associated with death or another serious adverse event, including hospitalization. 
•
Is judged by the Investigator to be of significant clinical impact
•
If any abnormal laboratory result is considered clinically significant, the investigator will 
provide details about the action taken with respect to the test drug and about the 
participant’s outcome.
The PI evaluation of each AE not captured in the clinical database determining that it meets the 
criteria above will be documented in the source documents.
End of study procedures: Data will be stored according to HHS, FDA regulations, and NIH 
Intramural Records Retention Schedule as applicable. 
Loss or destruction of data: Should we become aware that a major breach in our plan to protect 
subject confidentiality and trial data has occurred, this will be reported expeditiously per 
requirements in section 7.2.1. 
6.2
DATA SHARING PLANS
6.2.1
Human Data Sharing Plan
What data will be shared?
I will share human data generated in this research for future research as follows:
_x__ Coded, linked data in an NIH-funded or approved public repository.
_x__ Coded, linked data in BTRIS (automatic for activities in the Clinical Center)
_x__ Identified or coded, linked data with approved outside collaborators under appropriate 
agreements.
How and where will the data be shared? 
Data will be shared through:
__x_ An NIH-funded or approved public repository. Insert name or names: CCR BPC Figg lab.
__x_ BTRIS (automatic for activities in the Clinical Center)
__x_ Approved outside collaborators under appropriate individual agreements.
__x_ Publication and/or public presentations.
When will the data be shared? 
_x__ Before publication.
_x__ At the time of publication or shortly thereafter.


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6.2.2
Genomic Data Sharing Plan
Unlinked genomic data will be deposited in public genomic databases in compliance with the 
NIH Genomic Data Sharing Policy. 
6.3
RESPONSE CRITERIA
In addition to a baseline bone marrow biopsy, bone marrow biopsy samples from the 
participant’s previous biopsy procedures will be requested from outside institutions: a formalin-
fixed paraffin-embedded (FFPE) block or 10 unstained slides from initial MDS diagnosis, and an 
FFPE block from the most recent MDS biopsy prior to the participant arriving at NCI. These 
archival samples will be used to reconfirm the MDS diagnosis by NIH pathology department.
Participants will be assessed for response by standard response criteria for MDS.[85] For the 
purposes of this study, participants will be re-evaluated for response after each cycle by CBC 
with differential to assess for improvement in cytopenias and by protocol-defined time points for 
bone marrow evaluation. If results from interim bone marrow assessment demonstrate 
progression of disease (as defined by an increase in the number of malignant cells or blasts when 
compared to pre-treatment bone marrow examination or worsening cytopenias by amounts as 
defined below in section 6.3.1), the subject will be taken off study.
Participants with ECOG performance status if 0-2 who fail to achieve a CR but have achieved a 
PR, SD, or hematologic improvement will be eligible for receive additional therapy if no other 
contraindications to further treatment.
6.3.1
Response Criteria
The table below shows the 2006 International Working Group response criteria for altering the 
natural history of MDS,[115] with modified definitions for HI-E, HI-P, and HI-N in the 
suggested 2018 International Working Group response criteria.[85]
 
Category
Response criteria
(responses must last at least 4 weeks)
Complete remission
•      Bone marrow: ≤5% myeloblasts with normal maturation of 
all cell lines*
•      Persistent dysplasia will be noted*
•      Peripheral blood†
•
 Hgb ≥11 g/dL
•
Platelets ≥100 X 109/L
•
Neutrophils ≥1.0 X 109/L
•
Blasts 0%
Partial remission
All CR criteria if abnormal before treatment except:
•      Bone marrow blasts decreased by >50% over pretreatment 
but still >5%
•      Cellularity and morphology not relevant
Marrow CR
•      Bone marrow: ≤5% myeloblasts and decrease by ≥50% 
over pretreatment


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•      Peripheral blood: if HI responses, they will be noted in 
addition to marrow CR
Stable disease
Failure to achieve at least PR, but no evidence of progression 
for >8 wks
Failure
Death during treatment or disease progression characterized 
by worsening of cytopenias, increase in percentage of bone 
marrow blasts, or progression to more advanced MDS FAB 
subtype than pre-treatment
Relapse after CR or PR
At least 1 of the following:
•      Return to pre-treatment bone marrow blast percentage
•      Decrement of >50% from maximum remission/response 
levels in granulocytes or platelets
•      Reduction in Hgb concentration by >1.5 g/dL or 
transfusion dependence
Cytogenetic response
Complete
•      Disappearance of the chromosomal abnormality without 
appearance of new ones
Partial
•      At least 50% reduction of the chromosomal abnormality
Disease progression
For participants with:
•      Less than 5% blasts: ≥50% increase in blasts to >5% blasts
•      5%-10% blasts: ≥50% increase to 10% blasts
•      10%-20% blasts: ≥50% increase to >20% blasts
•      20%-30% blasts: ≥50% increase to >30% blasts
Any of the following:
•      At least 50% decrement from maximum 
remission/response in granulocytes or platelets
•      Reduction in Hgb by ≥2 g/dL
•      Transfusion dependence
Survival
Endpoints:
•      Overall: death from any cause
•      Event free: failure or death from any cause
•      PFS: disease progression or death from MDS
•      DFS: time to relapse
•      Cause-specific death: death related to MDS
MDS, myelodysplastic syndromes; Hgb, hemoglobin; CR, complete remission; HI, hematologic improvement; PR, partial
remission; FAB, French-American-British; AML, acute myeloid leukemia; PFS, progression-free survival; DFS, disease-free
survival.
To convert hemoglobin from grams per deciliter to grams per liter, multiply grams per deciliter by 10.
*Dysplastic changes should consider the normal range of dysplastic changes.
†In some circumstances, protocol therapy may require the initiation of further treatment (eg, consolidation, maintenance) before
the 4-week period. Such participants can be included in the response category into which they fit at the time the therapy is started.
Transient cytopenias during repeated chemotherapy courses should not be considered as interrupting durability of response, as
long as they recover to the improved counts of the previous course.
 
Hematologic Improvement


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Category
Participant pre-trial 
baseline
Response criteria
 
No Transfusion 
Dependence at 
baseline (0 RBC 
transfusions in 16 
weeks)
At least 2 consecutive Hgb measurements 
>1.5 g/dL for a period of minimum 8 weeks in 
an observation period of 16 to 24 weeks 
compared with the lowest mean of 2 Hgb 
measurements (apart from any transfusion) 
within 16 weeks before treatment onset; only 
a response duration of at least 16 weeks, 
however, is considered clinically meaningful
Low Transfusion 
Dependence at 
baseline (3-7 RBC 
transfusions in 16 
weeks in at least 2 
transfusion episodes, 
maximum 3 in 8 
weeks)
Transfusion independence, defined by the 
absence of any transfusions for at least 8 
weeks in an observation period of 16-24 
weeks with the same transfusion policy 
compared with 16 weeks prior to treatment; 
only a response duration of at least 16 weeks, 
however, is considered clinically meaningful
Major 
response
Transfusion independence, 
defined by the absence of any 
transfusions over a period of 
minimum 8 weeks in an 
observation period of 16-24 
weeks with the same transfusion 
policy compared with 16 weeks 
prior to treatment; only a response 
duration of at least 16 weeks, 
however, is considered clinically 
meaningful
Erythroid response 
(HI-E)
High Transfusion 
Dependence at 
baseline (>8 RBC 
transfusions in 16 
weeks, > 4 
transfusion episodes 
in 8 weeks)
Minor 
response
Transfusion independence, 
defined by the absence of any 
transfusions over a period of 
minimum 8 weeks in an 
observation period of 16-24 
weeks with the same transfusion 
policy compared with 16 weeks 
prior to treatment; only a response 
duration of at least 16 weeks, 
however, is considered clinically 
meaningful
Platelet response 
(HI-P)
Pre-treatment PLT 
<100 x 109/L
•      Absolute increase of 30 x 109/L for 
participants starting with >20 x 109/L 
PLTs
or


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•      Increase from <20 x 109/L to >20 x 109/L 
and by at least 100%
In addition:
•      In addition, evolution of bleeding 
symptoms is to be taken into account
•      Increments of platelets also for participants 
with a pre-treatment PLT count of >100 x 
109 are to be reported
Neutrophil response 
(HI-N)
 
Pre-treatment ANC 
<1.0 x 109/L
•      At least 100% increase and an absolute 
increase >0.5 x 109/L
•      Increments of neutrophils also for 
participants with a pre-treatment ANC of 
>1.0 x 109/L are to be reported
6.4
TOXICITY CRITERIA
The following adverse event management guidelines are intended to ensure the safety of each 
participant while on the study.  The descriptions and grading scales found in the revised NCI 
Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for AE 
reporting.  All appropriate treatment areas should have access to a copy of the CTCAE version 
5.0.  A copy of the CTCAE version 5.0 can be downloaded from the CTEP web site 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm).  
7
NIH REPORTING REQUIREMENTS / DATA AND SAFETY MONITORING PLAN
7.1
DEFINITIONS
Please refer to definitions provided in Policy 801: Reporting Research Events found at: 
https://irbo.nih.gov/confluence/pages/viewpage.action?pageId=36241835#Policies&Guidance-
800Series-ComplianceandResearchEventReportingRequirements.
7.2
OHSRP OFFICE OF COMPLIANCE AND TRAINING / IRB REPORTING
7.2.1
Expedited Reporting 
Please refer to the reporting requirements in Policy 801: Reporting Research Events and Policy 
802 Non-Compliance Human Subjects Research found at: 
https://irbo.nih.gov/confluence/pages/viewpage.action?pageId=36241835#Policies&Guidance-
800Series-ComplianceandResearchEventReportingRequirements. Note: Only IND Safety 
Reports that meet the definition of an unanticipated problem will need to be reported per these 
policies.
7.2.2
IRB Requirements for PI Reporting at Continuing Review
Please refer to the reporting requirements in Policy 801: Reporting Research Events found at: 
https://irbo.nih.gov/confluence/pages/viewpage.action?pageId=36241835#Policies&Guidance-
800Series-ComplianceandResearchEventReportingRequirements. 


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7.3
NCI CLINICAL DIRECTOR REPORTING 
Problems expeditiously reviewed by the OHSRP in the NIH eIRB system will also be reported to 
the NCI Clinical Director/designee; therefore, a separate submission for these reports is not 
necessary.
In addition to those reports, all deaths that occur within 30 days after receiving a research 
intervention should be reported via email unless they are due to progressive disease.  
To report these deaths, please send an email describing the circumstances of the death to 
NCICCRQA@mail.nih.gov within one business day of learning of the death.
7.4
NIH REQUIRED DATA AND SAFETY MONITORING PLAN
7.4.1
Principal Investigator/Research Team 
The clinical research team will meet on a regular weekly basis when participants are being 
actively treated on the trial to discuss each participant. Decisions about dose level enrollment and 
dose escalation if applicable will be made based on the toxicity data from prior participants. 
All data will be collected in a timely manner and reviewed by the principal investigator or a lead 
associate investigator. Events meeting requirements for expedited reporting as described in 
section 7.2.1 will be submitted within the appropriate timelines.  
The principal investigator will review adverse event and response data on each participant to 
ensure safety and data accuracy. The principal investigator will personally conduct or supervise 
the investigation and provide appropriate delegation of responsibilities to other members of the 
research staff. 
8
SPONSOR PROTOCOL/SAFETY REPORTING
8.1
DEFINITIONS
8.1.1
Adverse Event 
Any untoward medical occurrence in a participant or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have a causal relationship with this 
treatment. An adverse event (AE) can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of a medicinal (investigational) product, whether or not related to the medicinal 
(investigational) product. (ICH E6 (R2))
8.1.2
Serious Adverse Event (SAE)
An adverse event or suspected adverse reaction is considered serious if in the view of the 
investigator or the sponsor, it results in any of the following:
•
Death
•
A life-threatening adverse event (see section 8.1.3)
•
Inpatient hospitalization or prolongation of existing hospitalization 


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o
A hospitalization/admission that is pre-planned (i.e., elective or scheduled surgery 
arranged prior to the start of the study), a planned hospitalization for pre-existing 
condition, or a procedure required by the protocol, without a serious deterioration in 
health, is not considered a serious adverse event.
o
A hospitalization/admission that is solely driven by non-medical reasons (e.g., 
hospitalization for participant or subject convenience) is not considered a serious 
adverse event. 
o
Emergency room visits or stays in observation units that do not result in admission to 
the hospital would not be considered a serious adverse event. The reason for seeking 
medical care should be evaluated for meeting one of the other serious criteria.
•
Persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions
•
A congenital anomaly/birth defect
•
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the participant or subject and may 
require medical or surgical intervention to prevent one of the outcomes listed in this 
definition.
8.1.3
Life-threatening 
An adverse event or suspected adverse reaction is considered "life-threatening" if, in the view of 
either the investigator or sponsor, its occurrence places the participant or subject at immediate 
risk of death. It does not include an adverse event or suspected adverse reaction that, had it 
occurred in a more severe form, might have caused death. (21CFR312.32)
8.1.4
Severity
The severity of each Adverse Event will be assessed utilizing the CTCAE version 5.0.
8.1.5
Relationship to Study Product
All AEs will have their relationship to study product assessed using the terms:  related or not 
related.  
•
Related – There is a reasonable possibility that the study product caused the adverse 
event. Reasonable possibility means that there is evidence to suggest a causal relationship 
between the study product and the adverse event.
•
Not Related – There is not a reasonable possibility that the administration of the study 
product caused the event.
8.1.6
Adverse Events of Special Interest (AESI)
•
Potential Drug Induced Liver Injury (DILI), positive Hy’s Law, defined as:
o
AT (ALT or AST) elevation > 3 times upper limit of normal (ULN), AND


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o
Total bilirubin > 2 times ULN, without initial findings of cholestasis (elevated serum 
alkaline phosphatase), AND
o
No other immediately apparent possible causes of AT elevation and 
hyperbilirubinemia, including, but not limited to, viral hepatitis, pre-existing chronic 
or acute liver disease, or the administration of other drug(s) known to be hepatotoxic.
8.2
ASSESSMENT OF SAFETY EVENTS
AE information collected will include event description, date of onset, assessment of severity 
and relationship to study product and alternate etiology (if not related to study product), date of 
resolution of the event, seriousness and outcome. The assessment of severity and relationship to 
the study product will be done only by those with the training and authority to make a diagnosis 
and listed on the Form FDA 1572 as the site principal investigator or sub-investigator.  AEs 
occurring during the collection and reporting period will be documented appropriately regardless 
of relationship. AEs will be followed through resolution.
SAEs will be:
•
Assessed for severity and relationship to study product and alternate etiology (if not 
related to study product) by a licensed study physician listed on the Form FDA 1572 as 
the site principal investigator or sub-investigator.
•
Recorded on the appropriate SAE report form, the medical record and captured in the 
clinical database.
•
Followed through resolution by a licensed study physician listed on the Form FDA 1572 
as the site principal investigator or sub-investigator.
For timeframe of recording adverse events, please refer to section 6.1. All serious adverse events 
recorded from the time of first investigational product administration must be reported to the 
sponsor with the exception of any listed in section 8.4. 
8.3
REPORTING OF SERIOUS ADVERSE EVENTS
Any AE that meets protocol-defined serious criteria or meets the definition of Adverse Event of 
Special Interest that require expedited reporting must be submitted immediately (within 24 hours 
of awareness) to OSRO Safety using the CCR SAE report form.  Any exceptions to the 
expedited reporting requirements are found in section 8.4.
All SAE reporting must include the elements described in section 8.2.
SAE reports will be submitted to the Center for Cancer Research (CCR) at: 
OSROSafety@mail.nih.gov and to the CCR PI and study coordinator.  CCR SAE report form 
and instructions can be found at: 
https://ccrod.cancer.gov/confluence/display/CCRCRO/Forms+and+Instructions
Following the assessment of the SAE by OSRO, other supporting documentation of the event 
may be requested by the OSRO Safety and should be provided as soon as possible.


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8.4
WAIVER OF EXPEDITED REPORTING TO CCR 
As death/hospitalization due to disease progression are part of the study objectives in the phase 2 
portion of the study (PFS, OS, ORR), and captured as an endpoint in this study, they will not be 
reported in expedited manner to the sponsor during the phase II portion of the study. However, if 
there is evidence suggesting a causal relationship between the study drug and the event, report 
the event in an expedited manner according to section 8.3.
8.5
SAFETY REPORTING CRITERIA TO THE PHARMACEUTICAL COLLABORATOR
Note: The PI/study team designee will be required to handle all reporting noted below to the 
pharmaceutical collaborator.  
•
For Non-Serious AEs:
o
Adverse Events that are routinely collected according to GCP shall be submitted 
to BMS every three (3) months by the last working day of the third month.  
o
The collection of non-serious AE information should begin following the 
subject’s study drug administration. All non-serious adverse events (not only 
those deemed to be treatment-related) should be collected continuously during the 
treatment period and for a minimum of 100 days following the last dose of study 
treatment, except for Grade 1 AEs, which will be collected and recorded for first 
30 days on study only. 
o
Non-serious AEs should be followed to resolution or stabilization or reported as 
SAEs if they become serious. Follow-up is also required for non-serious AEs that 
cause interruption or discontinuation of study drug and for those present at the 
end of study treatment as appropriate. 
•
For Serious Adverse Events (SAEs):
o
All SAEs that occur following the subject’s study drug administration through 
(100) days of discontinuation of dosing must be reported to BMS Worldwide 
Safety, whether related or not related to study drug. 
o
An SAE report should be completed for any event where doubt exists regarding 
its seriousness
o
If the investigator believes that an SAE is not related to study drug, but is 
potentially related to the conditions of the study (such as withdrawal of previous 
therapy or a complication of a study procedure), the relationship should be 
specified in the narrative section of the SAE Report Form.
o
An appropriate SAE form (e.g.  ex-US = CIOMS form or USA = Medwatch 
form) should be used to report SAEs to BMS.   Note:  Please include the BMS 
Protocol number on the SAE form or on the cover sheet with the SAE form 
transmission.  
o
For studies with long-term follow-up periods in which safety data are being 
reported, include the timing of SAE collection. 
o
The Sponsor will reconcile the clinical database AE cases (case level only) 
transmitted to BMS Global Pharmacovigilance (Worldwide.Safety@bms.com).
o
The Investigator will request from BMS GPV&E, aepbusinessprocess@bms.com 
the SAE reconciliation report and include the BMS protocol number every 3 
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o
GPV&E will send the investigator the report to verify and confirm all SAEs have 
been transmitted to BMS GPV&E.
▪
The data elements listed on the GPV&E reconciliation report will be used 
for case identification purposes. If the Investigator determines a case was 
not transmitted to BMS GPV&E, the case should be sent immediately to 
BMS (Worldwide.Safety@bms.com).
o
In addition to the Sponsor Investigator’s responsibility to report events to their 
local HA, suspected serious adverse reactions (whether expected or unexpected) 
shall be reported by BMS to the relevant competent health authorities in all 
concerned countries according to local regulations (either as expedited and/or in 
aggregate reports).
o
In accordance with local regulations, BMS will notify sponsor investigators of all 
reported SAEs that are suspected (related to the investigational product) and 
unexpected (ie, not previously described in the IB). An event meeting these 
criteria is termed a Suspected, Unexpected Serious Adverse Reaction (SUSAR). 
Sponsor investigator notification of these events will be in the form of either a 
SUSAR Report or a Semi-Annual SUSAR Report. 
o
Other important findings which may be reported by BMS as an Expedited Safety 
Report (ESR) include: increased frequency of a clinically significant expected 
SAE, an SAE considered associated with study procedures that could modify the 
conduct of the study, lack of efficacy that poses significant hazard to study 
subjects, clinically significant safety finding from a nonclinical study, , or sponsor 
or BMS decision to end or temporarily halt a clinical study for safety reasons.
▪
Upon receiving an ESR from BMS, the investigator must review and 
retain the ESR with the IB. Where required by local regulations or when 
there is a central IRB/IEC for the study, the sponsor will submit the ESR 
to the appropriate IRB/IEC. The investigator and IRB/IEC will determine 
if the informed consent requires revision. The investigator should also 
comply with the IRB/IEC procedures for reporting any other safety 
information. 
SAEs, whether related or not related to study drug, and pregnancies must be reported to BMS 
within 24 hours \ 1 Business Day of becoming aware of the event. SAEs must be recorded on 
either CIOMS, MedWatch, or approved site SAE form.  
•
Pregnancies must be reported and submitted to BMS.  BMS will perform due diligence 
follow-up using the BMS Pregnancy Form which the investigator must complete. 
o
SAE Email Address:  Worldwide.Safety@BMS.com
o
SAE Facsimile Number:  +1 609-818-3804
•
If only limited information is initially available, follow-up reports are required. (Note: 
Follow-up SAE reports should include the same investigator term(s) initially reported.)
•
If an ongoing SAE changes in its intensity or relationship to study drug or if new 
information becomes available, a follow-up SAE report should be sent within 24 hours \ 
1 Business Day to BMS using the same procedure used for transmitting the initial SAE 
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BMS Safety Reporting.  Study Team shall report to BMS all Serious Adverse Events. Reports 
shall be provided in accordance with applicable federal laws. Study Team shall comply with 
BMS’s reasonable follow-up requests.
•
Case-level Reconciliation. 
o
Study Team shall perform case-level reconciliation as instructed by BMS to 
confirm BMS’s receipt of all reports from Study Team.  Study Team shall initiate 
reconciliation activity by e-mailing AEPBUSINESSPROCESS@BMS.com to 
request a reconciliation report. 
o
Such reconciliation shall be performed quarterly, unless otherwise agreed by 
BMS in writing. 
•
Study Team shall comply with all applicable federal laws, including those related to data 
privacy, when undertaking these safety reporting-related obligations.
•
Study Team shall promptly report to BMS all Product Quality Complaints (as defined at 
http://www.globalbmsmedinfo.com) associated with a BMS product no later than one (1) 
business day or three (3) calendar days, whichever is earlier after becoming aware of the 
event.  Study Team shall report the information to IMPQualityComplaints@bms.com.
8.6
REPORTING PREGNANCY 
All required pregnancy reports/follow-up to OSRO will be submitted to: 
OSROSafety@mail.nih.gov and to the CCR PI and study coordinator.  Forms and instructions 
can be found here: 
https://ccrod.cancer.gov/confluence/display/CCRCRO/Forms+and+Instructions 
8.6.1
Maternal exposure
If a participant becomes pregnant during the course of the study, the study treatment should be 
discontinued immediately, and the pregnancy reported to the Sponsor no later than 24 hours of 
when the Investigator becomes aware of it. The Investigator should notify the Sponsor no later 
than 24 hours of when the outcome of the Pregnancy becomes known,
Pregnancy itself is not regarded as an SAE. However, congenital abnormalities or birth defects 
and spontaneous miscarriages that meet serious criteria (section 8.1.2) should be reported as 
SAEs. 
The outcome of all pregnancies should be followed up and documented.
If, following initiation of the investigational product, it is subsequently discovered that a study 
participant is pregnant or may have been pregnant at the time of investigational product 
exposure, including during at least 5 half-lives after product administration, the investigational 
product will be permanently discontinued in an appropriate manner (eg, dose tapering if 
necessary for participant). 
The investigator must immediately notify Worldwide.Safety@bms.com of this event and 
complete one of the following forms within 24 hours of awareness of the event via either the 
CIOMS, MedWatch or appropriate Pregnancy Surveillance Form in accordance with SAE 
reporting procedures. 
Protocol-required procedures for study discontinuation and follow-up must be performed on the 
participant.


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8.6.2
Paternal exposure
Male participants should refrain from fathering a child or donating sperm during the study and 
for 6 months after the last dose of BMS-986253 or DNMTi.
Pregnancy of the participant’s partner is not considered to be an AE. However, the outcome of 
all pregnancies  occurring from the date of the first dose until 6 months after the last dose should, 
if possible, be followed up and documented. Pregnant partners may be offered the opportunity to 
participate in an institutional pregnancy registry protocol (e.g., the NIH IRP pregnancy registry 
study) to provide data about the outcome of the pregnancy for safety reporting purposes.
8.7
REGULATORY REPORTING FOR STUDIES CONDUCTED UNDER CCR-SPONSORED IND
Following notification from the investigator, CCR, the IND sponsor, will report any suspected 
adverse reaction that is both serious and unexpected.  CCR will report an AE as a suspected 
adverse reaction only if there is evidence to suggest a causal relationship between the study 
product and the adverse event.  CCR will notify FDA and all participating investigators (i.e., all 
investigators to whom the sponsor is providing drug under its INDs or under any investigator’s 
IND) in an IND safety report of potential serious risks from clinical trials or any other source, as 
soon as possible, in accordance to 21 CFR Part 312.32. 
All serious events will be reported to the FDA at least annually in a summary format.
8.8
SPONSOR PROTOCOL DEVIATION REPORTING
A Protocol Deviation is defined as any non-compliance with the clinical trial Protocol, Manual of 
Operational Procedures (MOP) and other Sponsor approved study related documents, GCP, or 
protocol-specific procedural requirements on the part of the participant, the Investigator, or the 
study site staff inclusive of site personnel performing procedures or providing services in support 
of the clinical trial.
It is the responsibility of the study Staff to document any protocol deviation identified by the Staff 
or the site Monitor in the CCR Protocol Deviation Tracking System (PDTS) online application. 
The entries into the PDTS online application should be timely, complete, and maintained per CCR 
PDTS user requirements.  
In addition, any deviation to the protocol should be documented in the participant’s source 
records and reported to the reviewing IRB per their guidelines. OSRO required protocol 
deviation reporting is consistent with E6(R2) GCP: Integrated Addendum to ICH E6(R1): 4.5 
Compliance with Protocol; 5.18.3 (a), and 5.20 Noncompliance; and ICH E3 16.2.2 Protocol 
deviations. 
9
CLINICAL MONITORING 
Clinical site monitoring is conducted to ensure:
•
that the rights of the participants are protected; 
•
that the study is implemented per the approved protocol, Good Clinical Practice and 
standard operating procedures; and 
•
the quality and integrity of study data and data collection methods are maintained.  
Monitoring for this study will be performed by NCI CCR Office of Sponsor and Regulatory 
Oversight (OSRO) Sponsor and Regulatory Oversight Support (SROS) Services contractor. 


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Clinical site monitoring activities will be based on OSRO standards, FDA Guidance E6(R2) 
Good Clinical Practice: Integrated Addendum to ICH E6(R1) March 2018, and applicable 
regulatory requirements.
Details of clinical site monitoring will be documented in a Clinical Monitoring Plan (CMP) 
developed by OSRO. CMPs will be protocol-specific, risk-based and tailored to address human 
subject protections and integrity of the study data. OSRO will determine the intensity and 
frequency of monitoring based on several factors, including study type, phase, risk, complexity, 
expected enrollment rate, and any unique attributes of the study and the site. The Sponsor will 
conduct a periodic review of the CMP to confirm the plan's continued appropriateness. A change 
to the protocol, significant or pervasive non-compliance with GCP, or the protocol may trigger 
CMP updates.
OSRO SROS Monitoring visits and related activities will be conducted throughout the life cycle 
of each protocol. The first activity is before the study starts to conduct a Site Assessment Visit 
(SAV) (as warranted), followed by a Site Initiation Visit (SIV), Interim Monitoring Visit(s) 
(IMVs), and a study Close-Out Visit (COV).
Some monitoring activities may be performed remotely, while others will occur at the study site(s). 
Monitoring visit reports will describe visit activities, observations, and associated action items or 
follow-up required for resolution of any issues, discrepancies, or deviations. Monitoring reports 
will be distributed to the study PI, NCI CCR QA, CCR Protocol Support Office, coordinating 
center (if applicable), and the Sponsor regulatory file.
The site Monitor will inform the study team of any deviations observed during monitoring visits. 
If unresolved, the Monitor will request that the site Staff enter the deviations in the CCR Protocol 
Deviation Tracking System (PDTS) for deviation reporting to the Sponsor and as applicable per 
institutional and IRB guidance.
10 STATISTICAL CONSIDERATIONS  
10.1 OBJECTIVES AND ENDPOINTS
OBJECTIVES
ENDPOINTS
JUSTIFICATION 
FOR ENDPOINTS
Primary
Phase I: To determine OBD for 
BMS-986253 and RP2D, separately 
by cohort.
-Incidence of AEs, SAEs
-AEs meeting protocol defined DLT 
criteria
-AEs leading to discontinuation, 
death, and laboratory abnormalities.
- OBD (RP2D) assessed during the 
first 30 days of treatment: 
- OBD will be the safest and lowest 
dose level showing optimal biological 
standard endpoint for 
phase I protocol, see 
Section 3.1.1
Due to this being a 
targeted therapy, will 
pursue OBD instead of 
MTD as primary 
endpoint. 


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OBJECTIVES
ENDPOINTS
JUSTIFICATION 
FOR ENDPOINTS
activity, defined as maximal 
suppression of serum free IL-8 
levels.*
*Maximal suppression of serum free 
IL-8 levels will be monitored for a 
goal of achieving IL-8 levels below 
the lower limit of detection of the 
assay in real time as outlined in 
Section 5.1.3.2 [ultrasensitive 
immunoassay based on Quanterix 
Simoa technology (lower limit of 
quantification = 0.86 pg/mL) by 
Myriad-RBM] 
Phase II: To determine efficacy as 
measured by overall response rate, 
separately by cohort.
-ORR per each cohort
-assessed from first cycle until time 
of disease relapse, disease 
progression, or death, whichever 
occurs first, assessed every 3-6 
months until 8 years.
Efficacy evaluation, 
standard for phase II 
protocol
Secondary
Phase 1:  To describe 
pharmacokinetic properties of 
BMS-986253 in MDS participants 
by cohort.
AUC, half-life, and steady state 
concentration
Assessed during the first 30 days of 
treatment
Pharmacokinetic 
studies to evaluates for 
adequate absorption of 
therapy and define 
half-life/AUC and 
other properties of the 
study drug 
Phase II:  To evaluate safety and 
secondary clinical outcomes of 
BMS-986253 in MDS participants 
by cohort.
-Safety, as measured by: Incidence of 
AEs, SAEs; and AEs leading to 
discontinuation, death, and laboratory 
abnormalities, assessed from first 
cycle until time of disease relapse, 
disease progression, or death, 
whichever occurs first, assessed every 
3-6 months
- Clinical outcomes including: overall 
improvement rate (OIR), cytogenetic 
Confirm safety and 
evaluate efficacy 
through long-term 
clinical outcomes


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OBJECTIVES
ENDPOINTS
JUSTIFICATION 
FOR ENDPOINTS
response rate, time to best response 
(CR, PR, marrow CR, or HI) , disease 
free survival (DFS: definition: time to 
relapse for participants who achieve 
CR), progression  free survival (PFS; 
definition: disease progression or 
death from MDS), leukemia free 
survival (LFS; definition: progression 
to AML or death from any cause), 
and overall survival (OS: definition: 
death from any cause); assessed every 
3-6 months
Exploratory
To evaluate changes in serum 
cytokine levels pre- and post-
treatment with BMS-986253.
To evaluate the cell composition in 
the peripheral blood and bone 
marrow microenvironment before 
and after treatment with BMS-
986253.
To evaluate changes in the 
transcriptome and proteome in 
response to treatment with BMS-
986253.
To determine the degree of bone 
marrow myeloid-derived 
suppressor cell (MDSC) 
infiltration.
To describe changes in genetic 
clonal diversity during treatment 
with BMS-986253 in combination 
with DNMTi.
Each of these will be evaluated using 
descriptive methods and reported as 
exploratory results. If any statistical 
tests are performed in these analyses, 
the results will be presented without 
adjustment for multiple comparisons 
but reported in the context of the 
number of tests performed. See 
section 5 for collection timepoints.
Evaluate mechanistic 
and immunologic 
effects of the study 
drug 


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OBJECTIVES
ENDPOINTS
JUSTIFICATION 
FOR ENDPOINTS
To assess cell-autonomous effects 
on the MDS clone by measuring 
biomarkers in the Akt pathway (i.e. 
pS743) in MDS blasts.
To evaluate cell-autonomous and 
microenvironment dependent 
activity of BMS-986253 using ex 
vivo culture of participant-derived 
hematopoietic stem and progenitor 
cells.
To 
assess 
quality 
of 
life 
improvement 
by 
participant 
reported 
outcomes 
using 
the 
EORTC QLQC30 score.
10.2 SAMPLE SIZE DETERMINATION
The trial will begin with a phase I dose escalation phase using a standard 3+3 design to 
determine OBD, separately for each cohort. With 3 dose levels per cohort (and dose level -1), 
and no more than 6 participants per dose level, up to 18 participants may be enrolled in phase I 
per cohort, total 36 maximum.
In phase I/II, there will be two cohorts:
1. “Higher-risk” MDS (HR-MDS) Cohort with R-IPSS ≥3.5: Intermediate and high-risk 
participants receiving combination treatment
2. “Lower-risk” MDS (LR-MDS) Cohort with R-IPSS <3.5: Lower intermediate and low-
risk participants receiving single agent anti-IL8 treatment.
Based on the literature, DNMTi previously untreated participants with intermediate and high-risk 
disease have clinical response rates of approximately 20-50%; thus, in view of heterogeneity of 
prior results a response rate of at least 40% in participants treated with combination therapy 
would be desirable. [75, 116] In participants with low-risk disease, response rates are likely to be 


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lower, and  expected to be less than 30% from monotherapy;[84, 91, 92] thus, also attaining a 
response rate of at least 30% with monotherapy would be considered desirable.
Participants enrolled during phase I who are treated at the OBD may be included in the first stage 
portion of the trial if they meet the same eligibility as the participants in the phase II portion.  
The two phase II cohorts will each have their own sample size determination:
•
In participants in the higher-risk HR-MDS cohort (with either intermediate or high-risk 
MDS), the trial will be conducted using a Simon optimal two-stage phase II trial design 
to rule out an unacceptably low response rate (CR+PR+mCR with HI) of 30% (p0=0.30) 
in favor of an improved response rate of 50% (p1=0.50) in order to determine if the 
combination will be able to potentially improve upon heterogeneous  20-50% response 
rates in participants who have received other agents. [75, 116] With alpha=0.10 
(probability of accepting a poor treatment=0.10) and beta=0.20 (probability of rejecting a 
good treatment=0.20), the first stage will enroll 15 evaluable participants, including the 6 
participants from the phase I dose escalation that reached OBD, and if 0 to 5 of the 15 has 
a response, then no further participants will be accrued.  If 6 or more of the first 15 
participants has a response, then accrual would continue until a total of 32 evaluable 
participants have been treated in that cohort. As it may take up to several   months to 
determine if a participant has experienced a response, a temporary pause in the accrual 
may be necessary to ensure that enrollment to the second stage is warranted. If there are 
only 6-12 participants with a response out of 32 participants, this would be an 
uninterestingly low response rate. If there were 13 or more of 32 (40.6%) who 
experienced a response, treatment in this cohort would be sufficiently interesting to 
warrant further study in later trials. Under the null hypothesis (30% response rate), the 
probability of early termination is 72.2%.
•
In participants with low-risk MDS, the trial will be conducted using a Simon optimal 
two-stage phase II trial design to rule out an unacceptably low response rate 
(CR+PR+mCR with HI) of 20% (p0=0.20) in favor of an improved response rate of 40% 
(p1=0.40) in order to determine if monotherapy with BMS-986253 will be able to 
improve upon an expected response rate below 30% in participants who have received 
other agents. [76, 83, 84] With alpha=0.10 (probability of accepting a poor 
treatment=0.10) and beta=0.20 (probability of rejecting a good treatment=0.20), the first 
stage will enroll 12 evaluable participants, including the 6 participants from the phase I 
dose escalation, that reached MTD, and if 0 to 2 of the 12 has a response, then no further 
participants will be accrued.  If 3 or more of the first 12 participants has a response, then 
accrual would continue until a total of 25 evaluable participants have been treated in that 
cohort. As it may take up to several months to determine if a participant has experienced 
a response, a temporary pause in the accrual may be necessary to ensure that enrollment 
to the second stage is warranted. If there are only 3-7 participants with a response out of 
25 participants, this would be an uninterestingly low response rate. If there were 8 or 
more of 25 (32.0%) who experienced a response, treatment in the appropriate cohort 
would be sufficiently interesting to warrant further study in later trials. Under the null 
hypothesis (20% response rate), the probability of early termination is 55.8%.
Secondary endpoints include progression free survival, overall survival, median survival, 
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the phase II cohorts.  Overall survival is considered an important endpoint in these participants 
and will be considered the most important secondary endpoint.
It is expected that up to 12-15 participants with MDS may be accrued per year. Thus, in order to 
accrue up to 18+18+32+25 = 93 participants, it is expected that 4-5 years may be required to 
accrue the total number of required evaluable participants. In order to allow for a small number 
of inevaluable participants and potentially large number of screen failures, the accrual ceiling 
will be set at 200 participants.
10.3 POPULATIONS FOR ANALYSES
10.3.1 Evaluable for toxicity
All participants will be evaluable for toxicity from the time of their first treatment with BMS-
986253.
10.3.2 Evaluable for objective response
Only those participants who have measurable disease present at baseline, have received at least 
one cycle of therapy with study drug, and have had their disease re-evaluated will be considered 
evaluable for response.  These participants will have their response classified according to the 
definitions stated below.  (Note:  Participants who exhibit objective disease progression prior to 
the end of cycle 1 will also be considered evaluable.)
10.4 STATISTICAL ANALYSES
10.4.1 General Approach
•
Participants in phase I will be evaluated for safety, reporting the toxicities noted per dose 
level. 
•
Participants in phase II will have their response rate reported along with a confidence 
interval.
10.4.2 Analysis of the Primary Endpoints
•
Participants enrolled in phase I will have the grades and types of toxicity reported at each 
dose level separately by cohort. The overall estimate of the fraction of participants who 
have a DLT at the OBD will be reported by cohort.
•
Participants evaluated in phase II will have the fraction with clinical responses reported 
separately by cohort, with a separate 95% confidence interval for each cohort.
10.4.3 Analysis of the Secondary Endpoint(s)
•
The secondary objectives for phase I are to describe pharmacokinetic properties of 
BMS-986253 in MDS participants and to evaluate safety and tolerability of BMS-
986253 in MDS participants. The AUC, half-life, and Css of BMS-986253 will be 
evaluated in participants, separately by dose level and cohort using descriptive 
statistics. 
•
The secondary objectives for phase II are:
•
(a) to evaluate the safety and tolerability of the agent as measured by the grades and 
types of toxicity noted for the agent at each dose level, separately by cohort; and,


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•
(b) to evaluate efficacy, as measured by clinical outcomes, including  OIR (CR + PR 
+ HI + marrow CR + SD), cytogenetic response rate, time to best response, disease 
free survival (DFS; definition: time to relapse for participants who achieve CR), 
progression  free survival (PFS; definition: disease progression or death from MDS), 
leukemia free survival (LFS; definition: progression to AML or death from any 
cause), and overall survival (OS; definition: death from any cause). 
o
OIR and cytogenic response rate will each be reported as a fraction, separately 
by cohort, along with a 95% confidence interval. Time to best response, DFS, 
PFS, LFS, and OS will be evaluated separately for each phase II cohort using 
the Kaplan-Meier method. In each case, the median time to event will be 
reported along with a 95% confidence interval for the median.
10.4.4 Safety Analyses
The safety and tolerability of the agent will be evaluated by reporting the grades and types of 
toxicity noted for the agent at each dose level.
Our goal toxicity rate is less than 20% and toxicity assessment will use Bayesian toxicity 
monitoring with maximum probability of DLT of 0.2, prior distribution (1,1), maximum patients 
32, minimum number of patients before stopping 6, cohort size 1, and posterior probability > 
80%. Using this approach, the study would be paused for review for toxicities in 2/6, 3/7, or 
4/11, 5/15, 6/20, 7/24, 8/28, or 9/32 patients. The same boundaries would apply to both the LR-
MDS and HR-MDS cohorts up to their respective enrollment goals.
10.4.5 Baseline Descriptive Statistics
Standard sample statistics will be provided for each cohort and overall.
10.4.6 Planned Interim Analyses
As indicated above in section 10.2, Participants in phase II will be evaluated after 15 or 12 
participants have been treated per cohort, an evaluation will be performed of the responses at that 
point to determine suitability to enroll the remaining participants. Specifically, the trial will 
proceed to the second stage if there is at least 1 of 6 responses in patients with MDS. With a 
safety evaluation through day 28 required for the interim analysis in each cohort, enrollment to 
the cohort will be halted to allow for an analysis by the study statistician. A brief memo will be 
created by the study statistician to document the number of responses in the first stage for each 
cohort and will be reviewed by the PI and study team. The memo will be provided to study 
sponsor prior to continuation of accrual. Also, if the required number of responses is observed 
before that time, the memo will be generated, reviewed and provided to the study sponsor at that 
point without a pause in accrual. Response rates will be calculated using the revised International 
Working Group (IWG) 2018 response criteria as described in the protocol.
10.4.7 Sub-Group Analyses
Results from phase II will be presented according to MDS-subgroup, disease risk category and 
genomic features.
10.4.8 Tabulation of individual Participant Data
None will be provided.


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10.4.9 Exploratory Analyses
The exploratory objectives and methods of analysis include:
•
To evaluate changes in serum cytokine levels pre- and post-treatment with BMS-986253; 
this will be a descriptive analysis and may be accompanied by Wilcoxon signed rank tests 
for phase II data, by cohort.
•
To evaluate the cell composition in the peripheral blood and bone marrow 
microenvironment before and after treatment with BMS-986253; this will be a 
descriptive analysis.
•
To determine the degree of myeloid-derived suppressor cell (MDSC) infiltration; this will 
be a descriptive analysis.
•
To describe changes in genetic clonal diversity during treatment with BMS-986253 in 
combination with DNMTi; this will be descriptive.
•
To assess cell-autonomous effects on the MDS clone by measuring biomarkers in the Akt 
pathway (i.e. pS743) in MDS blasts; this will be descriptive.
•
To assess quality of life improvement by participant reported outcomes using the EORTC 
QLQC30 score; this will be analyzed using standard methods for evaluating these 
outcomes.
All exploratory analyses will be performed with descriptive intent, largely done separately by 
cohort. In the cases in which a statistical test is performed, the tests will be done without formal 
adjustment for multiple comparisons, but in the context of the number of tests performed.[117]
11 COLLABORATIVE AGREEMENTS
11.1 COOPERATIVE RESEARCH AND DEVELOPMENT AGREEMENT (CRADA)
This study will be conducted under a Collaborative Research and Development Agreement 
(CRADA) with Bristol Myers Squibb (#03389).
12 HUMAN SUBJECTS PROTECTIONS 
12.1 RATIONALE FOR SUBJECT SELECTION
No subjects will be excluded from participation based on gender, race or ethnicity. The study 
will be open to all subjects who satisfy the inclusion criteria and provide an informed consent to 
the protocol.
12.2 PARTICIPATION OF CHILDREN
Children will not be eligible for participation in this study due to lack of adequate safety data in 
children. Biologic rationale and preclinical work were validated in adult population and would 
need reanalysis in children, where MDS may arise more so from inherited bone marrow failure 
syndromes than in adults and have a different pathophysiology. 
12.3 RISK/BENEFIT ASSESSMENT
12.3.1 Known Potential Risks
•
All known potential risks associated with BMS-986253 from prior experience in humans 
has been discussed in Section 14. No prior history of infusion reactions have been 


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reported in prior studies of this product. SAEs in prior trials (See Section 14 for toxicity 
data) have mostly been deemed not-treatment related, but of course there is an unknown 
element here which is why this is a phase I safety study and participants will be closely 
monitored for all AEs.
•
Other risks involved in the study include that of standard MDS procedures, including 
regular blood draws  and bone marrow evaluations. These are invasive procedures that 
carry with them the risk of infection, bleeding and damage to surrounding tissues/organs. 
Phlebotomy and bone marrow evaluations will be conducted by well-trained personnel 
who follow sterile techniques to minimize complications.
Due to the unknown effects of BMS-986253 on the fetus and infants, women of reproductive age 
will only be allowed to enroll if they commit to following a strict manner of contraception; 
Women who are breast-feeding will not be eligible for the trial. Men who are sexually active 
with women of childbearing age will also have to commit to strict contraceptive practices while 
on study. 
12.3.1.1 Procedure risks
12.3.1.1.1 Blood samples 
Side effects of repeated blood sampling depend in part on how the blood is drawn. If through an 
intravenous catheter, risks include contamination of the catheter which would result in a serious 
blood stream infection, requiring admission to the hospital and giving participants antibiotics 
through the vein; if blood is drawn through a needle into the skin, side-effects could include pain 
and bruising in the area where the blood was drawn. Other side-effects can include bruising, 
redness, discomfort or bleeding at the site of the needle stick, and possible lightheadedness, or 
rarely, fainting.  If too much blood is taken over a prolonged period, red blood cell count may 
drop (this is called “anemia”). As a precaution, red blood cell level will be checked, and iron 
treatments or a blood transfusion will be given if needed. Up to 50mL of blood may be collected 
at one time, no more than 300mL will be collected over an 8-week period.
12.3.1.1.2 Bone marrow aspiration/biopsy
The bone marrow aspiration and biopsy may cause pain, bruising, bleeding and infection.  
Soreness near the site may last for a couple of days after the procedure. Participants may have 
more pain, risk of bleeding and bruising if they complete both aspiration and biopsy rather than 
just the aspiration.  
12.3.1.1.3 Electrocardiogram
Other than possibly experiencing some minor skin irritation from the electrodes there are no 
anticipated risks related to complete the electrocardiogram and/or the echocardiogram.
12.3.1.1.4 Intravenous catheter
The risks of IV insertion include temporary pain and bleeding or bruising at the site where the IV 
enters the skin.  In placing the IV, there is a small chance of fluid leaking into the tissue 
surrounding the IV and infection, which may cause some swelling and discomfort. Rarely, the IV 
site may become infected, which might require treatment with antibiotics. 


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12.3.1.1.5 Questionnaires
Some of the questions in the questionnaire may be upsetting or make participants feel 
uncomfortable. Participants can skip any of the questions they do not want to answer or can stop 
at any time.
12.3.1.1.6 Risk of losing data 
This includes the risk that data obtained during this study, including data related to genotype, 
DNA sequencing, or risk for disease tendency or trait can be released to members of the public, 
insurers, employers, or law enforcement agencies. Although there are no plans to release results 
to the participants, family members, or health care providers, this risk will be included in the 
informed consent document.
12.3.1.1.7 Risk of receiving unwanted information
Anxiety and stress may arise as a result of the anticipation that unwanted information regarding 
disease-related DNA sequencing or disease tendencies, or misattributed paternity. Participants 
will be clearly informed that the data related to DNA sequencing and genetic analysis is coded, 
investigational and will not be shared with participants, family members, or health care 
providers.
12.3.2 Known Potential Benefits
Due to the significant preclinical and prior clinical experience with BMS-986253, this study 
hypothesis has strong evidence that BMS-986253 may have disease-modifying beneficial 
therapeutic activity in MDS. If this is confirmed via this trial, participants have the potential for 
immediate-benefits that include, improved cytopenias, less transfusion- and growth factor-
dependence, less complications of cytopenias such as infections and hemorrhagic complications. 
Transfusion independence also leads to improved quality of life. Long-range potential benefits, 
should our investigational agent confirm efficacy, include stability of MDS disease with 
improved quality of life and potential for less progression into AML, which is associated with 
significant morbidity and mortality. 
12.3.3 Assessment of Potential Risks and Benefits
Risks to participants were minimized in the study and involve no more than that expected from 
standard of care monitoring of MDS, which includes regular peripheral blood draws, transfusions 
and bone marrow evaluations. The potential disease modifying/therapeutic benefit of BMS-
986253 as an investigative agent outweighs the risks discussed, which are otherwise mostly 
standard procedures for participants with MDS. In terms of the rare risk of infusion-site reactions 
with BMS-986253 administrations, administering personnel will be trained to monitor for signs 
and symptoms of such reactions and act upon the earliest sign of its development. Should 
participants develop AEs at any point on trial or simply do not want to continue on study, they 
will be allowed to withdraw their consent and discontinue study at any time.
12.4 CONSENT PROCESS AND DOCUMENTATION
The informed consent document will be provided as a physical or electronic document to the 
participant for review prior to consenting.  A designated study investigator will carefully explain 
the procedures and tests involved in this study, and the associated risks, discomforts and benefits. 
In order to minimize potential coercion, as much time as is needed to review the document will 


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be given, including an opportunity to discuss it with friends, family members and/or other 
advisors, and to ask questions of any designated study investigator. A signed informed consent 
document will be obtained prior to entry onto the study.
The initial consent process as well as re-consent, when required, may take place in person or 
remotely (e.g., via telephone or other NIH approved remote platforms used in compliance with 
local policy, including HRPP Policy 303) per discretion of the designated study investigator and 
with the agreement of the participant.  Whether in person or remote, the privacy of the subject 
will be maintained. Consenting investigators (and participant, when in person) will be located in 
a private area (e.g., clinic consult room). When consent is conducted remotely, the participant 
will be informed of the private nature of the discussion and will be encouraged to relocate to a 
more private setting if needed. 
Consent will be documented with required signatures on the physical document (which includes 
the printout of an electronic document sent to participant) or as described below, with a manual 
(non-electronic) signature on the electronic document.  When required, witness signature will be 
obtained similarly as described for the investigator and participant.
Manual (non-electronic) signature on electronic document:
When a manual signature on an electronic document is used for the documentation of consent 
at the NIH Clinical Center, this study will use the following to obtain the required signatures:
•
Adobe platform (which is not 21 CFR Part 11 compliant); or,  
•
iMedConsent platform (which is 21 CFR Part 11 compliant)
During the consent process, participants and investigators will view individual copies of the 
approved consent document on screens at their respective locations (if remote consent); the 
same screen may be used when in the same location, but is not required.  
Both the investigator and the participant will sign the document using a finger, stylus or mouse. 
Note: Refer to the CCR SOP PM-2, Obtaining and Documenting the Informed Consent Process 
for additional information (e.g., verification of participant identity when obtaining consent 
remotely) found at:   
https://ccrod.cancer.gov/confluence/pages/viewpage.action?pageId=73203825.
13 REGULATORY AND OPERATIONAL CONSIDERATIONS 
13.1 STUDY DISCONTINUATION AND CLOSURE 
This study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause.  Written notification, documenting the reason for study suspension or 
termination, will be provided by the suspending or terminating party to study participants, 
investigators, funding agency, the Investigational New Drug (IND) sponsor and regulatory 
authorities.  If the study is prematurely terminated or suspended, the Principal Investigator (PI) 
will promptly inform study participants, the Institutional Review Board (IRB), and sponsor and 
will provide the reason(s) for the termination or suspension.  Study participants will be 
contacted, as applicable, and be informed of changes to study visit schedule.
 Circumstances that may warrant termination or suspension include, but are not limited to:
•
Determination of unexpected, significant, or unacceptable risk to participants


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•
Demonstration of efficacy that would warrant stopping   
•
Insufficient compliance to protocol requirements
•
Data that are not sufficiently complete and/or evaluable
•
Determination that the primary endpoint has been met
•
Determination of futility
Study may resume once concerns about safety, protocol compliance, and data quality are 
addressed, and satisfy the sponsor, IRB and as applicable, Food and Drug Administration (FDA).
13.2 QUALITY ASSURANCE AND QUALITY CONTROL
Investigational site will perform internal quality management of study conduct, data and 
biological specimen collection, documentation and completion.  An individualized quality 
management plan will be developed to describe a site’s quality management.
Quality control (QC) procedures will be implemented beginning with the data entry system and 
data QC checks that will be run on the database will be generated. Any missing data or data 
anomalies will be communicated to the site(s) for clarification/resolution.
Following written Standard Operating Procedures (SOPs), the monitors will verify that the 
clinical trial is conducted and data are generated and biological specimens are collected, 
documented (recorded), and reported in compliance with the protocol, International Council on 
Harmonisation Good Clinical Practice (ICH GCP), and applicable regulatory requirements (e.g., 
Good Laboratory Practices (GLP), Good Manufacturing Practices (GMP)). 
The investigational site will provide direct access to all trial related sites, source data/documents, 
and reports for the purpose of monitoring and auditing by the sponsor, and inspection by local 
and regulatory authorities.
13.3 CONFLICT OF INTEREST POLICY
The independence of this study from any actual or perceived influence, such as by the 
pharmaceutical industry, is critical.  Therefore, any actual conflict of interest of persons who 
have a role in the design, conduct, analysis, publication, or any aspect of this trial will be 
disclosed and managed. Furthermore, persons who have a perceived conflict of interest will be 
required to have such conflicts managed in a way that is appropriate to their participation in the 
design and conduct of this trial.  The study leadership in conjunction with the National Cancer 
Institute has established policies and procedures for all study group members to disclose all 
conflicts of interest and will establish a mechanism for the management of all reported dualities 
of interest.
13.4 CONFIDENTIALITY AND PRIVACY
Participant confidentiality and privacy is strictly held in trust by the participating investigators, 
their staff, and the sponsor(s). This confidentiality is extended to cover testing of biological 
samples and genetic tests in addition to the clinical information relating to participants. 
Therefore, the study protocol, documentation, data, and all other information generated will be 
held in strict confidence. No information concerning the study or the data will be released to any 
unauthorized third party without prior written approval of the sponsor. 
All research activities will be conducted in as private a setting as possible.


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The study monitor, other authorized representatives of the sponsor, representatives of the 
Institutional Review Board (IRB), and/or regulatory agencies may inspect all documents and 
records required to be maintained by the investigator, including but not limited to, medical 
records (office, clinic, or hospital) and pharmacy records for the participants in this study. The 
clinical study site will permit access to such records.
The study participant’s contact information will be securely stored at the/each clinical site for 
internal use during the study. At the end of the study, all records will continue to be kept in a 
secure location for as long a period as dictated by the reviewing IRB, Institutional policies, or 
sponsor requirements.
Study participant research data, which is for purposes of statistical analysis and scientific 
reporting, will be stored at the National Cancer Institute. This will not include the participant’s 
contact or identifying information. Rather, individual participants and their research data will be 
identified by a unique study identification number. The study data entry and study management 
systems used by the clinical site(s) and by National Cancer Institute research staff will be 
secured and password protected. At the end of the study, all study databases will be archived at 
the National Cancer Institute.
To further protect the privacy of study participants, a Certificate of Confidentiality has been 
issued by the National Institutes of Health (NIH).  This certificate protects identifiable research 
information from forced disclosure. It allows the investigator and others who have access to 
research records to refuse to disclose identifying information on research participation in any 
civil, criminal, administrative, legislative, or other proceeding, whether at the federal, state, or 
local level. By protecting researchers and institutions from being compelled to disclose 
information that would identify research participants, Certificates of Confidentiality help achieve 
the research objectives and promote participation in studies by helping assure confidentiality and 
privacy to participants.
14 PHARMACEUTICAL AND INVESTIGATIONAL INFORMATION  
14.1 BMS-986253  (IND # 157591)
14.1.1 Source/Acquisition and Accountability 
BMS-986253 is manufactured and supplied for the trial by Bristol-Myers Squibb (BMS). 
BMS-986253 will be provided to the clinical trial site by the manufacturer. The investigator or 
designee (e.g., pharmacist) will maintain an ongoing inventory of the investigational product 
supply according to standard site procedures. The investigational product will be dispensed at the 
direction of an investigator for administration to a study participant enrolled on the clinical trial. 
Disposal of expired or unused product will be returned to the manufacturer or disposed of 
according to standard site procedures based on agreement between the manufacturer and the site.
14.1.2 Toxicity 
See Section 1.2.4.
Because BMS-986253 is scheduled for intravenous (IV) administration, extravasation at the site 
of infusion may induce reactions such as edema, redness, itching, and tenderness. To date, no 
injection-site reactions have been reported.


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Overall, BMS-986253 given as monotherapy, in combination with nivolumab, or in combination 
with nivolumab and ipilimumab is tolerable in participants with advanced cancers. In Study 
CA027-001, a TRAE was reported in 5 of 15 participants treated with BMS-986253 
monotherapy; the most commonly reported TRAEs were nausea and fatigue (both n = 2). The 
frequency of AEs in Study CA027-001 did not correlate with the dose of BMS-986253.
In Study CA027-002, in participants treated with BMS-986253 in combination with nivolumab, 
TRAEs were reported in 69 of 144 participants. The most commonly reported TRAEs (> 2%) 
were fatigue (n = 21); pruritus (n = 12); decreased appetite (n = 11); nausea (n = 10); arthralgia 
(n = 8); asthenia (n = 7); diarrhea (n = 6); anemia, chills, dry mouth, vomiting, and rash (n = 4 
each); and alanine aminotransferase increased, aspartate aminotransferase increased, edema 
peripheral, headache, infusion-related reaction, pyrexia, and rash maculo-papular (n = 3 each).
In participants treated with BMS-986253 in combination with nivolumab plus ipilimumab, 
TRAEs were reported in 10 of 15 participants. TRAEs included diarrhea (n = 4); asthenia, 
hypothyroidism, rash, and fatigue (n = 2 each); and colitis, gastritis, nausea, vomiting, pyrexia, 
hyperthyroidism, hepatitis, hypertransaminasemia, paronychia, sialoadenitis, alanine 
aminotransferase increased, amylase increased, gamma-glutamyltransferase increased, 
hyperglycemia, iron deficiency, cytokine release syndrome, infusion-related reaction, arthralgia, 
arthritis, pruritus, rash maculo-papular, and urticaria (n = 1 each).
When BMS-986253 was given as monotherapy in Study CA027-001, no immune-related AEs 
were reported. Based on preliminary clinical data from Study CA027-002, there is a higher than 
expected rate of HLH cases with BMS-986253/placebo in combination with nivolumab and 
ipilimumab in Part 2, while there were no cases of HLH with BMS-986253 in combination with 
nivolumab and ipilimumab in Part 1. Additional clinical data are needed to determine if BMS-
986253 increases the rate of HLH associated with nivolumab monotherapy or in combination 
with ipilimumab.
14.1.3 Formulation and preparation 
•
BMS-986253 injection is a sterile, non-pyrogenic, single use, preservative-free, ready-to-
use IV injectable drug product supplied in a 20-cc (20R) Type I flint glass vial, stoppered 
with a 20-mm fluoropolymer film-laminated rubber stopper, and sealed with a 20-mm 
aluminum flip-off seal. 
•
BMS-986253 injection is formulated at a protein concentration of 100 mg/mL in 20 mM 
histidine buffer (pH of 6.0), which is composed of histidine, histidine hydrochloride 
monohydrate, sucrose, polysorbate 80, pentetic acid, and water for injection.
•
Each vial of drug product contains the labeled amount of BMS-986253 with a nominal 
fill of 10 mL and 12 mL for the 1,000-mg/vial and 1,200-mg/vial presentations, 
respectively, and sufficient overfill (0.8 mL) to account for vial, needle, and syringe hold-
up. 
•
The drug product must be diluted prior to dosing.
14.1.4 Stability and Storage 
1. BMS-986253-01 Injection, 1000 mg/Vial (100 mg/mL) and BMS-986253-01 Injection, 
1,200 mg/Vial (100 mg/mL) 
•
BMS-986253 injection should be stored refrigerated at 2°C to 8°C (36°F to 46°F) and 
protected from light and freezing.


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2. Diluted Solution of BMS-986253 Injection, 1000 mg/Vial (100 mg/mL) and 1,200 
mg/Vial (100/mL) in an IV bag:
•
Administration of diluted BMS-986253 injection must be completed within 24 hours 
of preparation. If not used immediately, the infusion solution may be stored for up to 
24 hours refrigerated at 2°C to 8°C (36°F to 46°F) protected from light; a maximum 
of 4 hours of the total 24 hours can be at room temperature (15°C to 25°C, 59°F to 
77°F), ambient light. 
•
The diluted solution in an IV bag should not be shaken or frozen. Equilibration to 
room temperature is recommended for the infusion bag, drug product, or their 
combination prior to administration.
14.1.5 Administration procedures
Dilution of BMS-986253-01 Injection, 1,000 mg/Vial (100 mg/mL) and 200 mg/Vial
(20 mg/mL):
•
BMS-986253 injection is to be administered as an IV infusion, following dilution with 
normal saline or 5% dextrose injection to concentrations outlined in section 3.2.1.3
•
The infusion is to be administered through a sterile, non-pyrogenic, and low protein 
binding polyethersulfone or nylon 0.2 microm in line filter. 
•
No incompatibilities have been observed between constituted BMS-986253 and the 
recommended IV infusion bags or syringe.
•
Dilution of BMS-986253 injection must be performed using sterile disposable syringes. 
Care must be taken to ensure sterility of the prepared solution as the drug product does 
not contain any antimicrobial preservative or bacteriostatic agent.
14.1.6 Incompatibilities
•
There are no special warnings or precautions in term of drug interactions with BMS-
986253.
•
Chemical structure: consists of 1,322 amino acids with 1 nitrogen-linked glycosylation 
site on the heavy chain and is produced from a CHO cell line.
•
Molecular weight: 145 kDa
•
Mechanism of action: Fully human mAb against IL-8.
A copy of the drug brochure will be provided to the Pharmacy department; however, NCI 
pharmacy has had experience with this investigational product from a prior study in solid tumors 
(Bilusic et al).[97]
14.2 DNMTI (DECITABINE AND CEDAZURIDINE)
DNMTi is a combination of decitabine, a nucleoside metabolic inhibitor, and cedazuridine, a 
cytidine deaminase inhibitor, indicated for treatment of adult patients with myelodysplastic 
syndromes (MDS).
14.2.1 Source/Acquisition and Accountability 
For subject administration, decitabine and cedazuridine will be purchased by the NIH Clinical 
Center Pharmacy Department from commercial sources.


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14.2.2 Toxicity 
Fatal and serious myelosuppression and infectious complications can occur. Can cause fetal 
harm. Most common adverse reactions (incidence ≥ 20%) are fatigue, constipation, hemorrhage, 
myalgia, mucositis, arthralgia, nausea, dyspnea, diarrhea, rash, dizziness, febrile neutropenia, 
edema, headache, cough, decreased appetite, upper respiratory tract infection, pneumonia, and 
transaminase increased. The most common Grade 3 or 4 laboratory abnormalities (≥ 50%) were 
leukocytes decreased, platelet count decreased, neutrophil count decreased, and hemoglobin 
decreased. [105, 118, 119]
14.2.3 Formulation and preparation 
DNMTi (decitabine and cedazuridine) tablets, for oral use contain 35 mg decitabine and 100 mg 
cedazuridine. The tablets are biconvex, oval-shaped, film-coated, red and debossed with “H35” 
on one side. Each film-coated tablet contains the following inactive ingredients: lactose 
monohydrate, hypromellose, croscarmellose sodium, colloidal silicon dioxide, and magnesium 
stearate. The film coating material contains polyvinyl alcohol, titanium dioxide, polyethylene 
glycol, talc, and iron oxide red.
14.2.4 Stability and Storage 
The tablet should be stored at 20°C to 25°C. Excursions of the tablet are permitted to 15°C to 
30°C. Any unused portion of the tablet should be discarded using special handling and disposal 
procedures.
14.2.5 Administration procedures
The tablet should be taken on an empty stomach, 2 hours before or 2 hours after meals, and at the 
same time each day.
Tablet should be swallowed whole, and may not be crushed, cut, or chewed. 
If a dose is missed within 12 hours of the time it is usually administered, administer the missed 
dose as soon as possible and then resume the normal daily dosing schedule. Extend the dosing 
period by 1 day for every missed dose to complete 5 daily doses for each cycle. If a dose is 
vomited, do not administer an additional dose (continue with the next scheduled dose).
14.2.6 Incompatibilities
Avoid coadministration of DNMTi with drugs that are metabolized by cytidine deaminase 
(CDA) enzymes.


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Breccia M, Salaroli A, Loglisci G, Finsinger P, Serrao A, Alimena G: MDS-specific 
comorbidity index is useful to identify myelodysplastic patients who can have better 
outcome with 5-azacitidine. Haematologica 2012, 97(2):e2.
109.
Fayers P, Bottomley A, Group EQoL, Quality of Life U: Quality of life research within 
the EORTC-the EORTC QLQ-C30. European Organisation for Research and 
Treatment of Cancer. Eur J Cancer 2002, 38 Suppl 4:S125-133.
110.
Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ, Filiberti A, 
Flechtner H, Fleishman SB, de Haes JC et al: The European Organization for 
Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in 
international clinical trials in oncology. J Natl Cancer Inst 1993, 85(5):365-376.
111.
Stauder R, Lambert J, Desruol-Allardin S, Savre I, Gaugler L, Stojkov I, Siebert U, 
Chevrou-Severac H: Patient-reported outcome measures in studies of 


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myelodysplastic syndromes and acute myeloid leukemia: Literature review and 
landscape analysis. Eur J Haematol 2020, 104(5):476-487.
112.
Wiener L, Battles H, Zadeh S, Smith CJ, Helman LJ, Kim SY: Gastrointestinal stromal 
tumor: psychosocial characteristics and considerations. Support Care Cancer 2012, 
20(6):1343-1349.
113.
Henter JI, Arico M, Egeler RM, Elinder G, Favara BE, Filipovich AH, Gadner H, 
Imashuku S, Janka-Schaub G, Komp D et al: HLH-94: a treatment protocol for 
hemophagocytic lymphohistiocytosis. HLH study Group of the Histiocyte Society. 
Med Pediatr Oncol 1997, 28(5):342-347.
114.
Yoshimura T, Matsushima K, Oppenheim JJ, Leonard EJ: Neutrophil chemotactic 
factor produced by lipopolysaccharide (LPS)-stimulated human blood mononuclear 
leukocytes: partial characterization and separation from interleukin 1 (IL 1). J 
Immunol 1987, 139(3):788-793.
115.
Cheson BD, Greenberg PL, Bennett JM, Lowenberg B, Wijermans PW, Nimer SD, Pinto 
A, Beran M, de Witte TM, Stone RM et al: Clinical application and proposal for 
modification of the International Working Group (IWG) response criteria in 
myelodysplasia. Blood 2006, 108(2):419-425.
116.
Lubbert M, Suciu S, Baila L, Ruter BH, Platzbecker U, Giagounidis A, Selleslag D, 
Labar B, Germing U, Salih HR et al: Low-dose decitabine versus best supportive care 
in elderly patients with intermediate- or high-risk myelodysplastic syndrome (MDS) 
ineligible for intensive chemotherapy: final results of the randomized phase III 
study of the European Organisation for Research and Treatment of Cancer 
Leukemia Group and the German MDS Study Group. J Clin Oncol 2011, 
29(15):1987-1996.
117.
Dueck AC, Scher HI, Bennett AV, Mazza GL, Thanarajasingam G, Schwab G, Weitzman 
AL, Rogak LJ, Basch E: Assessment of Adverse Events From the Patient Perspective 
in a Phase 3 Metastatic Castration-Resistant Prostate Cancer Clinical Trial. JAMA 
Oncol 2020, 6(2):e193332.
118.
Garcia-Manero G, Griffiths EA, Roboz GJ, Busque L, Wells RA, Odenike O, Steensma 
DP, Yee KWL, Faderl S, Amrein PC et al: A Phase 2 Dose-Confirmation Study of 
Oral ASTX727, a Combination of Oral Decitabine with a Cytidine Deaminase 
Inhibitor (CDAi) Cedazuridine (E7727), in Subjects with Myelodysplastic 
Syndromes (MDS). Blood 2017, 130.
119.
Savona MR, Odenike O, Amrein PC, Steensma DP, DeZern AE, Michaelis LC, Faderl S, 
Harb W, Kantarjian H, Lowder J et al: An oral fixed-dose combination of decitabine 
and cedazuridine in myelodysplastic syndromes: a multicentre, open-label, dose-
escalation, phase 1 study. Lancet Haematology 2019, 6(4):E194-E203.


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16 LIST OF ABBREVIATIONS
Abbreviation
Term
ACAT
Ability to Consent Assessment Team
AE
Adverse Event/Adverse Experience
AESI
Adverse Event/Experience of Special Interest
ANC
Absolute neutrophil count
BTRIS
Biomedical Translational Research Information System
CCR
Center for Cancer Research
CDA
Confidential Disclosure Agreement
CFR
Code of Federal Regulations
CNS
Central nervous system
CONSORT
Consolidated Standards of Reporting Trials
COV
Close-out Visit
CR
Complete Response
CSR 
Clinical Study Report
CRADA
Cooperative Research and Development Agreement
CT
Computed Tomography
CTA
Clinical Trials Agreement
CTCAE
Common Terminology Criteria for Adverse Events
DLT
Dose-limiting toxicity
DSMB
Data Safety Monitoring Board (DSMB)
DTA
Data Transfer Agreement
EC
Ethics Committee
eCRF
Electronic Case Report Form
ECOG
Eastern Cooperative Oncology Group
EFS
Event-free survival
EKG
Electrocardiogram
FDA
Food and Drug Administration
FWA
Federal-Wide Assurance
GCP
Good Clinical Practice
GDS
Genomic Data Sharing
GLP
Good Laboratory Practices
GMP
Good Manufacturing Practices
HBV
Hepatitis B virus
HCV
Hepatitis C virus
HHS
Health and Human Services
HIV
Human immunodeficiency virus
IB
Investigator’s Brochure
IBC
Institutional Biosafety Committee
ICD/ICF
Informed Consent Document/Form
ICH
International Council on Harmonisation
IMV
Interim Monitoring Visit


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Abbreviation
Term
IND
Investigational New Drug 
IRB
Institutional Review Board
IRBO
Institutional Review Board Office
IV
Intravenous
LAR
Legally Authorized Representative
MRI
Magnetic Resonance Imaging
MTA
Material Transfer Agreement
MTD
Maximal tolerated dose
N
Number (typically refers to subjects)
NCT
National Clinical Trial (number)
NDA
New Drug Application
NIH
National Institutes of Health
NOS
Not otherwise specified
OHSRP
Office for Human Subjects Research Protections
OHRP
Office for Human Research Protections
OS
Overall survival
OSRO
Office of Sponsor and Regulatory Oversight
PD
Progressive Disease
PET
Positron Emission Tomography
PFS
Progression-free survival
PI
Principal Investigator
PR
Partial Response
PS
Performance Status
QA
Quality Assurance
QC
Quality Control
rCR
Revised Common Rule
RECIST
Response Evaluation Criteria in Solid Tumors
RP2D
Recommended Phase II dose
SAE
Serious Adverse Event/Serious Adverse Experience
SAV
Site Assessment Visit
SIV
Site Initiation Visit
SD
Stable Disease
SMC
Safety Monitoring Committee
SOP
Standard Operating Procedure
ULN
Upper limit of normal
US
United States
WHO
World Health Organization


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17 APPENDICES
17.1 APPENDIX A:  PERFORMANCE STATUS CRITERIA
ECOG Performance Status Scale
Karnofsky Performance Scale
Grade
Descriptions
Percent
Description
100
Normal, no complaints, no 
evidence of disease.
0
Normal activity. Fully active, able 
to carry on all pre-disease 
performance without restriction.
90
Able to carry on normal activity; 
minor signs or symptoms of 
disease.
80
Normal activity with effort; 
some signs or symptoms of 
disease.
1
Symptoms, but ambulatory. 
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work).
70
Cares for self, unable to carry on 
normal activity or to do active 
work.
60
Requires occasional assistance, 
but is able to care for most of 
his/her needs.
2
In bed <50% of the time. 
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities. Up and about 
more than 50% of waking hours.
50
Requires considerable assistance 
and frequent medical care.
40
Disabled, requires special care 
and assistance.
3
In bed >50% of the time. Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours.
30
Severely disabled, 
hospitalization indicated. Death 
not imminent.
20
Very sick, hospitalization 
indicated. Death not imminent.
4
100% bedridden. Completely 
disabled. Cannot carry on any 
self-care. Totally confined to bed 
or chair.
10
Moribund, fatal processes 
progressing rapidly.
5
Dead.
0
Dead.


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17.2 APPENDIX B:  2016 WHO CLASSIFICATION FOR MYELODYSPLASTIC SYNDROME
Myelodysplastic syndromes (MDS)
•
MDS with single lineage dysplasia (MDS-SLD)
•
MDS with ring sideroblasts (MDS-RS)
o
MDS-RS and single lineage dysplasia
o
MDS-RS and multilineage dysplasia
•
MDS with multilineage dysplasia (MDS-MLD)
•
MDS with excess blasts
•
MDS with isolated del(5q)
•
MDS, unclassifiable
•
Provisional entity: Refractory cytopenia of childhood


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17.3 APPENDIX C:  REVISED INTERNATIONAL PROGNOSTIC SCORING SYSTEM (IPSS-R) FOR 
MYELODYSPLASTIC SYNDROMES
Score
Prognostic variable
0
0.5
1.0
1.5
2.0
3.0
4.0
Cytogenetics*
Very 
good
 
Good
 
Intermediate
Poor
Very 
poor
Bone marrow blast (percent)
≤2
 
>2 to 
<5
 
5 to 10
>10
 
Hemoglobin (g/dL)
≥10
 
8 to <10
<8
 
 
 
Platelets (cells/microL)
≥100
50 to 
100
<50
 
 
 
 
Absolute neutrophil count 
(cells/microL)
≥0.8
<0.8
 
 
 
 
 
Risk group
IPSS-R score
Median overall 
survival (years)
Median time to 
25 percent AML 
evolution (years)
Very low
≤1.5
8.8
>14.5
Low
>1.5 to 3.0
5.3
10.8
Intermediate
>3 to 4.5
3.0
3.2
High
>4.5 to 6
1.6
1.4
Very high
>6
0.8
0.7
AML: acute myeloid leukemia; MDS: myelodysplastic syndromes.
* Cytogenetic definitions:
Very good: –Y, del(11q)
Good: Normal, del(5q), del(12p), del(20q), double including del(5q)
Intermediate: del(7q), +8, +19, i(17q), any other single, double not including del(5q) or –7/del(7q), or independent 
clones
Poor: –7, inv(3)/t(3q)/del(3q), double including –7/del(7q), complex: 3 abnormalities.
Very poor: Complex: >3 abnormalities
This research was originally published in Blood. Greenberg PL, Tuechler H, Schanz J, et al. Revised International 
Prognostic Scoring System (IPSS-R) for myelodysplastic syndromes. Blood 2012. Copyright © 2012 the American 
Society of Hematology.


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17.4 APPENDIX D:  THE 2006 INTERNATIONAL WORKING GROUP RESPONSE CRITERIA WITH 
MODIFIED DEFINITIONS FOR HEMATOLOGIC IMPROVEMENT BY THE 2018 
INTERNATIONAL WORKING GROUP RESPONSE CRITERIA.[85]
Category
Response criteria
(responses must last at least 4 weeks)
Complete remission
•      Bone marrow: ≤5% myeloblasts with normal maturation of 
all cell lines*
•      Persistent dysplasia will be noted*
•      Peripheral blood†
•
 Hgb ≥11 g/dL
•
Platelets ≥100 X 109/L
•
Neutrophils ≥1.0 X 109/L
•
Blasts 0%
Partial remission
All CR criteria if abnormal before treatment except:
•      Bone marrow blasts decreased by >50% over pretreatment 
but still >5%
•      Cellularity and morphology not relevant
Marrow CR
•      Bone marrow: ≤5% myeloblasts and decrease by ≥50% 
over pretreatment
•      Peripheral blood: if HI responses, they will be noted in 
addition to marrow CR
Stable disease
Failure to achieve at least PR, but no evidence of progression 
for >8 weeks
Failure
Death during treatment or disease progression characterized 
by worsening of cytopenias, increase in percentage of bone 
marrow blasts, or progression to more advanced MDS FAB 
subtype than pre-treatment
Relapse after CR or PR
At least 1 of the following:
•      Return to pre-treatment bone marrow blast percentage
•      Decrement of >50% from maximum remission/response 
levels in granulocytes or platelets
•      Reduction in Hgb concentration by >1.5 g/dL or 
transfusion dependence
Cytogenetic response
Complete
•      Disappearance of the chromosomal abnormality without 
appearance of new ones
Partial
•      At least 50% reduction of the chromosomal abnormality
Disease progression
For patients with:
•      Less than 5% blasts: ≥50% increase in blasts to >5% blasts
•      5%-10% blasts: ≥50% increase to 10% blasts


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•      10%-20% blasts: ≥50% increase to >20% blasts
•      20%-30% blasts: ≥50% increase to >30% blasts
Any of the following:
•      At least 50% decrement from maximum 
remission/response in granulocytes or platelets
•      Reduction in Hgb by ≥2 g/dL
•      Transfusion dependence
Survival
Endpoints:
•      Overall: death from any cause
•      Event free: failure or death from any cause
•      PFS: disease progression or death from MDS
•      DFS: time to relapse
•      Cause-specific death: death related to MDS
MDS, myelodysplastic syndromes; Hgb, hemoglobin; CR, complete remission; HI, hematologic improvement; PR, partial
remission; FAB, French-American-British; AML, acute myeloid leukemia; PFS, progression-free survival; DFS, disease-free
survival.
To convert hemoglobin from grams per deciliter to grams per liter, multiply grams per deciliter by 10.
*Dysplastic changes should consider the normal range of dysplastic changes.
†In some circumstances, protocol therapy may require the initiation of further treatment (eg, consolidation, maintenance) before
the 4-week period. Such patients can be included in the response category into which they fit at the time the therapy is started.
Transient cytopenias during repeated chemotherapy courses should not be considered as interrupting durability of response, as
long as they recover to the improved counts of the previous course.
 
Hematologic Improvement
Category
Patient pre-trial 
baseline
Response criteria
 
No Transfusion 
Dependence at 
baseline (0 RBC 
transfusions in 16 
weeks)
At least 2 consecutive Hgb measurements 
>1.5 g/dL for a period of minimum 8 weeks in 
an observation period of 16 to 24 weeks 
compared with the lowest mean of 2 Hgb 
measurements (apart from any transfusion) 
within 16 weeks before treatment onset; only 
a response duration of at least 16 weeks, 
however, is considered clinically meaningful
Low Transfusion 
Dependence at 
baseline (3-7 RBC 
transfusions in 16 
weeks in at least 2 
transfusion episodes, 
maximum 3 in 8 
weeks)
Transfusion independence, defined by the 
absence of any transfusions for at least 8 
weeks in an observation period of 16-24 
weeks with the same transfusion policy 
compared with 16 weeks prior to treatment; 
only a response duration of at least 16 weeks, 
however, is considered clinically meaningful
Erythroid response 
(HI-E)
High Transfusion 
Dependence at 
baseline (>8 RBC 
transfusions in 16 
Major 
response
Transfusion independence, 
defined by the absence of any 
transfusions over a period of 
minimum 8 weeks in an 


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observation period of 16-24 
weeks with the same transfusion 
policy compared with 16 weeks 
prior to treatment; only a response 
duration of at least 16 weeks, 
however, is considered clinically 
meaningful
weeks, > 4 
transfusion episodes 
in 8 weeks)
Minor 
response
Transfusion independence, 
defined by the absence of any 
transfusions over a period of 
minimum 8 weeks in an 
observation period of 16-24 
weeks with the same transfusion 
policy compared with 16 weeks 
prior to treatment; only a response 
duration of at least 16 weeks, 
however, is considered clinically 
meaningful
Platelet response 
(HI-P)
Pre-treatment PLT 
<100 x 109/L
•      Absolute increase of 30 x 109/L for 
patients starting with >20 x 109/L PLTs
or
•      Increase from <20 x 109/L to >20 x 109/L 
and by at least 100%
In addition:
•      In addition, evolution of bleeding 
symptoms is to be taken into account
•      Increments of platelets also for patients 
with a pre-treatment PLT count of >100 x 
109 are to be reported
Neutrophil response 
(HI-N)
 
Pre-treatment ANC 
<1.0 x 109/L
•      At least 100% increase and an absolute 
increase >0.5 x 109/L
•      Increments of neutrophils also for patients 
with a pre-treatment ANC of >1.0 x 109/L 
are to be reported


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17.5 APPENDIX E:  BLOOD AND MARROW PROCESSING CORE PROTOCOLS
Anti-IL8 in MDS (IRB 000356):
1. Peripheral Blood: 2 x 5 mL SST tubes (1 tube for Antibody PK, 1 tube for free IL8 assay, 
protocols below)
2. Peripheral Blood: 1 x 10mL EDTA tube (for separation and storage of MNC and plasma, 
protocol below)
3. Peripheral Blood: 1 x 2.5mL Paxgene Tube (for storage, see protocol below)
4. Bone Marrow: 1 x 10mL EDTA tube (for separation and storage of MNC and plasma, 
protocol below)
5. Bone Marrow: 1 x 2.5mL Paxgene Tube (for storage, see protocol below)
Processing Protocols:
Bone Marrow and Peripheral Blood Processing from EDTA tubes
1. Spin the bone marrow (BM) aspirate or peripheral blood (PB) at 2500 rpm (1500 rcf) for 
5 minutes to isolate neat plasma prior to adding the PBS/Ficoll.
2. Store 5 x 300uL aliquots of plasma at -80deg C.
3. Add 2 volumes of PBS to the PB/BM and be sure to mix well to ensure a good underlay 
of the Ficoll. 
4. Add a 1:1 volume of Ficoll to the diluted BM/PB by carefully dispensing at the bottom of 
the conical tube. The BM/PB should lay on top of the Ficoll layer. Try not to mix the 
Ficoll and BM/PB.
5. Spin the tubes at 3000 rpm (2000 rcf) for 15 minutes.
6. The mononuclear layer interface will lay between the Ficoll and plasma/PBS layers and 
will often appear whitish if there is a larger number of cells. Carefully remove this 
interface taking as little Ficoll as possible. If you cannot see the layer, just remove several 
mL from on top of the Ficoll layer, this will contain all the cell. Dilute the interface 
containing the cells, with 4 volumes of RPMI (supplemented with 10%FBS, and 1% 
Pen/Strep). The remaining Ficoll and RBCs at the bottom of the tube can be discarded. 
7. Spin the mononuclear cells at 1000rpm for 5 min.
8. Resuspend the cell pellet in 10 to 40ml of RBC Lysis Buffer (ie; Qiagen RBC Lysis 
Buffer). The volume of lysis buffer depends on the cell pellet. For very small pellets use 
10mL, for very large pellets, use 40mL RBC lysis .
9. Resuspend the cells in RPMI (supplemented with 10%FBS, and 1% Pen/Strep) and count 
the cells using a hemacytometer.
10. Freeze the cells in 10% DMSO, 20% FBS, and 70% RPMI with no more than 10million 
cells per mL and 1 mL per cryotube. Freeze samples either using a cell freezer container 
in a -80deg C freezer (i.e.; Mr Frosty container) or a controlled rate freezer. Once cells 
have reached -80deg C, transfer cryotubes to a liquid nitrogen cryounit.  
Antibody PK Studies (IL8 study), Peripheral Blood Processing from SST Tube:
1. Blood samples will be collected by direct venipuncture or through an indwelling catheter. 
If a catheter is used for blood collection, then approximately 1mL of blood should be 


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withdrawn initially then discarded. Only saline is permitted to keep catheters patent, 
unless discussed and agreed upon by the Sponsor. If samples are obtained through a 
heparin lock, sufficient blood (~1mL) must be withdrawn to remove the heparin solution. 
2. Immediately after collection, gently invert each tube 5 times and allow blood to clot for 
30-45m at room temperature (tube standing upright).
3. Centrifuge samples at 4deg C for 10min (singing buckets) or 15 minutes (fixed buckets) 
at 100-1300g until clot and serum are well separated. Note: If refrigerated centrifuge is 
not available, prechill centrifuge tube holders at -20deg C for 20m prior to centrifugation.
4. Transfer 1mL aliquots of serum into 4 appropriately labeled screw cap polypropylene 
tubes.
5. Keep samples at -80deg C until requested for shipment.  
Free IL8 Studies (IL8 study), Peripheral Blood Processing from SST Tube: 
1. Blood samples will be collected by direct venipuncture or through an indwelling catheter. 
If a catheter is used for blood collection, then approximately 1mL of blood should be 
withdrawn initially then discarded. Only saline is permitted to keep catheters patent, 
unless discussed and agreed upon by the Sponsor. If samples are obtained through a 
heparin lock, sufficient blood (~1mL) must be withdrawn to remove the heparin solution. 
2. Immediately after collection, gently invert each tube 5 times and allow blood to clot for 
30-45m at room temperature (tube standing upright).
3. Centrifuge samples at 4deg C for 10min (singing buckets) or 15 minutes (fixed buckets) 
at 100-1300g until clot and serum are well separated. Note: If refrigerated centrifuge is 
not available, prechill centrifuge tube holders at -20deg C for 20m prior to centrifugation.
4. Transfer 1mL aliquots of serum into 4 appropriately labeled screw cap polypropylene 
tubes.
5. Keep samples at -80deg C until requested for shipment.  
PAXgene Tube Storage for BM/PB:
1. Tubes should remain upright. Incubate tubes at room temp for 2-72hrs after collection, 
then place at -20deg C for 24hr, then place in a -80deg C freezer.


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17.6 APPENDIX F:  CLINICAL DATA ELEMENTS FOR CRF ENTRY IN CLINICAL DATABASE
Patient (recipient) characteristics at protocol entry
•
Sex (male, female)
•
Age at enrollment (number)
•
Ethnicity (white, black, American Indian/Alaskan native, Asian/Pacific islander, 
Hispanic, other)
•
ECOG and Karnofsky performance status
•
Diagnosis - MDS (high risk or low risk)
•
2016 WHO classification of MDS (MDS with single lineage dysplasia [MDS-SLD], 
MDS with ring sideroblasts and single lineage dysplasia [MDS-RS-SLD], MDS with ring 
sideroblasts and multilineage dysplasia [MDS-RS-MLD], MDS with multilineage 
dysplasia [MDS-MLD], MDS with excess blasts [MDS-EB], MDS with isolated del(5q), 
MDS unclassifiable [MDS-U], 
•
Date of MDS diagnosis (month, year)
•
Age at MDS diagnosis 
•
Revised International Prognostic Scoring System (IPSS-R) score at MDS diagnosis 
•
Cytogenetic profile at diagnosis and enrollment, if available (see Appendix C)- only need 
overall score (very good, good, intermediate, poor, very poor) 
•
Bone marrow blasts %, if available
•
Hemoglobin, if available
•
Platelet count, if available
•
Absolute neutrophil count (ANC), if available
•
RBC transfusion dependance (transfusion dependent or independent)
•
Platelet transfusion dependance (transfusion dependent or independent) 
•
Average # of transfusions per month (RBCs units and instances of platelets transfusions) 
in the 3 months leading up to baseline on study
•
Laboratory values will be collected from time of screening for duration of trial
•
TP53 mutation status at enrollment, if available (TP53 mutation positive or negative) 
•
Names and # of cycles of prior Lines of therapy for MDS.
•
Response to most recent line of therapy: CR (complete response), PR (partial response), 
HI (hematologic improvement), mCR with HI (marrow CR with hematologic 
improvement), mCR without HI (marrow CR without hematologic improvement), SD 
(stable disease), PD (disease progression)
•
MDS-CI (low risk, intermediate risk, high risk)
•
Rockwood frailty index (see Clinical Frailty Scale)
•
Disease status at time of enrollment:  CR (complete response), PR (partial response), HI 
(hematologic improvement), mCR with HI (marrow CR with hematologic improvement), 
mCR without HI (marrow CR without hematologic improvement), SD (stable disease), 
PD (disease progression)
•
Patient Reported Outcome Questionnaires (per section 3.5.3)
o
Subjects > 18 years of age:
1. EORTC QLQC30 score (patient reported)- see questionnaire 
2. NIH developed psychosocial assessment scale – see questionnaire 


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Data collection during study/treatment
•
Cycle number & day of treatment
•
Study Drug Administration 
•
Disease response at assessment timepoints: CR (complete response), PR (partial 
response), HI (hematologic improvement), mCR with HI (marrow CR with hematologic 
improvement), mCR without HI (marrow CR without hematologic improvement), SD 
(stable disease), PD (disease progression)
•
Best overall response to study treatment: CR (complete response), PR (partial response), 
HI (hematologic improvement), mCR with HI (marrow CR with hematologic 
improvement), mCR without HI (marrow CR without hematologic improvement), SD 
(stable disease), PD (disease progression)
•
Bone marrow percent blasts
•
RBC transfusion dependence (transfusion dependent or transfusion independent) 
•
Platelet transfusion dependence (transfusion dependent or transfusion independent)
•
# of transfusions per month (RBCs units and instances of platelets transfusions)
•
Adverse events 
•
Patient Reported Outcome Questionnaires: (per section 3.5.3)
o
EORTC QLQC30 score (patient reported) – see questionnaire 
o
NIH developed psychosocial assessment scale – see questionnaire 
Data collection at post-therapy follow-up visits 
•
Alive (yes/no)
•
Adverse events
•
Progression of MDS (if yes, to what and when)
•
Diagnosed with sAML (yes/no)
o
If diagnosed with sAML, date of sAML diagnosis (month, year)
o
subsequent MDS/AML specific treatments including BMT until off study if 
information available.
Data collection at time of death
•
Date of death
•
Disease status at time of death: CR or not CR
•
Cause of death: disease progression/relapse vs non-relapse mortality (definition of non-
relapse mortality: subject in clinical remission at time of death)
•
If non-relapse mortality, primary cause of death (e.g., infection, organ failure, other – per 
CTCAE)


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17.7 APPENDIX G:  DIAGNOSIS AND MANAGEMENT OF HLH
The following clinical and laboratory parameters can be indicative of a diagnosis of HLH:
•
Fever ≥38.5°C, not explained by infection
•
Peripheral blood cytopenia, with at least two of the following: hemoglobin <9 g/dL; 
platelets <100,000/microL; absolute neutrophil count <1000/microL, not explained by 
malignancy or treatment
•
Hypertriglyceridemia (fasting triglycerides >265 mg/dL) and/or hypofibrinogenemia 
(fibrinogen <150 mg/dL)
•
Hemophagocytosis in bone marrow, spleen, lymph node, or liver
•
Ferritin >500 ng/mL
•
Elevated soluble CD25 (soluble IL-2 receptor alpha [sIL-2R]) two standard deviations 
above age-adjusted laboratory-specific norms
•
Elevated CXCL9 
•
Hemophagocytosis on bone marrow examination
If patient is not severely ill (eg, does not have deteriorating cardiovascular, pulmonary, renal, 
hepatic, or neurologic function), it may be possible to manage with stoppage of indefinite anti-IL8 
therapy and close monitoring. In patients who are acutely ill or deteriorating, particularly those 
displaying end-organ damage, HLH-specific therapy would be initiated per institution specific 
protocols. 

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CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
PRINCIPAL INVESTIGATOR:  Steven Pavletic, MD
STUDY TITLE:  A Phase I/II Trial of BMS-986253 in Myelodysplastic Syndromes
STUDY SITE:  NIH Clinical Center
Cohort: 
Affected Patient, Treatment
Consent Version:  
1/23/2023
WHO DO YOU CONTACT ABOUT THIS STUDY? 
  Principal Investigator:
Steven Pavletic, MD, MS
240-760-6174
pavletis@mail.nih.gov
KEY INFORMATION ABOUT THIS RESEARCH 
This consent form describes a research study and is designed to help you decide if you would 
like to be a part of the research study.  
You are being asked to take part in a research study at the National Institutes of Health (NIH). 
This section provides the information we believe is most helpful and important to you in making 
your decision about participating in this study. Additional information that may help you decide 
can be found in other sections of the document. Taking part in research at the NIH is your choice.
You are being asked to take part in this study because you have been diagnosed with 
Myelodysplastic Syndromes (MDS). In addition, you completed the screening evaluation and 
were found to be eligible to take part in this research study. 
The purpose of this research study is to determine if BMS-986253 is a safe and effective 
treatment for Myelodysplastic Syndromes (MDS). The first phase of this research study will 
determine the largest dose of BMS-986253 that can be safely given to patients with MDS. The 
second phase of this research study will determine how well patients with MDS respond to 
BMS-986253.
The use of BMS-986253 in this study is considered investigational, which means that is has not 
been approved by the U.S. Food and Drug Administration (FDA) to treat MDS. However, the 
FDA has given us permission to use BMS-986253 in this study.
If you have high risk MDS you will receive a DNA methyltransferase inhibitors (DNMTi) per 
standard of care practice in combination with the study drug. This FDA-approved DNMTi 
(decitabine and cedazuridine) therapy will be administered orally by the NIH doctors. 
There are other drugs that may be used to treat your disease, and these can be prescribed/given 
by your regular doctor, even if you are not in this study.  Some examples include: other DNMTi 
therapy such as azacitidine or decitabine, other oral treatments such as lenalidomide, or drugs 


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that would not treat the disease directly but may help improve your blood counts and overall 
symptoms, such as erythropoietin stimulating agents. 
If you decide to join this study, here are some of the most important things you should know:

You will be seen regularly during the study and will continue to receive study therapy 
until your disease gets worse or you have unacceptable side effects. 

You will have clinical, laboratory, and other testing, including bone marrow biopsies to 
see how you are doing and to assess your disease.

You may experience side effects from taking part in this study. Some can be mild or very 
serious, temporary, or long-lasting, or permanent, and may include death. Side effects 
may include nausea, fatigue, rash, and decreased appetite.

You may not father children or become pregnant during your participation in this study.

If you are sexually active capable of becoming pregnant or are a male with a partner 
capable of becoming pregnant you must agree to using adequate contraception 
(hormonal or barrier method of birth control; abstinence prior to study enrollment and 
up to 6 months after treatment.  
Just as we do not know what side effects you might have; we cannot know if you may benefit 
from taking part in this study.  If you do not benefit, this study and the results of our research 
will help others in the future. 
We will cover the cost for some of your expenses, such as travel and a portion of lodging, and/or 
meals.  Someone will work with you to review your cost of taking part and what we will support. 
You are free to stop taking part in the trail at any time. If you decide to stop, the study doctor 
may ask you to agree to certain tests to make sure it is safe for you to stop.
The remaining document will now describe the research study in more detail.  This information 
should be considered before you make your choice. Members of the study team will talk with you 
about the information in this document. Some people have personal, religious, or ethical beliefs 
that may limit the kinds of medical or research interventions in which they would want to 
participate. Take the time you need to ask any questions and discuss this study with NIH staff, and 
with your family, friends, and personal health care providers.
IT IS YOUR CHOICE TO TAKE PART IN THE STUDY
You may choose not to take part in this study for any reason. If you join this study, you may change 
your mind and stop participating in the study at any time and for any reason. In either case, you 
will not lose any benefits to which you are otherwise entitled. However, to be seen at the NIH, you 
must be taking part in a study or are being considered for a study. If you do choose to leave the 
study, please inform your study team to ensure a safe withdrawal from the research.  
WHY IS THIS STUDY BEING DONE?
The purpose of the phase I portion of this study is to test the safety of BMS-986253 at different 
doses to find out what effects, if any, it has on participants with MDS to determine the 
recommended dose for the phase 2 part of the trial.  The purpose of the phase II portion of the 
study is to determine the response rate to BMS-986253. 


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WHAT WILL HAPPEN DURING THE STUDY?
If you decide to take part in this study, you will be asked to:

Be willing and able to follow study directions and procedures, which are described below.

Come to all study visits

Take the study drugs as prescribed

Tell the study staff about any side effects or problems

Ask questions as you think of them

Tell the study staff if you change your mind about staying in the study

Tell the study doctor about any prescribed and non-prescribed medicine you are using 
before and during the study.
You must not take part in other research studies at the same time as you are taking part in this 
study. 
You will receive the study drug as long as your doctor feels that it is safe, you are receiving benefit, 
and you agree to be in the study.  
If you have bad side effects or the MDS gets worse, you or your doctor might decide to stop you 
from continuing the study.
The study is divided into 2 main periods that are known as  Treatment and Follow-up.  Each period 
is described below.
During the study
BMS-986253 will be tested at different dose levels to see which dose is safe and well tolerated 
when given once every two weeks. Based on this information we will determine the dose for the 
phase II part of the study.
Treatment Period
The treatment period will consist of treatment cycles. These cycles will each be 28 days long.  If 
you are participating in phase I of the trial and have low risk MDS you will receive BMS-986253 
alone on days 1 and 15 of each cycle.  If you are participating in phase I of the trial and have high 
risk MDS you will receive BMS-986253 on days 1 and 15 of each cycle and an oral DNA 
methyltransferase inhibitors (DNMTi) per standard of care practice on days 2-6.   
Once the largest dose of BMS-986253 that is safe to give is established we will move to Phase II 
of the study.  If you are participating in phase II of the trial and have low risk MDS you will receive 
BMS-986253 alone on days 1 and 15 of each cycle.  If you are participating in phase II of the trial 
and have high risk MDS you will receive BMS-986253 on days 1 and 15 of each cycle and DNA 
methyltransferase inhibitors (DNMTi) per standard of care practice on days 2-6. 
The DNMTi therapy will be administered by your NIH study doctors.  
Study Assessments:


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During the study, we will perform tests to determine whether you are having side effects or if you 
are responding to the study therapy. These are listed below under required study procedures 
section.  
Pre-treatment required tests:
Before receiving your first dose of study drug you will have the following assessments performed

Visit the NIH Clinical Center to answer questions about your medical history.

Answer questions about how well you are able to take care of yourself.

List any prescriptions or non-prescription medicines you have taken.

Discuss the history of you MDS and any other medicines you have taken for the MDS.

Have a physical exam (including height and weight).

Have your temperature, blood pressure, breathing rate, and heart rate monitored.

Have an electrocardiogram (ECG), a test to show how well your heart is working.

Have blood samples taken to check your blood counts, blood minerals, liver and kidney 
function, and for certain virus that might be present (approximately 3 tablespoons).

Have a bone marrow biopsy sample taken (if not already completed at screening within 30 
days prior to treatment).

If you are a female who can have children, a urine and/or blood pregnancy test will be 
done. If urine test if positive, it will be confirmed with a blood test (less than 1 teaspoon). 
The results of the blood test must be negative for you be allowed in the study.

Functional status assessments and questionnaires, including questions about your ability to 
function in your daily activities and psychological assessment (questionnaires are only 
required if you are able to read English).
Study Drug and Required Evaluations:
Each dose of BMS-986253 will be given at the NIH.  If you are also receiving DNMTi therapy it 
will be given also by your NIH doctors.
For both phase I and phase II the following assessments will be performed:
Day 1:

Visit the NIH Clinical Center to answer questions about your medical history.

Answer questions about how well you are able to take care of yourself.

List any prescriptions or non-prescription medicines you have taken.

Discuss the history of your MDS and any other medicines you have taken for the MDS.

Have a physical exam (including height and weight)

Have your temperature, blood pressure, breathing rate, and heart rate monitored.

Have blood samples taken to check your blood counts, blood minerals, liver and kidney 
function, and for certain virus that might be present (approximately 3 tablespoons).

A urine sample will be obtained

If you are a female who can have children, a urine and/or blood pregnancy test will be 
done. If urine test if positive, it will be confirmed with a blood test (less than 1 teaspoon). 
The results of the blood test must be negative for you be allowed in the study.


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
Blood samples for pharmacokinetics (PK) and pharmacodynamics (PD) (approximately 5 
teaspoons)

For Phase I patients only Research blood samples (approximately 3 tablespoons)

BMS-986253 administration
Day 2:

Have a physical exam (including weight)

Have your temperature, blood pressure, breathing rate, and heart rate monitored

Blood samples for 24-hour PK/PD timepoint (approximately 2 teaspoons)
Days 2-6:
For patients with high risk MDS only
DNMTi to be given by your NIH doctors as standard of care.
Day 15 (also day 8 and day 22 during the first cycle where indicated by*):

Visit the NIH Clinical Center to answer questions about your medical history*

Answer questions about how well you are able to take care of yourself*

List any prescriptions or non-prescription medicines you have taken*

Discuss the history of you MDS and any other medicines you have taken for the MDS*

Have a physical exam (including height and weight)*

Have your temperature, blood pressure, breathing rate, and heart rate monitored*

Have blood samples taken to check your blood counts, blood minerals, liver and kidney 
function,* and for certain virus that might be present (approximately 3 tablespoons).

A urine sample will be obtained*

If you are a female who can have children, a urine and/or blood pregnancy test will be 
done. If urine test if positive, it will be confirmed with a blood test (less than 1 teaspoon). 
The results of the blood test must be negative for you be allowed in the study.

Blood samples for pharmacokinetics (PK) and pharmacodynamics (PD) (approximately 5 
teaspoons)
o
For Phase I patients only 

BMS-986253 administration
Days 16:

Have a physical exam (including height and weight)

Have your temperature, blood pressure, breathing rate, and heart rate monitored

Blood samples for 24-hour PK timepoint (approximately 2 teaspoons)
Day 28:
Have a bone marrow biopsy taken at the following timepoint 

Phase I post cycle 1

Phase II post cycle 2

Phase II post cycle 6 


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
With development of treatment-related aplasia or concern that your disease is getting 
worse

If your study doctor feels it is indicated.

Research blood sample (approximately 6 teaspoons)
End of treatment visit: This will be done approximately 30 days from the end of the last cycle of 
therapy you received.

Visit the NIH Clinical Center to answer questions about your medical history

Answer questions about how well you are able to take care of yourself

List any prescriptions or non-prescription medicines you have taken

Discuss the history of you MDS and any other medicines you have taken for the MDS.

Have a physical exam (including height and weight)

Have your temperature, blood pressure, breathing rate, and heart rate monitored

Have blood samples taken to check your blood counts, blood minerals, liver and kidney 
function, and for certain virus that might be present.

Research blood samples (approximately 3 tablespoons)

Questionnaires (questionnaires are only required if you are able to read English)
Follow-up Period
About 30 days from the end of the last cycle on therapy you will return to the clinic to have tests 
performed to see how you are doing. After the 1st follow up visit, follow up will occur via phone 
call every 3 months for first 24 months, then every 6 months to at least 5 years post enrollment to 
see how you are doing. Outside medical records will be requested at the time of the first follow-
up phone call only. 
Additional Research Testing 
All of your samples collected for research purposes on this study (such as the cancer cells from 
peripheral blood/bone marrow samples and normal tissue) may be used to look for specific changes 
in the DNA in tumors that could be used to develop new ways of diagnosing and treating cancer. 
DNA (also called deoxyribonucleic acid) in the cells carries genetic information and passes it from 
one generation of cells to the next – like an instruction manual. Normal tissue contains the DNA 
that you were born with, DNA in cancer cells has changed – or mutated – and we think that change 
in the DNA is what causes tumors to form and to grow. 
To look at your DNA, we may do what is called “whole genome sequencing.”  This where we will 
do special tests in the lab to look at the entire sequence, or order, of how your DNA is put together.  
This is what makes you unique.  
To determine which parts of the DNA have mutated, we will compare DNA in your cancer cells 
to DNA from your normal cells. We will then analyze the results from similar cancers to see if 
there are any changes in the samples that are common to a particular type of tumor. To examine 
the tumor and normal tissue we may use several different techniques depending on the type of 
tissue we collect. These could include growing cell lines (cells which keep dividing and growing 
in the laboratory, sometimes for years allowing us to continually study those cells), xenograft 


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studies (placing or growing cells in another animal, such as mice), and looking in detail at the parts 
of the genes that produce specific proteins.
However, you should know that the analyses that we perform in our laboratory are for research 
purposes only; they are not nearly as sensitive as the tests that are performed in a laboratory that 
is certified to perform genetic testing or testing for routine clinical care. For this reason, in most 
cases we will not give you the results of the research tests done on your research samples. There 
may be exceptions to what we share with you and this is described later in this consent form in the 
section for “Error! Reference source not found..”
HOW LONG WILL THE STUDY TAKE?
If you agree to take part in this study, your involvement is expected to last for as long as you are 
responding to the therapy and do not have an unacceptable side effect. We will also continue to 
follow you by phone call after you complete therapy for at least 5 years. 

You will be seen every 2 weeks to receive the study drug BMS-986253. You will also be 
seen prior to the start of each cycle of therapy.  

Each infusion will last approximately 1-2 hours. 

Some treatment visits will require an overnight admission for blood draws.

Most treatments will be given in the Outpatient Day Hospital and will take approximately 
2-4 hours total time
After a treatment cycle is completed, we will continue to follow you to reassess your disease and 
whether additional cycles of treatment are recommended for you or refer you back to your doctor 
for continued care if other treatment options are needed. You may decide to stop participating at 
any time. 
HOW MANY PEOPLE WILL PARTICIPATE IN THIS STUDY?
Not everyone screened for the study will be eligible to receive study therapy. It is expected that 
up to 93 people may receive study therapy in this study.
WHAT ARE THE RISKS AND DISCOMFORTS OF BEING IN THE STUDY?
In a clinical study like this one, every risk or side effect cannot be predicted. Each person’s reaction 
to a study drug, device or procedure may be different. You may have a side effect or be at risk for 
symptoms, illnesses and/or complications that could not be predicted by your study doctor or the 
sponsor of this clinical study. If such side effects occur, you must inform your study doctor 
immediately. 
The study doctor will be testing your blood and will let you know if changes occur that may affect 
your health. Below we list the most common and the most serious side effects that researchers 
know about. There might be other side effects that researchers do not yet know about. If important 
new side effects are found, the study doctor will discuss these with you.
BMS-986253 
BMS-986253 used in this study, in rare cases, may affect how different parts of your body work 
including your blood counts, bone marrow, heart, brain, kidney, liver, and skin.


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Common side effects (occurring in more than 5% of patients): 

Nausea

Fatigue

Decreased appetite

Rash
Occasional side effects (occurring in less than 5% of patients): 

Localized infusion reactions

Cytokine release - patients may experience systemic effects such as myalgia, arthralgia, 
headache, sweats, fever, nausea, and skin rashes. These symptoms are typically observed 
after the first dose and are usually transient. Rarely, bronchospasm/chest tightness and 
hypotension or hypertension may be seen.

Anaphylaxis

Hemophagocytic Lymphohistiocytosis (HLH)/Macrophage Activating Syndrome (MAS): 
HLH/MAS is a rare immune system disease. It can be caused by infections, cancer, certain 
drugs, and autoimmune diseases. If you develop HLH, your body's immune system does 
not work normally. Some white blood cells called histiocytes and lymphocytes attack your 
other blood cells. Abnormal blood cells then build up in your spleen and liver. This causes 
your spleen and liver to enlarge. HLH is a life-threatening condition. It can cause death in 
weeks or months even if treated. HLH has been reported in very rare instances in patients 
with certain advanced cancers that have been treated with this study drug in combination 
with other drugs but never with BMS-986253 alone.
Decitabine and Cedazuridine:
Side effects include low blood counts (symptoms include fever, anemia, or bleeding) and increased 
risk of infection. 
The most common side effects reported, include:
• Fatigue
• Constipation
• Hemorrhage
• Myalgia
• Mucositis
• Arthralgia
• Nausea
• Dyspnea
• Diarrhea
• Rash
• Dizziness
• Febrile neutropenia
• Edema
• Headache
• Cough
• Decreased appetite
• Upper respiratory tract infection
• Pneumonia
• Transaminase increased
Other side effects linked to medical procedures during the trial:
Blood samples 
Side effects of repeated blood sampling depend in part on how the blood is drawn. If blood is 
drawn through a needle into your skin, side-effects could include pain and bruising in the area 


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where the blood was drawn. Other side-effects can include bruising, redness, discomfort or 
bleeding at the site of the needle stick, and possible lightheadedness, or rarely, fainting.  If you 
have too much blood taken over a prolonged period, your red blood cell count may drop (this is 
called “anemia”). As a precaution, we will check your red blood cell level, and give you iron 
treatment or a blood transfusion if needed. If blood is drawn through a central intravenous catheter, 
risks include contamination of the catheter which could result in a serious blood stream infection, 
requiring admission to the hospital and giving you antibiotics through the vein. Up to 
approximately 10 teaspoons of blood will be collected during one visit and no more than 20 
tablespoons will be collected over an 8-week period.
Bone Marrow Aspiration/Biopsy
The bone marrow aspiration and biopsy may cause pain, bruising, bleeding and infection.  Soreness 
near the site may last for a couple of days after the procedure. You may have more pain, risk of 
bleeding and bruising if you complete both aspiration and biopsy rather than just the aspiration.  If 
your pain is severe or you develop a fever following the procedure, please contact the study team 
immediately.  
Electrocardiogram
Other than possibly experiencing some minor skin irritation from the electrodes there are no 
anticipated risks related to complete the electrocardiogram and/or the echocardiogram.
Intravenous Catheter
The risks of IV insertion include temporary pain and bleeding or bruising at the site where the IV 
enters the skin.  Sometimes the IV catheter can become displaced, and if this happens there is a 
small chance of fluid leaking into the tissue surrounding the IV, which may cause some swelling 
and discomfort. Rarely, the IV site may become infected, which might require treatment with 
antibiotics. 
Questionnaires
Some of the questions in the questionnaire may be upsetting or make you feel uncomfortable. You 
can skip any of the questions you do not want to answer, and you can stop at any time.
What are the risks related to pregnancy?
If you are able to become pregnant, we will ask you to have a pregnancy test before starting this 
study. You must use effective birth control methods prior to study entry and try not to become 
pregnant while participating in this study or during study treatment, and for 6 months after you 
finish study treatment. If you become pregnant, there may be unknown risks to the fetus or unborn 
child, or risks that we did not anticipate. There may be long-term effects of the treatment being 
studied that could increase the risk of harm to a fetus. You must tell the study doctor if your birth 
control method fails while you are in the study. If you think or know you have become pregnant 
while participating in this research study, please contact the study team as soon as possible. If you 
plan to become pregnant in the future, please discuss with the study team how long you need to 
wait before becoming pregnant after completing the study.


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If you are a sexually active person with a partner able to become pregnant, it is important that your 
partner not become pregnant during your participation in this study or during study treatment, and 
for 6 months after you finish study treatment. There may be unknown risks to a fetus or risks we 
did not anticipate. You and your partner must agree to use birth control if you want to take part in 
this study. If you think your partner has become pregnant during your participation in this study, 
please contact the study team as soon as possible.  If you and your partner plan for your partner to 
become pregnant after your participation in this study, please discuss this with the study team.
Privacy Risks Associated with Genetic Testing
It may be possible that genetic information from you could be used by law enforcement agencies 
or other entities to identify you or your blood relatives.
Psychological or Social Risks Associated with Return of Incidental or Secondary Findings
As part of the research study, it is possible that you could learn that you have genetic risks for 
another disease or disability. This may be upsetting and, depending on what you learn, might create 
a need to make challenging decisions about how to respond. 
Although your genomic information is unique to you, you share some genomic similarities with 
your children, parents, brothers, sisters, and other blood relatives. Therefore, learning your 
research results could mean something about your family members and might cause you or your 
family distress. Before joining the study, it may be beneficial to talk with your family members 
about whether and how they want you to share your results with them. 
Protections against misuse of genetic information 
This study involves genetic testing on samples.  Some genetic information can help predict future 
health problems of you and your family and this information might be of interest to your employers 
or insurers. The Genetic Information Nondiscrimination Act (GINA) is a federal law that prohibits 
plans and health insurers from requesting genetic information or using genetic information. It also 
prohibits employment discrimination based on your health information. However, GINA does not 
address discrimination by companies that sell life insurance, disability insurance, or long-term care 
insurance. GINA also does not protect you against discrimination based on an already-diagnosed 
condition or disease that has a genetic component.
WHAT ARE THE BENEFITS OF BEING IN THE STUDY?
You might not benefit from being in this study. However, the potential benefit to you given the 
scientific rationale of this study is that the study drug may reduce inflammation that may be driving 
your cancer and leading to other physiologic stress on your body and other organs; may reduce 
your cancer burden and improve your blood counts; may prevent progression to leukemia – while 
these are all potential benefits, you may not benefit from the study drug. Participating in this study 
will also help benefit other patients with your condition, MDS, by contributing more to the current 
knowledge of effective therapies and will help move progress in the field forward.


IRB NUMBER: 000356
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Are there any potential benefits to others that might result from the study?
There is a need for new treatments in patients with MDS as standard therapies often do not work. 
In the future, other people might benefit from this study because of the knowledge gained from 
the outcome of this trial using BMS-986253. 
WHAT OTHER OPTIONS ARE THERE FOR YOU?
Before you decide whether or not to be in this study, we will discuss other options that are 
available to you. Instead of being in this study, you could: 

choose to be treated with drugs already approved by the FDA for your disease, to be 
prescribed by your home provider,

choose to take part in a different study clinical trials at NIH or at another institution

choose not to be treated for cancer at all but instead opt to receive comfort care to relieve 
symptoms.
DISCUSSION OF FINDINGS
New information about the study
If we find out any new information that may affect your choice to participate in this study, we 
will get in touch with you to explain what we have learned. This may be information we have 
learned while doing this study here at the NIH or information we have learned from other 
scientists doing similar research in other places.
Return of research results
When we are examining your DNA, it is possible that we could identify possible changes in other 
parts of your DNA that are not related to this research. These are known as “incidental medical 
findings”. 
These include: 

Changes in genes that are related to diseases other than cancer 

Changes in genes that are not known to cause any disease. These are known as normal 
variations. 

Changes in genes that are new and of uncertain clinical importance. This means that we do 
not know if they could cause or contribute to a disease or if they are normal variations. 
Since the analyses that we perform in our laboratory are not nearly as sensitive as the tests that are 
performed in a laboratory that is certified to perform genetic testing, the genetic changes that we 
find may or may not be valid.  Therefore, we do not plan to inform you of all of the genetic results 
of testing on your tissue and blood that is performed in our research lab. However, in the unlikely 
event that we discover a finding believed to be clinically important based on medical standards at 
the time we first analyze your results, we will contact you. This could be many years in the future. 
We will ask you to have an additional sample drawn to verify the findings we have seen in our lab. 
If the results are verified, you will be re-contacted and offered a referral to a genetic healthcare 
provider to discuss the results.


IRB NUMBER: 000356
IRB APPROVAL DATE: 4/18/2023
PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
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EARLY WITHDRAWAL FROM THE STUDY 
Your doctor may decide to stop your therapy for the following reasons:

if he/she believes that it is in your best interest

if your disease worsens or comes back during treatment

if you have side effects from the treatment that your doctor thinks are too severe

if you become pregnant

if BMS-986253 may become unavailable

if new information shows that another treatment would be better for you

if you do not follow the study rules

if the study is stopped for any reason
In this case, you will be informed of the reason therapy is being stopped.  
After therapy is stopped we would like to see you for a safety visit 30 days after your last dose.
You can stop taking part in the study at any time. However, if you decide to stop taking part in the 
study, we would like you to talk to the study doctor and your regular doctor first.
If you decide at any time to withdraw your consent to participate in the trial, we will not collect 
any additional medical information about you. However, according to FDA guidelines, 
information collected on you up to that point may still be provided to our collaborators or 
designated representatives.
STORAGE, SHARING AND FUTURE RESEARCH USING YOUR SPECIMENS AND 
DATA
Will your specimens or data be saved by the study team for use in other studies?
As part of this study, we are obtaining specimens and data from you. We plan to store and use 
these specimens and data for studies other than the ones described in this consent form that are 
going on right now, as well as studies that may be conducted in the future. The specimens and 
data will be kept in a way that we will still know that they came from you (i.e., they will be 
identifiable to us). If we use your identifiable specimens or data for future research, our study 
will be reviewed and approved by an Institutional Review Board who will make sure that we are 
protecting your confidentiality. These future might help us to better understand myelodysplastic 
syndromes, or other diseases or conditions. This could include studies to develop other research 
tests, treatments, drugs, or devices, that may lead to the development of a commercial product 
by the NIH and/or its research or commercial partners. There are no plans to provide financial 
compensation to you if this happens. Also, it is unlikely that we will learn anything from these 
studies that may directly benefit you.
I give permission for my identifiable specimens and data to be stored and used by the study team 
for future studies as described above.
_____ Yes
_____ No
Initial
Initial


IRB NUMBER: 000356
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Will your specimens or data be shared with other researchers for use in other studies?
We may share your specimens and data with other researchers. The other researchers may be 
doing studies in similar areas to this study or in other unrelated areas. These researchers may be 
at NIH, other research centers and institutions, or commercial entities.
If we do share your specimens or data, we will know that the specimens and data came from you. 
However, the other researchers will not know that they came from you (i.e., they will be de-
identified).  
I give permission for my identifiable specimens and data to be shared with and used by other 
researchers for future studies.
_____ Yes 
_____ No
Initial
Initial
In addition to the planned use and sharing described above, we might remove labels from your 
specimens and data that might identify you (i.e., anonymize them), and use them or share them 
with other researchers for future studies at the NIH or other places. When we or the other 
researchers use your anonymized specimens and data for these projects, there will be no way to 
know that they came from you. We want to make sure that you understand that this is a possibility 
if you participate in this study. Once we do this, we would not be able to remove your specimens 
or data from these studies to prevent their use in future research studies because we would not 
be able to tell which specimens or data belong to you.
Can you change your mind about use and sharing for future research?
If you change your mind and do not want us to store and use your specimens and data for future 
studies, you should contact the study team. We will do our best to comply with your request but 
cannot guarantee that we will always be able to destroy your specimens and data. For example, 
if some research with your specimens and data is already complete, the information from that 
research may still be used. Also, if the specimens and data have been shared already, it might 
not be possible to withdraw them. 
Will your genomic data be shared outside of this study?
As part of this study, we will put your genomic information in a large database for broad sharing 
with the research community. These databases are commonly called data repositories.  The 
information in this database will include but is not limited to, genetic information, race, ethnicity 
and sex.  If your information is placed in one of these repositories, it will be labeled with a code 
(not with your name or other information that could be used to easily identify you), and and only 
qualified researchers will be able to access it. These researchers must receive permission from 
individuals or committees with the authority to determine whether these researchers can access the 


IRB NUMBER: 000356
IRB APPROVAL DATE: 4/18/2023
PATIENT IDENTIFICATION
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NIH-2977 (4-17)
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
data. Before receiving the data, the researchers must promise that they will not attempt to re-
identify the subjects whose data they will receive.
Genomic summary information about all of the participants included in this study (including you) 
is being placed in a database and will be available through open access. This information will help 
the researchers understand if some genetic patterns are more common than others among the 
subjects who participated in the study. The researchers and non-researchers will be able to access 
genomic summary information about all the participants included in the study, or summary 
information combined from multiple studies, without applying for permission. The risk of anyone 
identifying you based on this information is very low.
How long will your specimens and data be stored by the NIH?
Your specimens and data may be stored by the NIH indefinitely. 
Risks of storage and sharing of specimens and data
When we store your specimens and data, we take precautions to protect your information from 
others that should not have access to it. When we share your specimens and data, we will do 
everything we can to protect your identity, for example, when appropriate, we remove information 
that can identify you. Even with the safeguards we put in place, we cannot guarantee that your 
identity will never become known or that no one will gain unauthorized access to your information. 
New methods may be created in the future that could make it possible to re-identify your specimens 
and data.
PAYMENT
Will you receive any type of payment for taking part in this study?
You will not receive any payment for taking part in this study. 
REIMBURSEMENT
Will you receive reimbursement or direct payment by NIH as part of your participation?
On this study, the NCI will reimburse the cost for some of your expenses such as those for hotel, 
travel, meals. Some of these costs may be paid directly by the NIH and some may be reimbursed 
after you have paid. The amount and form of these payments are determined by the NCI Travel 
and Lodging Reimbursement Policy. You will be given a summary of the policy which provides 
more information.
If your travel to the NIH Clinical Center (e.g. flight, hotel) is arranged and paid for by the NIH, 
the agency making the reservations and their representatives will have access to your identifiable 
information.
COSTS
Will taking part in this research study cost you anything? 
NIH does not bill health insurance companies or participants for any research or related clinical 
care that you receive at the NIH Clinical Center. 


IRB NUMBER: 000356
IRB APPROVAL DATE: 4/18/2023
PATIENT IDENTIFICATION
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NIH-2977 (4-17)
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY

If some tests and procedures are performed outside the NIH Clinical Center, you may have 
to pay for these costs.
CONFLICT OF INTEREST (COI)
The NIH reviews NIH staff researchers at least yearly for conflicts of interest. This process is 
detailed in a COI Guide.  You may ask your research team for a copy of the COI Guide or for more 
information.  Members of the research team who do not work for NIH are expected to follow these 
guidelines or the guidelines of their home institution, but they do not need to report their personal 
finances to the NIH.
The NIH and the research team for this study are using BMS-986253 developed by Bristol Myers 
Squibb through a collaboration between your study team and the company. The company also 
provides financial support for this study.
CLINICAL TRIAL REGISTRATION AND RESULTS REPORTING  
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law. This Web site will not include information that can identify you. At most, the Web 
site will include a summary of the results. You can search this Web site at any time.
CONFIDENTIALITY PROTECTIONS PROVIDED IN THIS STUDY  
Will your medical information be kept private?
We will do our best to make sure that the personal information in your medical record will be kept 
private.  However, we cannot guarantee total privacy.  Organizations that may look at and/or copy 
your medical records for research, quality assurance, and data analysis include:

The NIH and other government agencies, like the Food and Drug Administration (FDA), 
which are involved in keeping research safe for people.

National Institutes of Health Intramural Institutional Review Board

The study Sponsor (Center for Cancer Research) or their agent(s)

Qualified representatives from Bristol Myers Squibb, the pharmaceutical company who 
produces BMS-986253.
The researchers conducting this study and the NIH follow applicable laws and policies to keep 
your identifying information private to the extent possible.  However, there is always a chance 
that, despite our best efforts, your identity and/or information about your participation in this 
research may be inadvertently released or improperly accessed by unauthorized persons.
In most cases, the NIH will not release any identifiable information collected about you without 
your written permission.  However, your information may be shared as described in the section of 
this document on sharing of specimens and data, and as further outlined in the following sections.  
Further, the information collected for this study is protected by NIH under a Certificate of 
Confidentiality and the Privacy Act. 


IRB NUMBER: 000356
IRB APPROVAL DATE: 4/18/2023
PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
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CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
Certificate of Confidentiality
To help us protect your privacy, the NIH Intramural Program has received a Certificate of 
Confidentiality (Certificate). With this certificate, researchers may not release or use data or 
information about you except in certain circumstances.  
NIH researchers must not share information that may identify you in any federal, state, or local 
civil, criminal, administrative, legislative, or other proceedings, for example, if requested by a 
court.  
The Certificate does not protect your information when it:  
1. is disclosed to people connected with the research, for example, information may be used 
for auditing or program evaluation internally by the NIH; or 
2. is required to be disclosed by Federal, State, or local laws, for example, when information 
must be disclosed to meet the legal requirements of the federal Food and Drug 
Administration (FDA); 
3. is for other research;
4. is disclosed with your consent. 
The Certificate does not prevent you from voluntarily releasing information about yourself or your 
involvement in this research. 
The Certificate will not be used to prevent disclosure to state or local authorities of harm to self or 
others including, for example, child abuse and neglect, and by signing below you consent to those 
disclosures. Other permissions for release may be made by signing NIH forms, such as the Notice 
and Acknowledgement of Information Practices consent.
Privacy Act
The Federal Privacy Act generally protects the confidentiality of your NIH medical information 
that we collect under the authority of the Public Health Service Act.  In some cases, the Privacy 
Act protections differ from the Certificate of Confidentiality.  For example, sometimes the Privacy 
Act allows release of information from your record without your permission, for example, if it is 
requested by Congress. Information may also be released for certain research purposes with due 
consideration and protection, to those engaged by the agency for research purposes, to certain 
federal and state agencies, for HIV partner notification, for infectious disease or abuse or neglect 
reporting,  to tumor registries, for quality assessment and medical audits, or when the NIH is 
involved in a lawsuit.  However, NIH will only release information from your medical record if it 
is permitted by both the Certificate of Confidentiality and the Privacy Act.
POLICY REGARDING RESEARCH-RELATED INJURIES  
The NIH Clinical Center will provide short-term medical care for any injury resulting from your 
participation in research here. In general, no long-term medical care or financial compensation for 
research-related injuries will be provided by the NIH, the NIH Clinical Center, or the Federal 
Government. However, you have the right to pursue legal remedy if you believe that your injury 
justifies such action.


IRB NUMBER: 000356
IRB APPROVAL DATE: 4/18/2023
PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 1/23/2023
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
PROBLEMS OR QUESTIONS
If you have any problems or questions about this study, about your rights as a research participant, 
or about any research-related injury, contact the Principal Investigator, Steven Pavletic, MD, 
pavletis@mail.nih.gov, 240-760-6174. Other researchers you may call are: Noa Holtzman, MD, 
at 240-858-3224. You may also call the NIH Clinical Center Patient Representative at 301-496-
2626, or the NIH Office of IRB Operations at 301-402-3713, if you have a research-related 
complaint or concern.
CONSENT DOCUMENT 
Please keep a copy of this document in case you want to read it again.


IRB NUMBER: 000356
IRB APPROVAL DATE: 4/18/2023
PATIENT IDENTIFICATION
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NIH-2977 (4-17)
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CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
Adult Research Participant: I have read the explanation about this study and have been given the opportunity 
to discuss it and to ask questions. I consent to participate in this study.
Signature of Research Participant
Print Name of Research Participant
Date
Investigator:
Signature of Investigator
Print Name of Investigator
Date
Witness should sign below if either: 
1. A short form consent process has been used to enroll a non-English speaking subject or
2. An oral presentation of the full consent has been used to enroll a blind or illiterate subject
Signature of Witness
Print Name of Witness
Date
NIH ADMINISTRATIVE SECTION TO BE COMPLETED REGARDING THE USE OF AN 
INTERPRETER:
An interpreter, or other individual, who speaks English and the participant’s preferred language facilitated
the administration of informed consent and served as a witness. The investigator obtaining consent may not 
also serve as the witness.
An interpreter, or other individual, who speaks English and the participant’s preferred language facilitated
the administration of informed consent but did not serve as a witness. The name or ID code of the person 
providing interpretive support is:
.

ICF_001.pdf: 
IRB NUMBER: 000356
IRB APPROVAL DATE: 4/18/2023
PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (2)
Version Date: 1/23/2023
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
PRINCIPAL INVESTIGATOR:  Steven Pavletic, MD
STUDY TITLE:  A Phase I/II Trial of BMS-986253 in Myelodysplastic Syndromes
STUDY SITE:  NIH Clinical Center
Cohort: Screening 
Consent Version:  1/23/2023 
WHO DO YOU CONTACT ABOUT THIS STUDY? 
  Principal Investigator:
Steven Pavletic, MD, MS
240-760-6174
pavletis@mail.nih.gov
KEY INFORMATION ABOUT THIS RESEARCH 
This consent form describes a research study and is designed to help you decide if you would 
like to be a part of the research study.  
You are being asked to take part in a research study at the National Institutes of Health (NIH). 
This section provides the information we believe is most helpful and important to you in making 
your decision about participating in this study. Additional information that may help you decide 
can be found in other sections of the document. Taking part in research at the NIH is your choice.
You are being asked to be screened for this study because you have been diagnosed with 
Myelodysplastic Syndromes (MDS).
This consent form requests your permission for us to determine your eligibility for our study 
involving treatment with BMS-986253 as a treatment for MDS. 
The use of BMS-986253 in this study is considered investigational, which means that is has not 
been approved by the U.S. Food and Drug Administration (FDA) to treat MDS. However, the 
FDA has given us permission to use BMS-986253 in this study.
There are other drugs that may be used to treat your disease, and these can be prescribed/given 
by your regular doctor, even if you are not in this study.  Some examples include: other DNMTi 
therapy such as azacitidine or decitabine, other oral treatments such as lenalidomide, or drugs 
that would not treat the disease directly but may help improve your blood counts and overall 
symptoms, such as erythropoietin stimulating agents.
The goal of this study is to determine if BMS-986253 is a safe and effective treatment for 
Myelodysplastic Syndromes (MDS). The first phase of this research study will determine the 
largest dose of BMS-986253 that can be safely given to patients with MDS. The second phase 
of this research study will determine how well patients with MDS respond to BMS-986253.
This consent is for “screening.” We would like to “screen” you to find out if you are able to take 
part in this study, and this could mean that we will use samples from procedures you have 
undergone at home or in the Clinical Center. 


IRB NUMBER: 000356
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PATIENT IDENTIFICATION
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CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
If you decide to be screened for this study, here are some of the most important things that you 
should know that will happen.
We will first do some basic tests to make sure you qualify for the trial. These basic tests involve 
blood tests, images, and physical exams, etc. Other tests are described further on in this consent 
form. It is important that you read these.
There is a chance that you may experience side effects from the tests to be done (for example: 
pain from blood draws where the needle enters the skin). 
You will not benefit from this screening evaluation. 
You may choose not to be tested for eligibility or to have any other studies done.
You are free to stop participating in the trial at any time.  
The remaining document will now describe the research study in more detail.  This information 
should be considered before you make your choice. Members of the study team will talk with you 
about the information in this document. Some people have personal, religious, or ethical beliefs 
that may limit the kinds of medical or research interventions in which they would want to 
participate. Take the time you need to ask any questions and discuss this study with NIH staff, and 
with your family, friends, and personal health care providers.
IT IS YOUR CHOICE TO TAKE PART IN THE STUDY
You may choose not to take part in this study for any reason. If you join this study, you may change 
your mind and stop participating in the study at any time and for any reason. In either case, you 
will not lose any benefits to which you are otherwise entitled. However, to be seen at the NIH, you 
must be taking part in a study or are being considered for a study. If you do choose to leave the 
study, please inform your study team to ensure a safe withdrawal from the research.  
WHY IS THIS STUDY BEING DONE?
The purpose of the phase I portion of this study is to test the safety of BMS-986253 at different 
doses to find out what effects, if any, it has on participants with MDS to determine the 
recommended dose for the phase 2 part of the trial.  The purpose of the phase II portion of the 
study is to determine the response rate to BMS-986253. 
You are being asked to join this study because you have been diagnosed with MDS.
You may not be eligible for our study with BMS-986253 for several reasons, such as the presence 
of certain other diseases, infections, or blood counts which are not in the correct range.   
In order to see if you are eligible to take part in the research, we are asking you to first take part in 
this screening portion of the study.
WHAT WILL HAPPEN DURING THE STUDY?
During the screening period, your doctor will make sure you are able to take part in the study.
You will be asked questions about your medical history, and prescription or non-prescription 
medications you take or have taken, the history or your disease and how well you are able to care 
for yourself.


IRB NUMBER: 000356
IRB APPROVAL DATE: 4/18/2023
PATIENT IDENTIFICATION
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NIH-2977 (4-17)
File in Section 4: Protocol Consent (2)
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
You will undergo the following tests/assessments to see whether you are able to take part in the 
study:

Medical history

Physical examination

Laboratory evaluations

ECG
Required screening assessments:
During your screening period you will:

Visit the NIH Clinical Center to answer questions about your medical history

Answer questions about how well you are able to take care of yourself

List any prescriptions or non-prescription medicines you have taken

Discuss the history of you MDS and any other medicines you have taken for the MDS.

Have a physical exam (including height and weight)

Have your temperature, blood pressure, breathing rate, oxygen saturation, and heart rate 
monitored

Have an electrocardiogram (ECG) a test to show how well your heart is working

Have blood samples taken to check your blood counts, blood minerals, liver and kidney 
function, and to screen for certain viruses (approximately 3 tablespoons).

A bone marrow biopsy may be performed to confirm your diagnosis of MDS if unable to 
confirm by obtaining an outside bone marrow sample

If you are a female who can have children, a urine and/or blood pregnancy test will be 
done. If urine test if positive, it will be confirmed with a blood test (approximately 1 
teaspoon). The results of the blood test must be negative for you be allowed to participate 
in the study.
As part of this study, we will test you for infection with HIV, the virus that causes AIDS. If you 
are infected with HIV, you will not be able to take part in this study. We will tell you what the 
results mean, how to find care, how to avoid infecting others, how we report HIV infections, and 
the importance of informing your partners at possible risk because of your HIV infection.
If the tests or if your answers show that you are not able to take part in the study, you will not be 
allowed to continue. Your study doctor will discuss other care options with you.
If you are able to take part in the study, your study doctor will assign you to a specific group.
You will also be assigned to a specific subgroup to receive either BMS-986253 monotherapy or in 
combination with a DNMTi (decitabine and cedazuridine). Your study doctor will inform you of 
your treatment plan.
HOW LONG WILL THE STUDY TAKE?
If you agree to take part in this screening, your involvement will last for the length of time to see 
if you are eligible to take part in the research treatment phase of the study. The length of time may 
range anywhere from a couple weeks to several months. You will be required to come to NIH at 
least one-time during screening and the visit may last anywhere from 1 to 14 days.


IRB NUMBER: 000356
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PATIENT IDENTIFICATION
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NIH-2977 (4-17)
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HOW MANY PEOPLE WILL PARTICIPATE IN THIS STUDY?
As not all persons screened will be eligible for study therapy, up to 200 patients will be enrolled 
in order to treat about 93 subjects on the study.
WHAT ARE THE RISKS AND DISCOMFORTS OF BEING IN THE STUDY?
Listed below are possible risks and discomforts with being in this screening part of the study:
Blood samples 
Side effects of repeated blood sampling depend in part on how the blood is drawn. If through an 
intravenous catheter, risks include contamination of the catheter which could result in a serious 
blood stream infection, requiring admission to the hospital and giving you antibiotics through the 
vein; if blood is drawn through a needle into your skin, side effects could include pain and bruising 
in the area where the blood was drawn. Other side effects can include bruising, redness, discomfort 
or bleeding at the site of the needle stick, and possible lightheadedness, or rarely, fainting.  If you 
have too much blood taken over a prolonged period, your red blood cell count may drop (this is 
called “anemia”). As a precaution, we will check your red blood cell level, and give you  an iron 
treatment or a blood transfusion if needed. Approximately 3.5 tablespoons of blood may be drawn 
for this screening process.   
Electrocardiogram
Other than possibly experiencing some minor skin irritation from the electrodes, there are no 
anticipated risks related to completing the electrocardiogram and/or the echocardiogram.
Bone Marrow Aspiration/Biopsy
The bone marrow aspiration and biopsy may cause pain, bruising, bleeding, and infection.  
Soreness near the site may last for a couple of days after the procedure. You may have more pain, 
risk of bleeding and bruising if you complete both aspiration and biopsy rather than just the 
aspiration.  If your pain is severe or you develop a fever, please contact the study team 
immediately.  
What are the risks related to pregnancy?
If you are able to become pregnant, we will ask you to have a pregnancy test before starting this 
study. You must use effective birth control methods prior to study entry and try not to become 
pregnant while participating in this study or during study treatment, and for 6 months after you 
finish study treatment. If you become pregnant, there may be unknown risks to the fetus or unborn 
child, or risks that we did not anticipate. There may be long-term effects of the treatment being 
studied that could increase the risk of harm to a fetus. You must tell the study doctor if your birth 
control method fails while you are in the study. If you think or know you have become pregnant 
while participating in this research study, please contact the study team as soon as possible. If you 
plan to become pregnant in the future, please discuss with the study team how long you need to 
wait before becoming pregnant after completing the study.
If you are a sexually active person with a partner able to become pregnant, it is important that your 
partner not become pregnant during your participation in this study or during study treatment, and 
for 6 months after you finish study treatment. There may be unknown risks to a fetus or risks we 


IRB NUMBER: 000356
IRB APPROVAL DATE: 4/18/2023
PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (2)
Version Date: 1/23/2023
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
did not anticipate. You and your partner must agree to use birth control if you want to take part in 
this study. If you think your partner has become pregnant during your participation in this study, 
please contact the study team as soon as possible.  If you and your partner plan for your partner to 
become pregnant after your participation in this study, please discuss this with the study team.
Privacy Risks Associated with Genetic Testing
It may be possible that genetic information from you could be used by law enforcement agencies 
or other entities to identify you or your blood relatives
PSYCHOLOGICAL OR SOCIAL RISKS ASSOCIATED WITH RETURN OF 
INCIDENTAL OR SECONDARY FINDINGS
As part of the research study, it is possible that you could learn that you have genetic risks for 
another disease or disability. This may be upsetting and, depending on what you learn, might create 
a need to make challenging decisions about how to respond. 
Although your genomic information is unique to you, you share some genomic similarities with 
your children, parents, brothers, sisters, and other blood relatives. Therefore, learning your 
research results could mean something about your family members and might cause you or your 
family distress. Before joining the study, it may be beneficial to talk with your family members 
about whether and how they want you to share your results with them. 
PROTECTIONS AGAINST MISUSE OF GENETIC INFORMATION 
This study involves genetic testing on samples.  Some genetic information can help predict future 
health problems of you and your family and this information might be of interest to your employers 
or insurers. The Genetic Information Nondiscrimination Act (GINA) is a federal law that prohibits 
plans and health insurers from requesting genetic information or using genetic information. It also 
prohibits employment discrimination based on your health information. However, GINA does not 
address discrimination by companies that sell life insurance, disability insurance, or long-term care 
insurance. GINA also does not protect you against discrimination based on an already-diagnosed 
condition or disease that has a genetic component.
WHAT ARE THE BENEFITS OF BEING IN THE STUDY?
You will not benefit from this screening evaluation; however, this will determine if you are eligible 
to participate in the clinical trial.
Are there any potential benefits to others that might result from the study?
In the future, other people might benefit from this study because the knowledge gained from this 
study may be used to help treat others who have MDS.  
WHAT OTHER OPTIONS ARE THERE FOR YOU?
You may choose not to be tested for eligibility or to have any other studies done. 
DISCUSSION OF FINDINGS
New information about the study
If we find out any new information that may affect your choice to participate in this study, we 
will get in touch with you to explain what we have learned. This may be information we have 


IRB NUMBER: 000356
IRB APPROVAL DATE: 4/18/2023
PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (2)
Version Date: 1/23/2023
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CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
learned while doing this study here at the NIH or information we have learned from other 
scientists doing similar research in other places.
Return of research results
The results from the evaluations for this screening will be reported to you. You will be informed 
at that time if you are eligible for the main study.
EARLY WITHDRAWAL FROM THE STUDY 
Your doctor may decide to stop your screening evaluation for the following reasons:

if he/she believes that it is in your best interest

if you are ineligible for the study

if you become pregnant

if new information shows that another treatment would be better for you

if the study is stopped for any reason
If your evaluation is stopped, you will be informed of the reason screening is being stopped. You 
can stop taking part in the study at any time. However, if you decide to stop taking part in the 
study, we would like you to talk to the study doctor and your regular doctor first.
If you decide at any time to withdraw your consent to participate in the trial, we will not collect 
any additional medical information about you. However, according to FDA guidelines, 
information collected on you up to that point may still be provided to our collaborators or 
designated representatives.
STORAGE, SHARING AND FUTURE RESEARCH USING YOUR SPECIMENS AND 
DATA
Will your specimens or data be saved by the study team for use in other studies?
As part of this study, we are obtaining specimens and data from you. We plan to store and use 
these specimens and data for studies other than the one described in this consent form that are 
going on right now, as well as studies that may be conducted in the future. The specimens and 
data will be kept in a way that we will still know that they came from you (i.e., they will be 
identifiable to us). If we use your identifiable specimens or data for future research, our study 
will be reviewed and approved by an Institutional Review Board who will make sure that we are 
protecting your confidentiality. These future studies might help us better understand 
myelodysplastic syndromes, or other diseases or conditions. This could include studies to 
develop other research tests, treatments, drugs, or devices, that may lead to the development of 
a commercial product by the NIH and/or its research or commercial partners. There are no plans 
to provide financial compensation to you if this happens. Also, it is unlikely that we will learn 
anything from these studies that may directly benefit you.
I give permission for my identifiable specimens and data to be stored and used by the study team 
for future studies as described above.
_____ Yes
_____ No
Initial
Initial


IRB NUMBER: 000356
IRB APPROVAL DATE: 4/18/2023
PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (2)
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Will your specimens or data be shared with other researchers for use in other studies?
We may share your specimens and data with other researchers. The other researchers may be 
doing studies in similar areas to this study or in other unrelated areas. These researchers may be 
at NIH, other research centers and institutions, or commercial entities.
If we do share your specimens or data, we will know that the specimens and data came from you. 
However, the other researchers will not know that they came from you (i.e., they will be de-
identified).  
I give permission for my de-identified specimens and data to be shared with and used by other 
researchers for future studies.
_____ Yes 
_____ No
Initial
Initial
In some cases, it may help other researchers to know that the specimens or data were collected 
from you (i.e., they will have your identifiers). If we share your identity with other researchers, 
their study will be reviewed and approved by an Institutional Review Board who will make sure 
that the study team is protecting your confidentiality. 
I give permission for my identifiable specimens and data to be shared with and used by other 
researchers for future studies.
_____ Yes 
_____ No
Initial
Initial
In addition to the planned use and sharing described above, we might remove any labels from 
your specimens and data that might identify you (i.e., anonymize them), and use them or share 
them with other researchers for future studies at the NIH or other places. When we or the other 
researchers use your anonymized specimens and data for these projects, there will be no way to 
know that they came from you. We want to make sure that you understand that this is a possibility 
if you participate in this study. Once we do this, we would not be able to remove your specimens 
or data from these studies or prevent their use in future research studies because we would not 
be able to tell which specimens or data belong to you.
Can you change your mind about use and sharing for future research?
If you change your mind and do not want us to store and use your specimens and data for future 
studies, you should contact the study team. We will do our best to comply with your request but 
cannot guarantee that we will always be able to destroy your specimens and data. For example, 
if some research with your specimens and data is already complete, the information from that 
research may still be used. Also, if the specimens and data have been shared already, it might 
not be possible to withdraw them. 


IRB NUMBER: 000356
IRB APPROVAL DATE: 4/18/2023
PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (2)
Version Date: 1/23/2023
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CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
Will your genomic data be shared outside of this study?
As part of this research study, we will put your genomic information in a large database for broad 
sharing with the research community. These databases are commonly called data repositories. 
The information in this database will include, but is not limited to, genetic information, race, 
ethnicity and sex.  If your information is placed in one of these repositories, it will be labeled 
with a code (not with your name or other information that could be used to easily identify you), 
and only qualified researchers will be able to access it. These researchers must receive 
permission from individuals or committees with the authority to determine whether these 
researchers can access the data. Before receiving the data, the researchers must promise that they 
will not attempt to re-identify the subjects whose data they will receive.
Genomic summary information about all of the participants included in this study (including you) 
is being placed in a database and will be available through open access. This information will help 
the researchers understand if some genetic patterns are more common than others among the 
subjects who participated in the study. The researchers and non-researchers will be able to access 
genomic summary information about all the participants included in the study, or summary 
information combined from multiple studies, without applying for permission. The risk of anyone 
identifying you based on this information is very low.
How long will your specimens and data be stored by the NIH?
Your specimens and data may be stored by the NIH indefinitely.
Risks of storage and sharing of specimens and data
When we store your specimens and data, we take precautions to protect your information from 
others that should not have access to it. When we share your specimens and data, we will do 
everything we can to protect your identity, for example, when appropriate, we remove information 
that can identify you. Even with the safeguards we put in place, we cannot guarantee that your 
identity will never become known or that no one will gain unauthorized access to your information. 
New methods may be created in the future that could make it possible to re-identify your specimens 
and data.
PAYMENT
Will you receive any type of payment for taking part in this study?
You will not receive any payment for taking part in this study. 
REIMBURSEMENT
Will you receive reimbursement or direct payment by NIH as part of your participation?
On this study, the NCI will reimburse the cost for some of your expenses such as those for hotel, 
travel, meals. Some of these costs may be paid directly by the NIH and some may be reimbursed 
after you have paid. The amount and form of these payments are determined by the NCI Travel 
and Lodging Reimbursement Policy. You will be given a summary of the policy which provides 
more information.


IRB NUMBER: 000356
IRB APPROVAL DATE: 4/18/2023
PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (2)
Version Date: 1/23/2023
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
If your travel to the NIH Clinical Center (e.g. flight, hotel) is arranged and paid for by the NIH, 
the agency making the reservations and their representatives will have access to your identifiable 
information.
COSTS
Will taking part in this research study cost you anything?
NIH does not bill health insurance companies or participants for any research or related clinical 
care that you receive at the NIH Clinical Center. 

If some tests and procedures are performed outside the NIH Clinical Center, you may have 
to pay for these costs.
CONFLICT OF INTEREST (COI) 
The NIH reviews NIH staff researchers at least yearly for conflicts of interest.  This process is 
detailed in a COI Guide.  You may ask your research team for a copy of the COI Guide or for more 
information.  Members of the research team who do not work for NIH are expected to follow these 
guidelines or the guidelines of their home institution, but they do not need to report their personal 
finances to the NIH.
The NIH and the research team for this study are using BMS-986253 developed by Bristol Myers 
Squibb through a collaboration between your study team and the company. The company also 
provides financial support for this study.
CLINICAL TRIAL REGISTRATION AND RESULTS REPORTING  
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law. This Web site will not include information that can identify you. At most, the Web 
site will include a summary of the results. You can search this Web site at any time.
CONFIDENTIALITY PROTECTIONS PROVIDED IN THIS STUDY  
Will your medical information be kept private? 
We will do our best to make sure that the personal information in your medical record will be kept 
private.  However, we cannot guarantee total privacy.  Organizations that may look at and/or copy 
your medical records for research, quality assurance, and data analysis include:

The NIH and other government agencies, like the Food and Drug Administration (FDA), 
which are involved in keeping research safe for people.

National Institutes of Health Intramural Institutional Review Board

The study Sponsor (Center for Cancer Research) or their agent(s)

Qualified representatives from Bristol Myers Squibb, the pharmaceutical company who 
produces BMS-986253.
The researchers conducting this study and the NIH follow applicable laws and policies to keep 
your identifying information private to the extent possible.  However, there is always a chance 
that, despite our best efforts, your identity and/or information about your participation in this 
research may be inadvertently released or improperly accessed by unauthorized persons.


IRB NUMBER: 000356
IRB APPROVAL DATE: 4/18/2023
PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (2)
Version Date: 1/23/2023
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
In most cases, the NIH will not release any identifiable information collected about you without 
your written permission.  However, your information may be shared as described in the section of 
this document on sharing of specimens and data, and as further outlined in the following sections.  
Further, the information collected for this study is protected by NIH under a Certificate of 
Confidentiality and the Privacy Act. 
Certificate of Confidentiality
To help us protect your privacy, the NIH Intramural Program has received a Certificate of 
Confidentiality (Certificate). With this certificate, researchers may not release or use data or 
information about you except in certain circumstances.  
NIH researchers must not share information that may identify you in any federal, state, or local 
civil, criminal, administrative, legislative, or other proceedings, for example, if requested by a 
court.  
The Certificate does not protect your information when it:  
1. is disclosed to people connected with the research, for example, information may be used 
for auditing or program evaluation internally by the NIH; or 
2. is required to be disclosed by Federal, State, or local laws, for example, when information 
must be disclosed to meet the legal requirements of the federal Food and Drug 
Administration (FDA); 
3. is for other research;
4. is disclosed with your consent. 
The Certificate does not prevent you from voluntarily releasing information about yourself or your 
involvement in this research. 
The Certificate will not be used to prevent disclosure to state or local authorities of harm to self or 
others including, for example, child abuse and neglect, and by signing below you consent to those 
disclosures. Other permissions for release may be made by signing NIH forms, such as the Notice 
and Acknowledgement of Information Practices consent.
Privacy Act
The Federal Privacy Act generally protects the confidentiality of your NIH medical information 
that we collect under the authority of the Public Health Service Act.  In some cases, the Privacy 
Act protections differ from the Certificate of Confidentiality.  For example, sometimes the Privacy 
Act allows release of information from your record without your permission, for example, if it is 
requested by Congress. Information may also be released for certain research purposes with due 
consideration and protection, to those engaged by the agency for research purposes, to certain 
federal and state agencies, for HIV partner notification, for infectious disease or abuse or neglect 
reporting, to tumor registries, for quality assessment and medical audits, or when the NIH is 
involved in a lawsuit.  However, NIH will only release information from your medical record if it 
is permitted by both the Certificate of Confidentiality and the Privacy Act.
POLICY REGARDING RESEARCH-RELATED INJURIES  
The NIH Clinical Center will provide short-term medical care for any injury resulting from your 
participation in research here. In general, no long-term medical care or financial compensation for 


IRB NUMBER: 000356
IRB APPROVAL DATE: 4/18/2023
PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (2)
Version Date: 1/23/2023
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
research-related injuries will be provided by the NIH, the NIH Clinical Center, or the Federal 
Government. However, you have the right to pursue legal remedy if you believe that your injury 
justifies such action.
PROBLEMS OR QUESTIONS
If you have any problems or questions about this study, about your rights as a research participant, 
or about any research-related injury, contact the Principal Investigator, Steven Pavletic, MD, 
pavletis@mail.nih.gov, 240-760-6174. Other researchers you may call are: Noa Holtzman, MD, 
at 240-858-3224. You may also call the NIH Clinical Center Patient Representative at 301-496-
2626, or the NIH Office of IRB Operations at 301-402-3713, if you have a research-related 
complaint or concern.
CONSENT DOCUMENT 
Please keep a copy of this document in case you want to read it again.


IRB NUMBER: 000356
IRB APPROVAL DATE: 4/18/2023
PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (2)
Version Date: 1/23/2023
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
Adult Research Participant: I have read the explanation about this study and have been given the opportunity 
to discuss it and to ask questions. I consent to participate in this study.
Signature of Research Participant
Print Name of Research Participant
Date
Investigator:
Signature of Investigator
Print Name of Investigator
Date
Witness should sign below if either:
1. A short form consent process has been used to enroll a non-English speaking subject or
2. An oral presentation of the full consent has been used to enroll a blind or illiterate subject
Signature of Witness
Print Name of Witness
Date
NIH ADMINISTRATIVE SECTION TO BE COMPLETED REGARDING THE USE OF AN 
INTERPRETER:
An interpreter, or other individual, who speaks English and the participant’s preferred language facilitated
the administration of informed consent and served as a witness. The investigator obtaining consent may not 
also serve as the witness.
An interpreter, or other individual, who speaks English and the participant’s preferred language facilitated
the administration of informed consent but did not serve as a witness. The name or ID code of the person 
providing interpretive support is:
.