Clinical trial NCT03900715
Conditions: Myelodysplastic Syndromes
Keywords: Myelodysplastic Syndromes MDS ACE-536 Anemia
Sponsor: Celgene
Start date: 2019-05-20; Completion date: 2023-03-01
Enrollment: 21 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The study will be conducted in compliance with the International Council for Harmonisation (ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use/Good Clinical Practice (GCP) and applicable regulatory requirements.

This is a Phase 2, multicenter, single-arm study to evaluate the efficacy, safety and Pharmacokinetics (PK) of luspatercept (ACE-536) for the treatment of anemia due to International prognostic scoring system-Revised (IPSS-R) very low, low or intermediate risk Myelodysplastic syndromes (MDS)in Japanese subjects who are not requiring Red blood cell (RBC) transfusion.

The study is divided into the Screening Period, a Treatment Period and a Post-Treatment Follow up Period.

Detailed description:
Anemia is considered to be one of the most prevalent cytopenias in patients who have myelodysplastic syndromes, an umbrella term used to describe disorders relating to the ineffective production of red blood cells, white blood cells, and/or platelets. Ranging in severity from mild (asymptomatic) to severe, anemia can result in patients requiring regular red blood cell (RBC) transfusions, which can lead to further complications from iron overload. The goal of this study is to assess the efficacy, safety and PK of luspatercept in anemic patients who are categorized as International Prognostic Scoring System-Revised (IPSS-R) very low, low, or intermediate risk Myelodysplastic syndrome (MDS), and not requiring RBC transfusion. Subjects deemed eligible for the study will be enrolled and treated with luspatercept. Best supportive care (BSC) may be used in combination with study treatment when clinically indicated per investigator. Best supportive care includes, but is not limited to, treatment with transfusions, antibiotic, antiviral and/or antifungal therapy, and nutritional support as needed. Best supportive care for this study excludes the use of ESAs. Patients should receive treatment up to a minimum of 24 weeks after which an MDS Disease assessment visit is scheduled to assess the response to treatment. Patients who are determined to be experiencing clinical benefit may continue treatment. Continued clinical benefit will be re-assessed every 24 weeks. Once patients are discontinued from study treatment, they will enter a post treatment follow-up period.

Arms: arm 1: Luspatercept will be administered as a subcutaneous injection every 3 week (21 days; Q3W), at an initial dose level of 1.0 mg/kg. Doses may be titrated up starting at dosing visit Week 7 Day 1 (W7D1)
Interventions: intervention 1: Luspatercept
Intervention descriptions: intervention 1: Luspatercept

Protocol documents:
Prot_SAP_000.pdf: 
Official Title of Study: 
A Phase 2, Multicenter, Single-arm Study to Evaluate the Efficacy, Pharmacokinetics, and Safety of 
Luspatercept (ACE-536) for the Treatment of Anemia due to IPSS-R Very Low, Low or Intermediate Risk 
Myelodysplastic Syndromes (MDS) in Japanese Subjects who are Not Requiring Red Blood Cell 
Transfusion 
 
PROTOCOL(S) ACE-536-MDS-003 
 
NCT Number: NCT03900715 
  
Document Date (Date in which document was last revised): November 22, 2021 


EDMS Doc. Number: 25770028 - 22621913
Luspatercept (ACE-536)
Protocol ACE-536-MDS-003
Bristol-Myers Squibb K.K.
Confidential and Proprietary
1
ACE-536-MDS-003 Amendment 2.0 Final: 22 Nov 2021
TITLE PAGE
A PHASE 2, MULTICENTER, SINGLE-ARM STUDY TO 
EVALUATE THE EFFICACY, PHARMACOKINETICS,
AND SAFETY OF LUSPATERCEPT (ACE-536) FOR THE 
TREATMENT OF ANEMIA DUE TO IPSS-R VERY 
LOW, LOW OR INTERMEDIATE RISK 
MYELODYSPLASTIC SYNDROMES (MDS) IN 
JAPANESE SUBJECTS WHO ARE NOT REQUIRING 
RED BLOOD CELL TRANSFUSION
PROTOCOL NUMBER:
ACE-536-MDS-003
ORIGINAL PROTOCOL FINAL:
12 Jul 2018
AMENDMENT 1.0 DATE:
29 Aug 2018
AMENDMENT 2.0 DATE:
22 Nov 2021
EudraCT NUMBER:
Not applicable
IND NUMBER:
Not applicable
SPONSOR NAME/ ADDRESS:
Bristol-Myers Squibb K.K.
6-5-1 Nishi-Shinjuku, Shinjuku-ku,
Tokyo, 163-1327, Japan
CONFIDENTIAL
This protocol is provided to you as an Investigator, potential Investigator, or 
consultant for review by you, your staff, and ethics committee/institutional 
review board.  The information contained in this document is regarded as 
confidential and, except to the extent necessary to obtain informed consent, 
may not be disclosed to another party unless such disclosure is required by 
law or regulations.  Persons to whom the information is disclosed must be 
informed that the information is confidential and may not be further 
disclosed by them.
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EDMS Doc. Number: 25770028 - 22621913
Luspatercept (ACE-536)
Protocol ACE-536-MDS-003
Bristol-Myers Squibb K.K.
Confidential and Proprietary
2
ACE-536-MDS-003 Amendment 2.0 Final: 22 Nov 2021
MEDICAL MONITOR / EMERGENCY CONTACT INFORMATION 
Contact Information:
Name:
Title:
Address:
Phone:
E-mail:
Contact Information:
Name:
Title:
Clinical Trial Physician
Address: 86 Morris Avenue, Summit, NJ 07901, US
Phone:
+
E-mail:
Note: The back-up 24-hour global emergency contact call center should only be used if you 
are not able to reach the Clinical Research Physician(s) or Medical Monitor or designee for 
emergency calls. 
Back-up 24-hour Global Emergency Contact Call Center: +
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EDMS Doc. Number: 25770028 - 22621913
Luspatercept (ACE-536)
Protocol ACE-536-MDS-003
Bristol-Myers Squibb K.K.
Confidential and Proprietary
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ACE-536-MDS-003 Amendment 2.0 Final: 22 Nov 2021
CELGENE THERAPEUTIC AREA HEAD SIGNATURE PAGE
See appended electronic signature page
Signature of Celgene Therapeutic Area Head
dd mmm yyyy
 
Printed Name of Celgene Therapeutic Area Head and Title
By my signature, I indicate I have reviewed this protocol and find its content to be acceptable.  
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EDMS Doc. Number: 25770028 - 22621913
Luspatercept (ACE-536)
Protocol ACE-536-MDS-003
Bristol-Myers Squibb K.K.
Confidential and Proprietary
4
ACE-536-MDS-003 Amendment 2.0 Final: 22 Nov 2021
SITE PRINCIPAL INVESTIGATOR SIGNATURE PAGE
Signature of Site Principal Investigator
dd mmm yyyy
Printed Name of Site Principal Investigator
Institution Name:_______________________________________
By my signature, I agree to personally supervise the conduct of this study at my study site and 
to ensure its conduct is in compliance with the protocol, informed consent, Institutional 
Review Board (IRB)/Ethics Committee (EC) procedures, instructions from Celgene 
representatives, the Declaration of Helsinki, International Council for Harmonisation (ICH)
Good Clinical Practices Guidelines, and local regulations governing the conduct of clinical 
studies.
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EDMS Doc. Number: 25770028 - 22621913
Luspatercept (ACE-536)
Protocol ACE-536-MDS-003
Bristol-Myers Squibb K.K.
Confidential and Proprietary
5
ACE-536-MDS-003 Amendment 2.0 Final: 22 Nov 2021
COORDINATING PRINCIPAL INVESTIGATOR SIGNATURE PAGE
Signature of Coordinating Principal Investigator
dd mmm yyyy
Printed Name of Coordinating Principal Investigator
Institution Name:_______________________________________
By my signature, I agree the protocol has been written to comply with ICH Good Clinical 
Practices guidelines and agree to offer guidance throughout the study as needed.
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EDMS Doc. Number: 25770028 - 22621913
Luspatercept (ACE-536)
Protocol ACE-536-MDS-003
Bristol-Myers Squibb K.K.
Confidential and Proprietary
6
ACE-536-MDS-003 Amendment 2.0 Final: 22 Nov 2021
PROTOCOL SUMMARY
Study Title
A Phase 2, Multicenter, Single-arm Study to Evaluate the Efficacy, Pharmacokinetics, and Safety 
of Luspatercept (ACE-536) for the Treatment of Anemia due to IPSS-R Very Low, Low or 
Intermediate Risk Myelodysplastic Syndromes (MDS) in Japanese Subjects who are Not 
Requiring Red Blood Cell Transfusion
Indication
Treatment of anemia due to very low, low, or intermediate risk myelodysplastic syndromes 
(MDS) according to the International Prognostic Scoring System – Revised (IPSS-R) in subjects 
who are not requiring red blood cell (RBC) transfusion (ie, no RBC transfusion in the 16 weeks 
prior to enrollment).
Myelodysplastic syndromes, primarily affecting older adults, are a heterogeneous group of clonal 
disorders of hematopoietic stem cells characterized by ineffective hematopoiesis that manifest 
clinically as anemia, neutropenia, and/or thrombocytopenia of variable severity; these often 
result in RBC- transfusion dependent (TD) anemia, increased risk of infection, and/or 
hemorrhage, as well as a potential to progress to acute myeloid leukemia (AML) (Ades, 2014; 
Brunning, 2008; Catenacci, 2005; Fenaux, 2009; Steensma, 2013; Visconte, 2014; Zeidan, 
2013).
Lower hemoglobin (Hgb) levels and RBC-TD have been associated with inferior cardiovascular 
outcomes and increased mortality in patients with MDS, representing a strong rationale for 
aggressive management of anemia in MDS patients (Zeidan, 2013). In addition, long-term RBC-
TD has clinical and economic consequences, including a potentially negative impact on health-
related quality-of-life (HRQoL), iron overload (and its associated complications), immune-
related disorders and increased risk of infections (Hellstrom-Lindberg, 2003; Jansen, 2003;
Thomas, 2007).
For most patients with MDS, anemia and associated transfusion dependency are the most 
prominent clinical problems and the main determinants of quality-of- life (QoL) (Balducci, 
2010; Chan, 2014; Hellstrom-Lindberg, 2013; Kao, 2008; Malcovati, 2005; Platzbecker, 2012).  
Subjects in the lower risk groups also often become dependent on frequent RBC transfusions, 
which leads to decreased HRQoL and increased morbidity and mortality (Hellstrom-Lindberg, 
2003; Malcovati, 2005).  Thus, the therapeutic goal in RBC - transfusion independent (TI)
patients is to increase Hgb levels and prevent from becoming RBC-TD.
Luspatercept (ACE-536), an erythroid maturation agent, is a recombinant fusion protein 
consisting of a modified form of the extracellular domain (ECD) of the human activin receptor 
type IIB (ActRIIB) linked to the Fc portion of human immunoglobulin G1 (IgG1-Fc). 
Luspatercept acts on endogenous inhibitors of late-stage erythropoiesis (eg, growth and 
differentiation factor 11, GDF11) to increase release of mature erythrocytes into circulation. 
Nonclinical data have demonstrated that luspatercept binds to negative regulators governing late-
stage erythroid development to inhibit their action, thereby promoting the maturation of 
erythrocytes in the bone marrow. These findings suggest that luspatercept may represent a novel 
therapeutic approach to anemia, particularly in diseases in which ineffective erythropoiesis is a 
contributing factor, as in β-thalassemia and MDS.
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EDMS Doc. Number: 25770028 - 22621913
Luspatercept (ACE-536)
Protocol ACE-536-MDS-003
Bristol-Myers Squibb K.K.
Confidential and Proprietary
7
ACE-536-MDS-003 Amendment 2.0 Final: 22 Nov 2021
Objectives
Primary objective:

To evaluate the hematologic improvement – erythroid response (HI-E) per the 
International Working Group (IWG) (Cheson, 2006) from W1D1 through Week 24
for the treatment of anemia due to IPSS-R very low, low, or intermediate risk MDS in 
Japanese subjects who are not requiring RBC transfusion
Secondary objectives:

To evaluate modified HI-E (mHI-E) per IWG (Cheson, 2006)

To evaluate HI-E per IWG (Cheson, 2006) from W1D1 through Week 48

To evaluate the time to HI-E and duration of HI-E 

To evaluate the time to mHI-E and duration of mHI-E

To evaluate the proportion of subjects who maintain TI at Week 24, Week 48 and 
Week 72

To assess the safety of luspatercept 

To assess the pharmacokinetics (PK) of luspatercept 

To assess the frequency of antidrug antibodies (ADA) and effects on efficacy, safety, 
or PK

To assess the number and percentage of subjects progressing to AML; time to AML 
progression

To assess the overall survival
Study Design
ACE-536-MDS-003 is a Phase 2, multicenter, single-arm study. The primary objective of the 
study is to evaluate HI-E per IWG (Cheson, 2006) from W1D1 through Week 24 for the 
treatment of anemia due to IPSS-R very low, low, or intermediate risk MDS in Japanese subjects 
who are not requiring RBC transfusion.
The study is divided into a Screening Period, a Treatment Period and a Post-Treatment Follow-
up Period.
Screening Period:
Subject screening procedures are to take place within 35 days prior to Week 1 Day 1 (W1D1)
(after the subject has given written informed consent). During the Screening Period, the subject 
will undergo safety and other assessments to determine eligibility for the study.
Central review of bone marrow aspirate smear and peripheral blood smear will be used to
confirm MDS diagnosis according to the World Health Organization (WHO) 2016 
classification (Appendix B) and to determine the baseline IPSS-R riskclassification (Greenberg, 
2012).  A bone marrow biopsy will be collected only when adequate aspirate is not attainable.
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EDMS Doc. Number: 25770028 - 22621913
Luspatercept (ACE-536)
Protocol ACE-536-MDS-003
Bristol-Myers Squibb K.K.
Confidential and Proprietary
8
ACE-536-MDS-003 Amendment 2.0 Final: 22 Nov 2021
Treatment Period:
The first dose of investigational product (IP) should be administered within 3 days of enrollment
at the latest.
Best supportive care includes, but is not limited to, treatment with transfusions, antibiotic, 
antiviral and/or antifungal therapy, and nutritional support as needed.  Best supportive care for
this study excludes the use of erythropoiesis stimulating agents (ESA)s.
Subjects should receive IP through to a minimum of the 24-week MDS Disease Assessment Visit 
scheduled for Day 169 unless the subject experiences unacceptable toxicities, withdraws consent, 
or meets any other treatment discontinuation criteria.
The MDS Disease Assessment (Section 6.4.2) on Day 169 (and every 24 weeks thereafter [ie, 
Day 337, Day 505, etc.] consists of the investigator’s assessment of clinical benefit from IP and 
status of underlying disease.  For subjects to remain on treatment beyond this timepoint, both of 
the following criteria must be confirmed in each subject:

Evidence of clinical benefit defined by either one of the following two criteria:

HI-E based on IWG (Cheson, 2006) (Appendix D) (Hgb increase of ≥ 1.5 g/dL
for the 8 weeks within the 12 weeks immediately preceding Day 169 and every 24 
weeks thereafter [ie, Day 337, Day 505, etc.])

Maintain RBC transfusion independence

Absence of disease progression per IWG criteria for altering natural history of 
MDS (Cheson, 2006) (Appendix E) based on central morphological assessment of 
bone marrow, peripheral blood and cytogenetics results
Based on the outcome of these assessments, subjects will either be discontinued from treatment 
with IP, undergo End of Treatment (EOT) evaluations and enter the Post-Treatment Follow-up 
Period or continue the treatment as long as the above criteria continue to be met or until the 
subject experiences unacceptable toxicities, withdraws consent, or meets any other 
discontinuation criteria.
Post-Treatment Follow-up Period:
All subjects who have received at least one dose of IP should undergo EOT and 42-Day Follow-
up evaluations.
This includes (but is not limited to) the collection of adverse events (AEs), concomitant drugs 
and RBC-transfusion data (until 8 weeks after last dose of IP or the EOT Visit, whichever occurs 
later).
In addition, subjects will continue to be followed for 5 years from the date of the first dose of IP, 
or 3 years from the last dose (whichever occurs later), for monitoring for other malignancies/pre-
malignances and progression to AML in the Long-term Post-Treatment Follow-up Period along 
with data collection of subsequent MDS therapies, and overall survival unless the subject 
withdraws consent from the study, dies or is lost to follow-up.  For that purpose, subjects will be 
followed after treatment every 12 weeks for 3 years from the date of last dose of IP and every 6 
months thereafter, if applicable.
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EDMS Doc. Number: 25770028 - 22621913
Luspatercept (ACE-536)
Protocol ACE-536-MDS-003
Bristol-Myers Squibb K.K.
Confidential and Proprietary
9
ACE-536-MDS-003 Amendment 2.0 Final: 22 Nov 2021
An antidrug antibodies (ADA) sample(s) may be required in the Post-Treatment Follow-up 
Period for subjects, who terminate the Treatment Period with less than 1 year of ADA 
monitoring if a subject is ADA positive at the time of treatment discontinuation.
The study will be conducted in compliance with International Council for Harmonisation (ICH) 
Good Clinical Practices (GCP).
Study Population
Adult subjects (≥ 20 years) with anemia due to a IPSS-R very low, low, or intermediate risk 
MDS according to the WHO 2016 classification and a bone marrow blast count of < 5% (Arber, 
2016; Greenberg, 2012), who are not requiring RBC transfusion (ie, no RBC transfusion 
administered within 16 weeks prior to W1D1 - except transfusions due to blood loss or infection 
that occurred between 16 and 8 weeks prior to W1D1), and ESAs naïve or previously used ESAs 
but not administered ESAs within 8 weeks prior to W1D1.
Length of Study
The expected duration ofthe study is approximately 8 years, which consists of approximately 
2 years of enrollment, approximately 1 additional year of luspatercept treatment after the last 
subject is enrolled, and 5 years of follow up from first dose of IP, or 3 years from last dose 
(whichever occurs later), to complete the Post-Treatment Follow-up Period.
The End of Trial is defined as either the date of the last visit of the last subject to complete the 
post-treatment follow-up, or the date of receipt of the last data point from the last subject that is 
required for primary, secondary and/or exploratory analysis, as prespecified in the protocol, 
whichever is the later date.
The sponsor may end the trial when all key endpoints and objectives of the study have been 
analyzed and the availability of a roll-over protocol exists into which subjects remaining on 
study may be consented and continue to receive access to luspatercept and/or complete long-term 
follow-up. Such a protocol would be written for a compound that would not yet be 
commercially available.
Study Treatments
Eligible subjects will be administered luspatercept (ACE-536): starting dose of 1.0 mg/kg 
subcutaneous injection every 3 weeks (21 days; Q3W). Dose levels can be increased in a 
stepwise manner beyond the starting dose to 1.33 mg/kg, and up to a maximum of 1.75 mg/kg.
For a detailed description of study treatments please refer to Section 7.
Overview of Key Efficacy Assessments
Efficacy assessments include the assessment of hematological parameters (eg, hemoglobin, 
platelet count, neutrophils), collection of transfusion data (eg, RBC transfusions) and central 
cytomorphology and cytogenetics review of bone marrow aspirate and peripheral blood for MDS 
disease assessment. 
Response assessment according to IWG criteria (Cheson, 2006) is to be performed at the 24-
Week MDS Disease Assessment Visit (ie, Day 169) and every 24 weeks (ie, 168 days) 
thereafter.
For a detailed description of efficacy assessments please refer to Section 6.4.
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EDMS Doc. Number: 25770028 - 22621913
Luspatercept (ACE-536)
Protocol ACE-536-MDS-003
Bristol-Myers Squibb K.K.
Confidential and Proprietary
10
ACE-536-MDS-003 Amendment 2.0 Final: 22 Nov 2021
Overview of Key Safety Assessments
Safety assessments include hematology (complete blood count [CBC] with differential) and 
serum chemistry analyses, recording of adverse events, physical exam, vital signs and 
electrocardiograms (ECGs).  In addition, subjects will be monitored for progression to AML and 
other malignancies/pre-malignancies.
Overview of Pharmacokinetic Assessments
Serial serum samples will be collected in all subjects to be received the study drug to analyze 
luspatercept concentrations in serum from W1D1 through 24-Week MDS Disease Assessment.  
The sampling time points for the dense PK in the initial 10 subjects will be W1D1, W1D3, 
W2D1, W2D3, W3D1, W4D1, W10D1, W13D1, W16D1, W17D1, W18D1, W19D1, W22D1, 
24-Week MDS Disease Assessment, and for the sparse PK in other 10 subjects will be W1D1, 
W2D1, W3D1, W4D1, W10D1, W16D1, W22D1, 24-Week MDS Disease Assessment.  Also, 
serum samples will be collected every 12 weeks for up to 1 year from the first dose in all 
subjects.
PK parameters including, but not limited to area under the concentration time curve (AUC), 
maximum plasma concentration of drug (Cmax), time to maximum plasma concentration of drug 
(Tmax), terminal elimination half-life (t1/2), apparent clearance of drug from plasma after 
extravascular administration (CL/F), and apparent volume of distribution during the terminal 
phase after extravascular administration (V/F) will be estimated for each subject.
Statistical Methods
The sample size calculation is based on one sample binomial exact test.  The null hypothesis to 
be tested is that the proportion of subjects achieving HI-E is ≤ 10%; the alternative hypothesis is 
that the proportion of subjects achieving HI-E is > 10%. With these hypotheses, a sample size of 
20 subjects are required with a power of 95% at a one-sided 0.025 alpha level if the expected 
proportion is 45%.
The primary efficacy endpoint of HI-E per IWG (Cheson, 2006) is defined as proportion of 
subjects meeting HI-E criteria of ≥ 1.5 g/dL increase in Hgb sustained over any consecutive 56-
day period in the absence of RBC transfusions from W1D1 through Week 24.  Subjects 
discontinued from the treatment period without achieving HI-E will be counted as non-
responders. Dose modification guidance for luspatercept in Section 7.2.2 defines that, if predose 
Hgb is ≥ 12.0 g/dL at the day of dosing, the dose should be delayed until Hgb is < 11.0 g/dL.  
For subjects who meet this criterion and then have their dose delayed, if their Hgb levels 
temporarily decrease to < 1.5 g/dL but achieve ≥ 1.5 g/dL again after treatment resumption, this 
period (ie, the time from dose delay to achieving a Hgb increase of ≥ 1.5 g/dL again) will be 
included as the period of sustained Hgb increase of ≥ 1.5 g/dL.
As the primary efficacy analysis, one sample binomial one sided exact test will be performed 
based on intent-to-treat (ITT) population, to provide p-value (significance level: 0.025).  The 
number and percentage of subjects who achieve the response and 95% confidence interval (CI) 
will be presented based on the ITT population.  
There is no planned interim analysis for this study. 
The primary analysis will be performed when all enrolled subjects have completed 24 weeks of 
treatment or discontinued before 24 weeks. 
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EDMS Doc. Number: 25770028 - 22621913
Luspatercept (ACE-536)
Protocol ACE-536-MDS-003
Bristol-Myers Squibb K.K.
Confidential and Proprietary
11
ACE-536-MDS-003 Amendment 2.0 Final: 22 Nov 2021
Additional follow-up analysis for efficacy and safety will be performed when all subjects have 
been followed for 5 years from the date of the first dose of IP, or 3 years from the last dose
(whichever occurs later) during the Post-Treatment Follow-Up Period of the study. 
For more details on statistical considerations please refer to Section 9 of the protocol.
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EDMS Doc. Number: 25770028 - 22621913
Luspatercept (ACE-536)
Protocol ACE-536-MDS-003
Bristol-Myers Squibb K.K.
Confidential and Proprietary
12
ACE-536-MDS-003 Amendment 2.0 Final: 22 Nov 2021
TABLE OF CONTENTS
TITLE PAGE..............................................................................................................................1
PROTOCOL SUMMARY ..........................................................................................................6
TABLE OF CONTENTS..........................................................................................................12
LIST OF TABLES....................................................................................................................18
LIST OF FIGURES ..................................................................................................................19
1.
INTRODUCTION..................................................................................................20
1.1.
Myelodysplastic Syndromes ...................................................................................20
1.1.1.
Current Treatment Options for Lower Risk MDS....................................................21
1.1.1.1.
Erythropoiesis Stimulating Agents..........................................................................21
1.1.1.2.
Red Blood Cell Transfusions ..................................................................................22
1.1.1.3.
Lenalidomide..........................................................................................................23
1.1.1.4.
Hypomethylating Agents ........................................................................................23
1.2.
Luspatercept Background .......................................................................................23
1.2.1.
Mechanism of Action .............................................................................................23
1.2.2.
Nonclinical Studies with Luspatercept ....................................................................25
1.2.3.
Summary of Clinical Experience ............................................................................25
1.2.3.1.
Potential Risks of Human Use ................................................................................26
1.2.3.2.
Overall Benefit Risk Assessment ............................................................................27
1.3.
Rationale ................................................................................................................27
1.3.1.
Study Rationale and Purpose ..................................................................................27
1.3.2.
Rationale for the Study Design ...............................................................................28
1.3.2.1.
Rationale for the Study Population..........................................................................28
1.3.2.2.
Rationale for Study Endpoints ................................................................................29
1.3.3.
Rationale for Dose, Schedule and Regimen Selection .............................................30
1.3.4.
Rationale for Exploratory Biomarkers.....................................................................30
2.
STUDY OBJECTIVES AND ENDPOINTS...........................................................33
3.
OVERALL STUDY DESIGN ................................................................................36
3.1.
Study Design ..........................................................................................................36
3.2.
Study Duration for Subjects....................................................................................40
3.3.
End of Trial ............................................................................................................40
4.
STUDY POPULATION.........................................................................................41
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EDMS Doc. Number: 25770028 - 22621913
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Bristol-Myers Squibb K.K.
Confidential and Proprietary
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ACE-536-MDS-003 Amendment 2.0 Final: 22 Nov 2021
4.1.
Number of Subjects ................................................................................................41
4.2.
Inclusion Criteria....................................................................................................41
4.3.
Exclusion Criteria...................................................................................................42
5.
TABLE OF EVENTS.............................................................................................46
6.
PROCEDURES......................................................................................................55
6.1.
Screening Period.....................................................................................................55
6.1.1.
Bone Marrow and Peripheral Blood Samples..........................................................55
6.1.2.
Prior Transfusion History .......................................................................................57
6.1.3.
Demographics.........................................................................................................57
6.1.4.
Medical History......................................................................................................57
6.1.4.1.
Assessment of HIV/Hepatitis B/Hepatitis C Status..................................................57
6.1.5.
Physical Examination .............................................................................................57
6.1.6.
Vital Signs, Height, and Weight..............................................................................57
6.1.7.
Eastern Cooperative Oncology Group Performance Status......................................57
6.1.8.
Electrocardiogram ..................................................................................................58
6.1.9.
Hematology............................................................................................................58
6.1.10.
Serum Chemistry....................................................................................................58
6.1.11.
Serum EPO Level...................................................................................................58
6.1.12.
Serum Ferritin and Other Iron-Related Markers......................................................59
6.1.13.
Urinalysis ...............................................................................................................59
6.1.14.
Pregnancy Testing and Counseling .........................................................................59
6.1.15.
Sample Collection for Exploratory Biomarker Assessments....................................59
6.1.16.
Sample Collection for Pharmacokinetic Analysis and ADA Evaluation ..................59
6.1.18.
Concomitant Medications and Procedures...............................................................60
6.1.19.
Adverse Event Evaluation.......................................................................................60
6.1.20.
Monitoring for Progression to AML and Other Malignancies/Pre-
malignancies...........................................................................................................60
6.1.21.
Information to be Collected on Screening Failures..................................................60
6.2.
Treatment Period ....................................................................................................61
6.2.1.
Unscheduled Visits.................................................................................................62
6.2.2.
End of Treatment....................................................................................................62
6.3.
Post-Treatment Follow-up Period ...........................................................................62
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6.3.1.
Safety Follow-up (42-Day Follow-up) ....................................................................62
6.3.2.
Long-term Follow-up..............................................................................................63
6.4.
Efficacy Assessment...............................................................................................63
6.4.1.
Transfusion Assessment..........................................................................................64
6.4.2.
MDS Disease Assessment.......................................................................................64
6.5.
Pharmacokinetics....................................................................................................65
6.6.
Antidrug Antibody (ADA)......................................................................................66
6.7.
Biomarkers, Pharmacodynamics, Pharmacogenomics.............................................66
6.8.
Additional and Optional Research...........................................................................67
6.8.1.
Additional Research ...............................................................................................67
6.8.2.
Optional Research ..................................................................................................67
7.
DESCRIPTION OF STUDY TREATMENTS........................................................69
7.1.
Description of Investigational Products...................................................................69
7.2.
Treatment Administration and Schedule .................................................................69
7.2.1.
Luspatercept Administration and Schedule .............................................................69
7.2.2.
Luspatercept Dose Adjustment and Dose Modification...........................................70
7.2.3.
Overdose ................................................................................................................72
7.3.
Method of Treatment Assignment...........................................................................73
7.4.
Packaging and Labeling..........................................................................................73
7.5.
Investigational Product Accountability and Disposal ..............................................73
7.5.1.
Accountability Procedures......................................................................................73
7.5.2.
Drug Disposal and Destruction ...............................................................................74
7.6.
Investigational Product Compliance........................................................................74
8.
CONCOMITANT MEDICATIONS AND PROCEDURES....................................75
8.1.
Permitted Concomitant Medications and Procedures...............................................75
8.1.1.
RBC Transfusions ..................................................................................................75
8.1.2.
Corticosteroids........................................................................................................75
8.1.3.
Attenuated Vaccines...............................................................................................75
8.1.4.
Phlebotomy ............................................................................................................75
8.2.
Prohibited Concomitant Medications and Procedures..............................................76
8.3.
Required Concomitant Medications and Procedures................................................76
9.
STATISTICAL CONSIDERATIONS ....................................................................77
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9.1.
Overview................................................................................................................77
9.2.
Study Population Definitions ..................................................................................77
9.3.
Sample Size and Power Considerations...................................................................77
9.4.
Background and Demographic Characteristics........................................................77
9.5.
Subject Disposition.................................................................................................78
9.6.
Efficacy Analysis....................................................................................................78
9.6.1.
Primary Efficacy Analysis ......................................................................................78
9.6.2.
Secondary Efficacy Analyses..................................................................................78
9.7.
Safety Analysis.......................................................................................................80
9.8.
Interim Analysis .....................................................................................................80
9.9.
Other Topics...........................................................................................................80
9.9.2.
Pharmacokinetic Analysis.......................................................................................80
9.9.3.
Exploratory Analysis ..............................................................................................81
9.9.4.
Subgroup Analysis..................................................................................................81
10.
ADVERSE EVENTS..............................................................................................82
10.1.
Monitoring, Recording and Reporting of Adverse Events .......................................82
10.2.
Evaluation of Adverse Events.................................................................................82
10.2.1.
Seriousness.............................................................................................................82
10.2.2.
Severity/Intensity....................................................................................................83
10.2.3.
Causality ................................................................................................................84
10.2.4.
Duration .................................................................................................................85
10.2.5.
Action Taken..........................................................................................................85
10.2.6.
Outcome.................................................................................................................85
10.3.
Abnormal Laboratory Values..................................................................................85
10.4.
Pregnancy...............................................................................................................85
10.4.1.
Females of Childbearing Potential ..........................................................................85
10.4.2.
Male Subjects .........................................................................................................86
10.5.
Other Malignancies/Pre-malignancies.....................................................................86
10.6.
Reporting of Serious Adverse Events......................................................................87
10.7.
Expedited Reporting of Adverse Events..................................................................87
10.8.
COVID-19 Reporting .............................................................................................88
11.
DISCONTINUATIONS .........................................................................................89
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11.1.
Treatment Discontinuation......................................................................................89
11.2.
Study Discontinuation ............................................................................................89
12.
EMERGENCY PROCEDURES.............................................................................91
12.1.
Emergency Contact.................................................................................................91
12.2.
Emergency Identification of Investigational Products .............................................91
13.
REGULATORY CONSIDERATIONS...................................................................91
13.1.
Good Clinical Practice............................................................................................91
13.2.
Investigator Responsibilities ...................................................................................91
13.3.
Subject Information and Informed Consent.............................................................92
13.4.
Confidentiality........................................................................................................92
13.5.
Protocol Amendments.............................................................................................93
13.6.
Institutional Review Board/Independent Ethics Committee Review and 
Approval ................................................................................................................93
13.7.
Ongoing Information for Institutional Review Board/ Ethics Committee ................94
13.8.
Termination of the Study ........................................................................................94
14.
DATA HANDLING AND RECORDKEEPING.....................................................95
14.1.
Data/Documents .....................................................................................................95
14.2.
Data Management...................................................................................................95
14.3.
Record Retention....................................................................................................95
15.
QUALITY CONTROL AND QUALITY ASSURANCE........................................97
15.1.
Study Monitoring and Source Data Verification......................................................97
15.2.
Audits and Inspections............................................................................................97
15.3.
Investigational Medicinal Product Quality Issues....................................................97
16.
PUBLICATIONS ...................................................................................................99
17.
REFERENCES.....................................................................................................100
18.
APPENDICES......................................................................................................104
APPENDIX A.
TABLE OF ABBREVIATIONS..................................................................104
APPENDIX B.
MYELODYSPLASTIC SYNDROMES WORLD HEALTH 
ORGANIZATION CLASSIFICATION SYSTEM (2016).....................................109
APPENDIX C.
INTERNATIONAL PROGNOSTIC SCORING SYSTEM SCORE -
REVISED.............................................................................................................110
APPENDIX D.
INTERNATIONAL WORKING GROUP RESPONSE CRITERIA 
FOR HEMATOLOGIC IMPROVEMENT ...........................................................112
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APPENDIX E.
INTERNATIONAL WORKING GROUP RESPONSE CRITERIA 
FOR MYELODYSPLASTIC SYNDROMES.......................................................113
APPENDIX F.
EASTERN COOPERATIVE ONCOLOGY GROUP (ECOG) 
PERFORMANCE STATUS.................................................................................115
APPENDIX G.
FOUR-VARIABLE MDRD GFR EQUATION ...........................................116
 
....................................................................................................117
 
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LIST OF TABLES
Table 1:
Study Objectives.....................................................................................................33
Table 2:
Study Endpoints .....................................................................................................33
Table 3:
Table of Events.......................................................................................................46
Table 4:
Luspatercept Starting Dose Level with Dose Reductions and Dose Titration...........70
Table 5:
Luspatercept Dose Modification: Dose Delay, Dose Reduction, and 
Discontinuation Guidelines.....................................................................................71
Table 6:
Abbreviations and Specialist Terms......................................................................104
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LIST OF FIGURES
Figure 1:
Luspatercept Schematic Representation and Mechanism of Action .........................24
Figure 2:
Overall Study Design..............................................................................................39
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1.
INTRODUCTION 
1.1.
Myelodysplastic Syndromes
Myelodysplastic syndromes (MDS), primarily affecting older adults, are a heterogeneous group 
of clonal disorders of hematopoietic stem cells characterized by ineffective hematopoiesis that 
manifest clinically as anemia, neutropenia, and/or thrombocytopenia of variable severity; these 
often result in red blood cell (RBC) transfusion dependent anemia, increased risk of infection, 
and/or hemorrhage, as well as a potential to progress to acute myeloid leukemia (AML) (Ades, 
2014; Brunning, 2008; Catenacci, 2005; Fenaux, 2009; Steensma, 2013; Visconte, 2014; Zeidan, 
2013). 
Lower hemoglobin (Hgb) levels and RBC transfusion dependence have been associated with 
inferior cardiovascular outcomes and increased mortality in patients with MDS, representing a 
strong rationale for aggressive management of anemia in MDS patients (Zeidan, 2013). In 
addition, long-term RBC transfusion dependence has clinical and economic consequences, 
including a potentially negative impact on health-related quality of life (HRQoL), iron overload 
(and its associated complications), immune-related disorders and increased risk of 
infections (Hellstrom-Lindberg, 2003; Jansen, 2003; Thomas, 2007).
For most patients with MDS, anemia and associated transfusion dependency are the most 
prominent clinical problems and the main determinants of quality-of- life (QoL) (Balducci, 2010; 
Chan, 2014; Hellstrom-Lindberg, 2013; Kao, 2008; Malcovati, 2005; Platzbecker, 2012).  Patients 
in the lower risk groups also often become dependent on frequent RBC transfusions, which leads 
to decreased HRQoL and increased morbidity and mortality (Hellstrom-Lindberg, 2003; 
Malcovati, 2005).  Thus, the therapeutic goal in RBC- transfusion independent (TI) patients is to 
increase Hgb levels and prevent from becoming RBC- transfusion dependent (TD).
Diagnosis of MDS is made according to the World Health Organization (WHO) classification 
system.  Also, the International Prognostic Scoring System (IPSS) and the International 
Prognostic Scoring System – Revised (IPSS-R) are internationally used for prognostic 
prediction, and the International Working Group IWG) including Japan released treatment 
response criteria for MDS (Cheson, 2006).  These systems and criteria are internationally 
standardized and therefore no differences exist in the clinical practices among countries 
including Japan.
Patients with MDS can be categorized into 1 of 5 risk groups according to the IPSS-R (very low, 
low, intermediate, high, and very high) based on cytogenetics, Hgb, platelets and absolute 
neutrophil count (ANC) levels and bone marrow (BM) blast percentages obtained at diagnosis. 
The 5 risk groups showed significantly different risk of progression to AML and overall survival 
(OS). The median survival rate is 8.8 years for patients with low risk MDS and is as short as 
0.8 years for very high-risk MDS (Germing, 2012).
In lower risk MDS, the risk of progression to AML is less and survival is longer, with 
approximately one-half of these elderly patients dying from a cause other than the consequences 
of MDS or AML (Germing, 2012). In these patients, the main priorities are the treatment of 
cytopenias, primarily anemia, and the improvement in QoL (Fenaux, 2013). A clinically 
prominent challenge in patients with lower-risk MDS is the management of preexisting 
conditions aggravated by anemia, such as cardiovascular diseases.
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A research revealed the prevalence rate of MDS in Japan was 3.8 (95% CI 3.6–4.1) cases per 
100000 for men and 2.4 (95% CI 2.2–2.6) cases per 100 000 for women in 2008. Median age at 
diagnosis was 76 years (interquartile range 68–82 years). Incidence sharply increased with age, 
particularly in those aged over 70 years, with 3.1 cases per 100 000 men and 1.1 cases per 100 
000 women in those aged 65–69 years versus 17.7 and 8.9 cases per 100 000, respectively, in 
those aged over 85 years (Chihara 2014).
1.1.1.
Current Treatment Options for Lower Risk MDS
The standard of care for lower risk MDS remains supportive treatment with erythropoiesis 
stimulating agents (ESA)s such as epoetin alfa or darbepoetin (DAR), administration of RBC 
and/or platelet transfusions, infection prophylaxis and/or treatment and use of hematopoietic
growth factors such as granulocyte colony-stimulating factor (G-CSF) and nutritional 
supplements when needed (National Comprehensive Cancer Network [NCCN], 2018; European 
Society for Medical Oncology [ESMO], 2014 [Fenaux, 2014]; European LeukemiaNet [ELN], 
2014 [Malcovati, 2013]; Japanese Society of Hematology [JSH], 2013).
1.1.1.1.
Erythropoiesis Stimulating Agents
The use of ESAs (ie, recombinant erythropoietin [EPO] or darbepoetin [DAR]) is the standard of 
care for low and intermediate IPSS risk patients with symptomatic anemia and an endogenous 
serum erythropoietin (sEPO) level < 500 U/L, and is recommended by European, United States 
(US), and Japanese treatment guidelines. The use of granulocyte-colony stimulating factor (G-
CSF) may be employed as needed but is not required, although in some cases it may further 
improve the efficacy of the ESA (NCCN, 2017; ESMO, 2014 [Fenaux, 2014]; ELN, 2014 
[Malcovati, 2013]; JSH, 2013).
The European and Japanese guidance also recommends the use of ESAs for patients who have a 
low RBC transfusion burden (< 2 units/month) and/or an endogenous sEPO levels ≤500 
U/L (ESMO, 2014 [Fenaux, 2014]; ELN, 2014 [Malcovati, 2013]; JSH, 2013). However, major 
favorable prognostic factors for response to ESAs are a low or no RBC transfusion requirement 
(< 2 units/month) and an endogenous sEPO level < 500 U/L (Fenaux, 2013).  Responses to ESAs 
are best in patients with low endogenous levels (eg, < 500 U/L) of EPO, normal blast counts and 
lower IPSS/WHO Prognostic Scoring System (WPSS) scores (Hellstrom-Lindberg, 2003; 
Santini, 2011).
Efficacy of ESAs in lower risk MDS patients have recently been demonstrated in 2 Phase 3 
studies:
In the EPOANE3021 Phase 3 study, a total of 130 subjects with IPSS low or int-1 risk MDS and 
anemia ≤10 g/dL with a requirement of RBC transfusion ≤ 4 units/8 weeks and an endogenous
sEPO level < 500 U/L, were randomized 2:1 to receive either epoetin alfa or matching placebo. 
Subjects were stratified by endogenous sEPO level (sEPO < 200 U/L versus sEPO ≥ 200 U/L) 
and prior transfusion status at screening (yes versus no).
In the modified intent-to-treat (ITT) analysis 2/45 (4.4%) subjects in the placebo group achieved 
the primary endpoint of IWG 2006 erythroid response versus 27/85 (31.8%) in the epoetin alfa 
group (p < 0.001). All of the responding subjects were in the stratum with endogenous
sEPO < 200 U/L during screening. In that stratum, 20/40 (50%) subjects without prior 
transfusions demonstrated erythroid response during the first 24 weeks, compared with 7/31 
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(22.6%) subjects with prior transfusions (2 subjects with prior transfusion reached the primary 
endpoint based on reduction of RBC units transfused by an absolute number of at least 4 units 
every 8 weeks compared to the 8 weeks prior to baseline).  The median duration of erythroid 
response in the epoetin alfa group was 197 days.  The percentage of subjects who were 
transfused in the epoetin alfa group decreased from 51.8% in the 8 weeks prior to baseline to 
24.7% between weeks 16 and 24, compared to the placebo group which had an increase in 
transfusion rate from 48.9% to 54.1% over the same time periods (Fenaux, 2016; Fenaux, 
2018a).  In an additional post-hoc analysis conducted by the response review committee with 
modified IWG 2006 criteria an erythroid response rate of 39/85 (45.9%) in the epoetin alfa group 
was estimated (Fenaux, 2017); Fenaux, 2018a).
In the ARCADE Phase 3 study, a total of 146 subject with IPSS low or int-1 risk MDS and 
anemia ≤ 10 g/dL, requirement of RBC transfusion < 4 units/8 weeks, and an endogenous sEPO 
level ≤500 U/L were randomized 2:1 to receive either darbepoetin alfa (DAR) or matching 
placebo (PBO). In the ITT analysis, 29 (59.2%) subjects in the PBO group achieved the primary 
endpoint (percentage of participants with at least 1 RBC transfusion during the double-blind 
treatment period: weeks 5 to 24) versus 35 (36.1%) subjects in the DAR group (p = 0.008). 
Transfusion rates were less with lower baseline sEPO for darbepoetin alfa (≤100 U/L: 23%, 
> 100 U/L: 57%, 95% confidence interval non-overlapping) but not placebo. The proportion 
achieving the hematologic improvement – erythroid response (HI-E), which was defined as a 
≥1.5 g/dL increase from baseline in hemoglobin with a mean rise of ≥1.5 g/dL for 8 weeks 
without transfusions as per IWG 2006 criteria, was significantly increased with DAR versus
PBO; DAR:14.7% (11 of 75 evaluable) versus PBO:0% (0 of 35 evaluable), p = 0.016. All 
subjects with HI-E (n=11) in the double-blind period had baseline sEPO ≤100 U/L and 10/11 
had no transfusions in the 16 weeks before randomization (none had transfusions in the 8 weeks 
before). The mean duration of response was 235 (21 days standard error) days. It should be 
noted, however, that the primary endpoint was switched during the course of the study. Before 
unblinding and while enrollment was ongoing, transfusion incidence from weeks 5 to 24 became 
the primary endpoint and HI-E a secondary endpoint (Platzbecker, 2017c).
In Japan, DAR was approved in 2014 regardless of patients’ sEPO levels based on the results of 
a Phase 2 study conducted in 50 patients in Japan and Korea.  However, the study only included 
the subjects with EPO < 500 U/L (Jang, 2015) and JSH Guideline recommends DAR to patients 
who have low serum EPO (< 500 mU/mL) (JSH, 2013).
1.1.1.2.
Red Blood Cell Transfusions 
Lower-risk MDS are characterized mainly by anemia and supportive care, primarily RBC cell 
transfusions, remain an important component of their treatment, but exposes patients to 
insufficient correction of anemia, alloimmunization, and organ iron overload. Treatment aimed 
at preventing anemia recurrence should therefore be used whenever possible (Fenaux, 2013).
In many patients with lower-risk MDS, anemia (ie, average hemoglobin levels < 10 g/dL) will 
eventually become resistant to all available drug treatments, even in the absence of evolution to 
higher-risk MDS, and will require repeated RBC transfusions. For those patients, it is 
recommended to administer transfusions at sufficiently high hemoglobin thresholds (ie, at least 
8 g/dL and 9 or 10 g/dL in cases of comorbidities worsened by anemia [eg, coronary artery 
disease, heart failure] or in cases of poor functional tolerance).  In addition, a sufficient number 
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of RBC concentrates should be transfused each time, over 2 or 3 days if needed, to increase the 
hemoglobin level to > 10 g/dL and thereby limit the effects of chronic anemia such as cardiac 
failure, falls, fatigue and lower quality-of-life (Nordic MDS Group Guideline, 2017; Fenaux, 
2013; ESMO, 2014 [Fenaux, 2014]).
However, the development of transfusion dependency significantly worsens the survival of 
patients with MDS (Malcovati, 2005).  In addition, long-term RBC transfusion dependency has 
several detrimental clinical effects including iron overload, economic consequences, and a 
negative impact on patients’ QoL (Hellstrom-Lindberg, 2003; Jansen, 2003; Thomas, 2007).
1.1.1.3.
Lenalidomide
Lenalidomide (Revlimid®) is approved in Japan for MDS associated with a del(5q) abnormality.  
In the US, it is approved for the treatment of patients with transfusion-dependent anemia due to 
low- or Int-1-risk MDS associated with a del(5q) abnormality with or without additional 
cytogenetic abnormalities. Lenalidomide is the standard of care (in countries where 
lenalidomide is approved) for the small proportion of patients with lower risk del(5q) MDS. In 
this population, lenalidomide led to transfusion independence for 67% of the patient population 
for a median duration of transfusion independence of 44 weeks.  However, it is not approved for 
the remaining majority of MDS.
1.1.1.4.
Hypomethylating Agents
Azacitidine for injection (Vidaza®) is a hypomethylating agent (HMA) currently approved in 30 
other countries including Japan, Canada, Switzerland, and Australia for the treatment of MDS
(approvals for specific subtypes vary by country). 
Azacitidine is indicated for treatment of patients with the following French-American-British 
(FAB) classification subtypes of MDS in the US:  refractory anemia (RA) or refractory anemia 
with ringed sideroblasts (RARS) (if accompanied by neutropenia or thrombocytopenia or 
requiring transfusions), refractory anemia with excess blasts (RAEB), refractory anemia with 
excess blasts in transformation (RAEB-T), and chronic myelomonocytic leukemia (CMML), but 
it is not routinely utilized in the lower risk disease setting.
Azacitidine is approved in the European Union (EU) for the treatment of adult patients who are 
not eligible for hematopoietic stem cell transplantation with IPSS Int-2 or High risk MDS, 
CMML with 10% to 29% marrow blasts without myeloproliferative disorder and AML with 20% 
to 30% blasts and multilineage dysplasia, according to WHO classification. 
In Japan, azacitidine is approved for treatment of various subtypes of MDS and no limitation to 
use only for higher-risk MDS.  However, data supporting the use in the lower-risk MDS patient 
population is currently limited, and it is not recommended for first-line therapy in this 
population (JSH, 2013).
1.2.
Luspatercept Background 
1.2.1.
Mechanism of Action
Luspatercept (ACE-536), an erythroid maturation agent, is a recombinant fusion protein 
consisting of a modified form of the extracellular domain (ECD) of the human activin receptor 
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type IIB (ActRIIB) linked to the immunoglobulin G1 - fragment crystallizable (IgG1-Fc) domain 
(Figure 1A).  The ActRIIB receptor and its ligands are members of the transforming growth 
factor-beta (TGF-β) superfamily, a group of proteins involved in the development, 
differentiation, and/or maturation of various tissues.  No species differences have been described 
in the ligand-receptor interactions among members of the TGF-β superfamily as the ligands and 
receptors are highly conserved across species (Massague, 1998).  Thus, observations from 
pharmacology studies of luspatercept or its murine ortholog RAP-536 in animal models provide 
significant insight into the potential of luspatercept to treat human disease. 
Members of the TGF-β superfamily ligands, through their binding to activin receptors, are 
involved in modulating the differentiation of late-stage erythrocyte precursors (normoblasts) in 
the bone marrow.  Luspatercept acts as a ligand trap for growth differentiation factor 11 
(GDF11) and other TGF-β superfamily ligands to suppress Smad2/3 signaling.  In nonclinical 
experiments, luspatercept has been shown to bind with high affinity to some TGF-β superfamily 
ligands (eg, GDF11, bone morphogenetic protein 6 [BMP6] and activin B) but substantially less 
to others (eg, bone morphogenetic protein 9 [BMP9] and activin A).  The mechanism of action 
(MOA) of luspatercept is independent from that of erythropoietin (EPO) (Suragani, 2014).  
While EPO stimulates proliferation and differentiation of early erythroid progenitors, 
luspatercept as an erythroid maturation agent promotes stimulation of the later, maturation phase 
of erythroblast differentiation and maturation in the bone marrow (refer to Figure 1B).
During normal erythropoiesis, GDF11 appears to inhibit differentiation and maintain the survival 
of immature erythroid progenitors. In a mouse model of thalassemia, defects in erythroid 
differentiation led to an accumulation of GDF11 expressing cells that maintained their own 
survival (Dussiot, 2014).  Recent studies (Dussiot, 2014; Suragani, 2014) identified GDF11 as a 
regulator of erythropoiesis and showed that its inhibition in mouse models of anemia with 
ineffective erythropoiesis restores normal erythropoietic differentiation and improves anemia.
Figure 1:
Luspatercept Schematic Representation and Mechanism of Action
A
B
ActRIIB = activin receptor type IIB; ECD = extracellular domain; EPO = erythropoietin; GDF11 = growth 
differentiation factor 11; IgG1 = immunoglobulin G1; RBC = red blood cell; TGF-β = transforming growth factor-
beta.
Please refer to the current version of the Investigator’s Brochure (IB) for detailed information 
concerning the available pharmacology, toxicology, drug metabolism, clinical studies, and 
adverse event profile of luspatercept.
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1.2.2.
Nonclinical Studies with Luspatercept
Please refer to the IB for information concerning the available nonclinical studies including 
pharmacology, toxicology, drug metabolism of the investigational product (IP). The most recent 
version of the luspatercept IB should be reviewed prior to initiating the study.
1.2.3.
Summary of Clinical Experience
Luspatercept is currently in Phase 3 of clinical development in MDS and beta-thalassemia. 
Across the ex-Japan Phase 2, multicenter, open-label, dose-finding program in MDS, responses 
to luspatercept treatment were observed in the majority of subjects at pharmacologic dose levels 
of approximately 0.75 up to 1.75 mg/kg, administered once every 3 weeks.  In particular, as 
described in more detail in the following sections, luspatercept treatment led to HI-E in a 
substantial proportion of MDS subjects within the initial 3 months of treatment.
Luspatercept is currently being assessed in the ex-Japan Phase 2 study for subjects with lower 
risk MDS and anemia.  Data is available for 58 subjects treated with doses of ≥ 0.75 mg/kg every 
3 weeks for up to 5 cycles.  Subjects had HI-E rates of 76% (19/25) (baseline endogenous 
sEPO < 200 U/L), 58% (7/12) (200-500 U/L), and 43% (6/14) (> 500 U/L) and rates of RBC-TI 
of 53% (10/19) (< 200 U/L), 44% (4/9) (200-500 U/L), and 14% (2/14) (> 500 U/L).  Although 
the efficacy rates are higher in the lower sEPO level subjects than in the higher sEPO level
subjects, luspatercept showed the efficacy in subjects with any sEPO level. For the subjects who 
are low (RBCs < 4 units within 8 weeks prior to dosing) and high (RBCs ≥ 4 units within 8 
weeks prior to dosing) transfusion burden, HI-E rates were 65% (11/17) and 62% (21/34), and 
rates of RBC-TI were 75% (6/8) and 29% (10/34), respectively (Platzbecker, 2017a).
Based on these preliminary Phase 2 study results, a Phase 3, randomized, open-label, active 
controlled study will be conducted in subjects with very low- to intermediate-risk MDS (IPSS-R) 
who require RBC transfusions (ACE-536-MDS-002). 
Luspatercept was also assessed in the MEDALIST trial outside Japan (Fenaux, 2018b; Fenaux, 
2020); a Phase 3, randomized, double-blind study in subjects with very low- to intermediate-risk 
MDS (IPSS-R) with ring sideroblasts (RS) who require RBC transfusions and who were 
refractory, intolerant, or ineligible to receive an ESA.  Subjects (N = 229) were randomized in a 
2:1 ratio against placebo.  Of 153 subjects receiving luspatercept, 58 (37.9%) achieved the 
primary endpoint of RBC-TI for ≥ 8 weeks compared with 10 of 76 subjects (13.2%) receiving 
placebo (odds ratio [OR] 5.1, p < 0.0001).  Of those receiving luspatercept, 43 of 153 (28.1%) 
achieved the key secondary endpoint of RBC-TI for ≥12 weeks (Weeks 1 to 24) compared with 
6 of 76 (7.9%) receiving placebo (OR 5.1, p = 0.0002).  Subjects receiving luspatercept were 
more likely to achieve a modified hematologic improvement – erythroid response, defined as a 
reduction in transfusion of ≥ 4 RBC units/8 weeks or a mean hemoglobin increase of ≥ 1.5 
g/dL/8 weeks in the absence of transfusions, compared with subjects receiving placebo (52.9% 
versus 11.8% during Weeks 1 to 24; p < 0.0001).  Luspatercept was well tolerated and resulted in 
a significantly reduced transfusion burden.
Additionally, luspatercept is currently being assessed in two ex-Japan Phase 2 studies in β-
thalassemia subjects (A536-04 and A536-06) in which luspatercept has demonstrated clinically 
significant efficacy in both RBC transfusion dependent and non-transfusion dependent subjects.  
Further, an ex-Japan Phase 3, randomized, double-blind study to determine the efficacy and 
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Luspatercept (ACE-536)
Protocol ACE-536-MDS-003
Bristol-Myers Squibb K.K.
Confidential and Proprietary
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safety of luspatercept versus placebo in subjects with β-thalassemia who require regular red 
blood cell transfusions (ACE-536-B-THAL-001) is ongoing. A536-04 study title is A Phase 2, 
Open-Label, Ascending Dose Study to Evaluate the Effects of ACE-536 in Patients With Beta-
Thalassemia Intermedia (NCT01749540), A536-06 study title is An Open-Label Extension 
Study to Evaluate the Long-Term Effects of ACE-536 in Patients With β-Thalassemia Previously 
Enrolled in Study A536-04 (NCT02268409), and the ex-Japan Phase 3 study title is A Phase 3, 
Double-Blind, Placebo Controlled Multicenter Study to Determine the Efficacy and Safety of 
Luspatercept (ACE-536) in Adults With Transfusion Dependent Beta (β)-Thalassemia
(NCT02604433)
Additional information regarding clinical experience with luspatercept is summarized in the 
current version of the luspatercept IB.  Please note that there have been no luspatercept exposure 
to date in Japanese subjects.
1.2.3.1.
Potential Risks of Human Use
Increases in hematologic parameters (ie, RBC, Hgb, hematocrit, reticulocytes) are expected as 
pharmacologic effects of luspatercept treatment.  Increases in systolic and diastolic blood 
pressures may occur in concert with increases in hemoglobin values.  Excessive or rapid 
increases in hemoglobin or blood pressure may occur and will be monitored.  Dose modification 
rules for individual subjects, including dose delay and/or dose reduction, will be utilized to 
minimize risks associated with increased RBC parameters.
Adverse events considered probably or possibly related to luspatercept that were reported in at 
least 5% of subjects in the Phase 1 study in healthy volunteers included injection site hemorrhage 
and injection site macule.  Adverse events reported in at least 10% of subjects regardless of 
causality in the open-label Phase 2 studies in MDS include (in order of decreasing frequency in 
the extension study) nasopharyngitis, fatigue, cough, diarrhea, dyspnea, hypertension, arthralgia, 
edema peripheral, pneumonia, and headache.  Adverse events reported in at least 15% of subjects 
regardless of causality (in order of decreasing frequency) in the open-label Phase 2 studies in 
β-thalassemia included pyrexia, headache, diarrhea, asthenia, bone pain, myalgia, oropharyngeal 
pain, arthralgia, musculoskeletal pain, back pain, influenza, dizziness, rhinitis, abdominal pain, 
nausea, pharyngitis, and vomiting.
As with all biologics, there is the potential for antidrug antibodies (ADA) that can be associated 
with increased drug clearance and hypersensitivity reactions.  Antidrug antibody formation 
against luspatercept as well as human ActRIIB protein will be monitored.
Luspatercept has exhibited toxicity both in terms of maternal health and fetal development in 
reproductive toxicity studies in preclinical species. If luspatercept is taken during pregnancy, a 
teratogenic effect in humans cannot be ruled out.  If a woman becomes pregnant while taking 
luspatercept, the medication must be stopped immediately.  In addition, since it is unknown if 
luspatercept is excreted in human breast milk, breastfeeding is prohibited.  Male and female 
subjects of childbearing potential participating in studies of luspatercept must be willing to 
abstain from sexual intercourse or use adequate contraception during the treatment period of the 
study and for at least 12 weeks after discontinuation of study therapy.
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Protocol ACE-536-MDS-003
Bristol-Myers Squibb K.K.
Confidential and Proprietary
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Hematologic malignancies were observed in rats in a nonclinical juvenile toxicity study at high 
doses not being used in humans.  No related tumors developed in adult rats and monkeys in 
similar studies.
Please refer to the current version of IB for additional information regarding findings from 
toxicology studies.  It is unknown if humans will experience any of the effects of luspatercept 
that were noted in the rat and monkey toxicology studies.  Safety effects will be monitored 
closely through adverse event (AE) reporting, clinical laboratory tests, vital signs, and physical 
examinations.
A comprehensive review of luspatercept, as well as details regarding the information 
summarized above, is provided in the IB.  The most recent version of the luspatercept IB should 
be reviewed prior to initiating the study.
1.2.3.2.
Overall Benefit Risk Assessment
Current available information continues to support an acceptable benefit-risk profile for 
luspatercept when used in accordance with the precautions, dosing, and safety monitoring 
outlined in the study protocol and the routine pharmacovigilance practices.
1.3.
Rationale
1.3.1.
Study Rationale and Purpose
Anemia is the predominant cytopenia observed in adult MDS and is present in 85% of MDS 
patients at the time of diagnosis (Noel, 1992). Anemia in MDS can range in severity from mild 
(asymptomatic) to severe, requiring regular transfusion support. Of the approximately 80% to 
90% of patients with MDS that develop anemia, 40% of those patients become transfusion 
dependent (TD). Lower hemoglobin (Hgb) levels and RBC transfusion-dependence have been 
associated with inferior cardiovascular outcomes and increased mortality in patients with MDS, 
representing a strong rationale for the aggressive management of anemia in MDS (Zeidan, 2013).
In addition, long-term RBC transfusion dependence has other clinical and economic 
consequences, including a potentially negative impact on quality-of-life (QoL), iron overload 
and its associated complications, immune-related disorders, and increased risk of 
infections (Hellstrom-Lindberg, 2003; Jansen, 2003; Thomas, 2007).
The use of ESAs is standard of care in lower risk MDS patients with endogenous sEPO ≤ 500 
U/L according to treatment guidelines (NCCN, 2017; ESMO, 2014 [Fenaux, 2014]; ELN, 2014 
[Malcovati, 2013]; JSH, 2013). Recent Phase 3 studies with epoetin alfa and darbepoetin have
demonstrated efficacy, but limited in both magnitude and size of patient population in whom a 
clinically significant effect is seen (see Section 1.1.1.1). In Japan, DAR has been approved in 
patients with low- or intermediate-1-risk primary MDS (according to IPSS).  However, Efficacy 
in patients with EPO > 500 U/L has not been assessed (Jang, 2015).
Therefore, a new therapeutic option that would prevent the RBC-TI subjects to become RBC-TD 
for a sustained period of time with high therapeutic effect would provide an important clinical 
benefit in this patient population.
Luspatercept has a novel mechanism of action distinct from ESAs which may be more beneficial 
in the treatment of anemia in IPSS-R lower-risk MDS patients. Preliminary ex-Japan Phase 2 
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Confidential and Proprietary
28
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results for luspatercept demonstrate promising results for erythroid response (HI-E), transfusion 
independence and duration of response in subjects who are requiring RBC transfusion as well as 
in subjects who are not requiring RBC transfusion.
Based on the ex-Japan Phase 2 study results, a Phase 3, randomized, open-label, direct 
comparison study with epoetin alfa and luspatercept will be conducted in subjects with very low-
to intermediate-risk MDS (IPSS-R) who require RBC transfusions (ACE-536-MDS-002). 
In parallel with the Phase 3 study, this study (ACE-536-MDS-003) was planned to evaluate the 
pharmacodynamics (PD) and efficacy in subjects with very low- to intermediate-risk MDS 
(IPSS-R) who are RBC-TI, and to evaluate PK in Japanese subjects.
1.3.2.
Rationale for the Study Design
ACE-536-MDS-003 is a Japanese Phase 2, multicenter, single-arm study.  The primary objective 
of the study is to evaluate HI-E of luspatercept from W1D1 through Week 24 for the treatment of 
anemia due to IPSS-R very low, low, or intermediate risk MDS in Japanese subjects who are not 
requiring RBC transfusion at least in the 16 weeks prior to Week 1 Day 1 (W1D1) - except 
transfusions due to blood loss or infection that occurred between 16 and 8 weeks prior to W1D1.
The multicenter nature of the study will provide assurance that the results are likely to have 
general applicability.  
1.3.2.1.
Rationale for the Study Population
This study targets subjects who have symptomatic anemia accompanied by Hgb concentration 
< 10.0 g/dL and are not requiring RBC transfusion to evaluate the PD and efficacy in IPSS-R 
very low- to intermediate-risk MDS subjects who are not influenced by RBC transfusions. The 
subjects will be ESAs naïve or previously used ESAs but not administered ESAs within 8 weeks 
prior to W1D1 to washout the effects of ESAs.
The IPSS-R classification has been chosen to define this Phase 2 study population because this 
classification provides better discrimination of MDS progression risk factors compared with the 
original IPSS (Greenberg, 1997) for evaluating clinical outcomes (survival duration and time to 
progression of AML) for MDS subjects (Greenberg, 2012).  For the purpose of this study, 
subjects with IPSS-R very-low, low and intermediate risk will be referred to as lower risk MDS.
Subjects in the lower risk groups often become dependent on frequent RBC transfusions, which 
leads to decreased HRQoL and increased morbidity and mortality (Hellstrom-Lindberg, 2003; 
Malcovati, 2005).  Thus, the therapeutic goal in this subject population is to increase Hgb level 
and prevent from becoming RBC-TD, which is evaluated in this study.
Subjects can be enrolled to this study regardless of their baseline endogenous EPO level.  
According to the recent published data (Suzuki, 2015), the endogenous EPO level has a strong 
correlation with transfusion dependency, and a significantly larger proportion of patients showed 
serum EPO levels higher than 500 U/L in TD patients (68 % of TD versus 14 % of TI patients).  
Since the target population of the study is lower risk MDS subjects who are not requiring RBC 
transfusion, it is anticipated that most of the patients have EPO levels < 500 U/L.  However, 
there is an unmet need for patients with EPO level ≥500 U/L in Japan because the use of ESAs 
are not recommended for these patients, and therefore, it is allowed to enroll subjects with EPO 
level ≥500 U/L.  As described before, in the preliminary ex-Japan Phase 2 study results for 
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EDMS Doc. Number: 25770028 - 22621913
Luspatercept (ACE-536)
Protocol ACE-536-MDS-003
Bristol-Myers Squibb K.K.
Confidential and Proprietary
29
ACE-536-MDS-003 Amendment 2.0 Final: 22 Nov 2021
luspatercept, HI-E rates are 76% (19/25) (baseline endogenous sEPO < 200 U/L), 58% (7/12) 
(200-500 U/L), and 43% (6/14) (> 500 U/L) and rates of RBC-TI of 53% (10/19) (< 200 U/L), 
44% (4/9) (200-500 U/L), and 14% (2/14) (> 500 U/L) (Platzbecker, 2017a).
This study is being conducted to gain additional experience in Japanese subjects and in particular 
to evaluate luspatercept in subjects with earlier stage non transfusion dependent disease.
1.3.2.2.
Rationale for Study Endpoints
The primary endpoint of HI-E is defined per IWG (Cheson, 2006) as the proportion of subjects 
achieving ≥ 1.5 g/dL increase in Hgb over any consecutive 56-day period in the absence of RBC 
transfusions and reflects the direct clinical benefit of the treatment in lower risk MDS subjects 
who are not requiring RBC transfusion because the therapeutic goal in this population is to 
increase Hgb level and prevent subjects from becoming RBC-TD.
While HI-E based on the IWG 2006 criteria is standard hematologic response criteria in lower-
risk MDS, difficulties in interpretation of the criteria were reported in the EPOANE3021 Phase 3 
study for epoetin alfa, in particular in the subjects who had to transiently discontinue the study 
treatment due to a rapid/excessive rise in Hgb level, and therefore often had responses of less 
than 8 week durations (due to drug interruption). To address these difficulties, an ad hoc analysis 
of erythroid response was conducted by adding some conditions including the condition of 
“patients with an increase in Hgb level by at least 1.5 g/dL lasting less than 8 weeks due to 
epoetin alfa discontinuation were considered responders if, when restarting epoetin alfa at lower 
dose, Hgb still increased by at least 1.5 g/dL” (Fenaux, 2016; Fenaux, 2018a). Recently, this 
undesired effect of dosing interruption on HI-E evaluation was also discussed in the IWG and 
modification of the criteria was suggested, which further supports the importance of addressing 
the effect of dosing interruption to avoid misinterpretation of HI-E outcome (Platzbecker, 2019; 
Platzbecker, 2020). Similar to epoetin alfa, the undesired effects of dosing interruption due to 
predose Hgb ≥ 12.0 g/dL on HI-E assessment is also expected in luspatercept treatment,
especially for lower risk MDS patients who are not requiring RBC transfusion. Therefore, in this 
ACE-536-MDS-003 study, for subjects who have a dose delay meeting the dose interruption 
criterion of predose Hgb ≥ 12.0 g/dL, if their Hgb levels temporarily decrease to < 1.5 g/dL but 
achieve ≥ 1.5 g/dL again after treatment resumption, this period (ie, the time from dose delay to 
achieving a Hgb increase of ≥ 1.5 g/dL again) will be included as the period of sustained Hgb 
increase of ≥ 1.5 g/dL for HI-E evaluation.
In the ARCADE Phase 3 study for DAR, HI-E as per IWG 2006 criteria was defined as 
≥1.5 g/dL increase from baseline in Hgb with a mean rise of ≥1.5 g/dL for 8 weeks without 
transfusions. To ensure better comparison of efficacy data between luspatercept and DAR, 
modified HI-E (mHI-E) per IWG 2006 criteria defined as ≥ 1.5 g/dL mean increase in Hgb
compared to baseline over any consecutive 56-day period in the absence of RBC transfusions is 
added in the secondary endpoints.
Other secondary objectives include evaluation of efficacy (eg, time to and duration of HI-E and 
mHI-E, duration of transfusion independence; HRQoL) as well as safety and PK.  Safety is 
assessed by evaluating adverse events and laboratory data.  Adverse events and abnormal 
laboratory value severity will be graded using version 4.03 of the National Cancer Institute 
Common Terminology Criteria for Adverse Events (NCI CTCAE).  Biomarkers will also be 
measured as exploratory endpoints.
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EDMS Doc. Number: 25770028 - 22621913
Luspatercept (ACE-536)
Protocol ACE-536-MDS-003
Bristol-Myers Squibb K.K.
Confidential and Proprietary
30
ACE-536-MDS-003 Amendment 2.0 Final: 22 Nov 2021
1.3.3.
Rationale for Dose, Schedule and Regimen Selection
The starting dose level of 1.0 mg/kg up to a maximum dose level of 1.75 mg/kg are based on 
clinical data from the ongoing ex-Japan Phase 2 A536-03 and A536-05 studies in MDS. 
Preliminary results indicate that the dose levels of up to 1.75 mg/kg have been generally safe and 
well-tolerated.  A higher response rate, including HI-E and RBC-TI, was observed in the higher 
dose groups (0.75 to 1.75 mg/kg subcutaneous every 3 weeks [Q3W]) compared to the lower 
dose groups (0.125 to 0.5 mg/kg subcutaneous Q3W).  Selection of the dosing schedule (every 3 
weeks, Q3W) was mainly based on the duration of the luspatercept responses in MDS patients.  
In the ex-Japan Phase 2 studies, the clinically significant increase in hemoglobin was maintained 
with the Q3W dosing schedule.
The same dosage and the administration regimen are considered appropriate for Japanese 
patients for the following reasons:

Luspatercept is an immunoglobulin G1 (IgG1) fusion protein and catabolism is expected 
to take place through the normal proteolytic pathways. No ethnic difference in drug 
elimination is expected.  

Serum exposure to luspatercept is approximately proportional to dose (0.125 to 1.75 
mg/kg), with no evidence of target-mediated disposition.

Luspatercept clearance tended to be higher with increasing body weight.  Thus, 
luspatercept dose is based on body weight.  This is expected to limit higher exposure due 
to lower average body weight in Asian populations.  

Sufficient clinical experiences have been gained in ex-Japan clinical trials for 
luspatercept in doses up to 1.75 mg/kg and no major safety issues are identified.  MTD 
has not been reached at 1.75 mg/kg. 

The 1 mg/kg starting dose is only 57% of the highest therapeutic dose (1.75 mg) in ex-
Japan clinical trials and considered to be safe for Japanese patients.  

The pharmacological effect on Hgb increase is exposure dependent and thus dose titration 
may be needed to achieve an adequate efficacy while avoiding Hgb overshoots.  Close 
monitoring via dose modifications to manage Hgb increase within desired level is 
implemented in this Phase 2 study.

117 Asian patients (including 12 subjects from Taiwan) have been enrolled into Phase 3 
β-thalassemia study (with luspatercept doses of up to 1.25 mg/kg for 48 weeks).  No 
safety concerns in Asian population have been identified. 
Additional information regarding these clinical studies is summarized in the current version of 
the luspatercept IB.
1.3.4.
Rationale for Exploratory Biomarkers
ActRIIB ligands (eg, GDF11 and Activin B)
Luspatercept binds with high affinity to both GDF11 and Activin B and inhibits subsequent 
signaling downstream of Activin Receptor IIB.  Growth differentiation factor 11 and Activin B 
are present in the serum and bone marrow and nonclinical studies have demonstrated increased 
circulating GDF11 levels in a murine model of MDS. It is possible that baseline levels of these 
proteins in patients may correlate with response.
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EDMS Doc. Number: 25770028 - 22621913
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Protocol ACE-536-MDS-003
Bristol-Myers Squibb K.K.
Confidential and Proprietary
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MDS-associated Molecular Mutations (eg, SF3B1)
Emerging literature describes the prognostic impact of gene mutations in MDS patients.  For 
example, Haferlach, et al surveyed genetic aberrations in 944 patients and demonstrated that 
90% of the population had at least one mutation.  Forty-seven genes were significantly mutated 
and many of the mutations were linked to higher risk groups and/or blast elevation.  Of the 47 
genes, almost half affected survival, suggesting that molecular profiling of multiple target genes 
could be valuable for classification and prognosis in MDS patients (Haferlach, 2014).  In 
particular, SF3B1 and other genes involved in ribonucleic acid (RNA) splicing such as SRSF2, 
U2AF1 and ZRSR2 have been observed in MDS patients (Pellagatti, 2015).  SF3B1 mutations 
were found in greater than 70% of ring sideroblast (RS)+ patients (Malcovati, 2011; 
Papaemmanuil, 2011) and thought to be causally related to chromosome stability, 
deoxyribonucleic acid (DNA) repair and gene regulation that may result in anemia and 
thrombocytopenia (Pellagatti, 2015; Visconte, 2014).  Preliminary results from ongoing Phase 2 
studies of luspatercept in MDS indicate that subjects harboring a SF3B1 mutation had increased 
HI-E response rates to luspatercept (A536-03, A536-05) but similar rates of RBC-TI (8 
weeks) (Platzbecker, 2017a).
In this study, we will make a preliminary assessment by evaluating the prognostic value of a 
discrete subset of MDS-related gene mutations in the study population, as well as evaluating the 
impact of these mutations on clinical benefit with luspatercept. Bone marrow aspirates will be 
collected from subjects at screening as the baseline for molecular biomarker analyses. While the 
IPSS-R prognostic classification system remains the gold standard for risk stratification of 
subjects with MDS at diagnosis, prognostic risk factors in addition to cytogenetics, blast count 
and cytopenias are being identified that will be important in understanding the study population.  
Finally, we also propose to collect and store an aliquot of bone marrow mononuclear cells for 
future analyses such as assessment of RNA expression to allow us to develop a gene signature 
that predicts response.
Terminal erythropoiesis
As previously mentioned, luspatercept acts on late stages of erythroid differentiation, through a 
mechanism unique from that of EPO.  We hypothesize that patients may respond differently to 
luspatercept depending on the stage at which erythropoiesis is affected in their bone marrow.
For example, responders may have bone marrow that is “primed” and rich in late-stage erythroid 
precursors compared to non-responders.  As such, we propose to isolate bone marrow 
mononuclear cells from patients and using flow cytometry, measure the extent of terminal 
erythroid differentiation in each patient (Hu, 2013) at baseline and after treatment.  
Subsequently, we will make a preliminary assessment by comparing this phenotypic profile to 
response to determine whether there is a correlation between erythroid differentiation state and 
response to luspatercept.  We will make a preliminary evaluation of the profile after treatment to 
determine which erythroid populations are modified following administration of luspatercept.  
SARS-CoV-2
Subjects who have evidence of a prior infection with severe acute respiratory syndrome 
coronavirus 2 (SARS-CoV-2) may be at risk for potential long-term sequelae.  The sequelae 
could potentially affect the safety profile of luspatercept.  In addition, some health authorities 
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Protocol ACE-536-MDS-003
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Confidential and Proprietary
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ACE-536-MDS-003 Amendment 2.0 Final: 22 Nov 2021
may want to know coronavirus disease 2019 (COVID-19) status as prior infection with SARS-
CoV-2 may increase toxicity and/or impact interpretation of study events or results.
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Protocol ACE-536-MDS-003
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2.
STUDY OBJECTIVES AND ENDPOINTS
Table 1:
Study Objectives
Primary Objective
The primary objective of the study is to evaluate HI-E per IWG (Cheson, 2006) from W1D1 through 
Week 24 for the treatment of anemia due to IPSS-R very low, low, or intermediate risk MDS in 
Japanese subjects who are not requiring RBC transfusion.
Secondary Objective(s)
The secondary objectives are:

To evaluate mHI-E per IWG (Cheson, 2006)

To evaluate HI-E per IWG (Cheson, 2006) from W1D1 through Week 48

To evaluate the time to HI-E and duration of HI-E

To evaluate the time to mHI-E and duration of mHI-E

To evaluate the proportion of subjects who maintain TI at Week 24, Week 48 and Week 72

To assess the safety of luspatercept 

To assess the PK of luspatercept 

To assess the frequency of antidrug antibodies (ADA) and effects on efficacy, safety, or PK

To assess the number and percentage of subjects progressing to AML; time to AML 
progression

To assess the overall survival
Exploratory Objective(s)
The exploratory objectives are:

To make a preliminary assessment of molecular and cellular markers in the bone marrow 
and/or in peripheral blood at baseline and during therapy that may provide further prognostic 
classification of MDS subtypes and potentially impact luspatercept efficacy

To make a preliminary assessment of molecular and cellular markers in the bone marrow 
and/or in peripheral blood at baseline and during therapy that may provide information on 
luspatercept mechanism of action and on-therapy markers predictive of response or relapse

To make a preliminary assessment of the effect of luspatercept on HRQoL 
 

To assess impact of SARS-CoV-2 serologic status on subjects receiving luspatercept and MDS 
and to support health authority requests.
Table 2:
Study Endpoints
Endpoint
Name 
Description
Timeframe
Primary
Hematologic 
improvement in 
erythroid response (HI-
E) per IWG (Cheson, 
2006)
Proportion of subjects 
achieving HI-E over any 
consecutive 56-day period in 
the absence of RBC 
transfusions
W1D1 through Week 
24
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EDMS Doc. Number: 25770028 - 22621913
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Protocol ACE-536-MDS-003
Bristol-Myers Squibb K.K.
Confidential and Proprietary
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ACE-536-MDS-003 Amendment 2.0 Final: 22 Nov 2021
Table 2:
Study Endpoints (Continued)
Endpoint
Name 
Description
Timeframe
Secondary
Modified hematologic 
improvement in 
erythroid response 
(mHI-E) per 
IWG (Cheson, 2006)
Proportion of subjects achieving ≥ 
1.5 g/dL mean increase in 
hemoglobin compared to baseline 
over any consecutive 56-day
period in the absence of RBC 
transfusions
W1D1 through Week 
24;
W1D1 through Week 48
Hematologic 
improvement in 
erythroid response 
(HI-E) per 
IWG (Cheson, 2006)
Proportion of subjects achieving 
HI-E over any consecutive 56-day 
period in the absence of RBC 
transfusions
W1D1 through Week 48 
Time to HI-E
Time from first dose to first onset 
of achieving ≥ 1.5 g/dL increase in 
hemoglobin over any consecutive 
56-day period in the absence of 
RBC transfusions
W1D1 through Week 
24;
W1D1 through Week 48
Time to mHI-E
Time from first dose to first onset 
of achieving ≥ 1.5 g/dL mean 
increase in Hgb compared to 
baseline over any consecutive 56-
day period in the absence of RBC 
transfusions
W1D1 through Week 
24;
W1D1 through Week 48
Duration of HI-E
Maximum duration of achieving ≥ 
1.5 g/dL increase in hemoglobin 
for subjects who achieve Hgb 
increase ≥56 days in the absence 
of RBC transfusions 
W1D1 through EOT
Duration of mHI-E
Maximum duration of achieving ≥ 
1.5 g/dL mean increase in Hgb
compared to baseline for subjects 
who achieve mean Hgb increase 
≥56 days in the absence of RBC 
transfusions 
W1D1 through EOT
RBC-TI
Proportion of subjects who 
maintain RBC-TI from W1D1 
through Week 24, 48, and 72. 
W1D1 through Week 24;
W1D1 through Week 48;
W1D1 through Week 72
Safety
Type, frequency, severity of AEs 
and relationship of AEs to
luspatercept
Screening through 42 
days post last dose
PK
Cmax, AUC, Tmax
W1D1 through 1-year 
post first dose
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EDMS Doc. Number: 25770028 - 22621913
Luspatercept (ACE-536)
Protocol ACE-536-MDS-003
Bristol-Myers Squibb K.K.
Confidential and Proprietary
35
ACE-536-MDS-003 Amendment 2.0 Final: 22 Nov 2021
Table 2:
Study Endpoints (Continued)
Endpoint
Name 
Description
Timeframe
Secondary
Antidrug antibodies 
(ADA) 
Frequency of antidrug antibodies 
and effects on efficacy, or safety, or 
PK
W1D1 through 1-year 
post first dose
Progression to AML 
Number and percentage of subjects 
progressing to AML; time to AML 
progression 
W1D1 through 5 years 
from first dose or 3 
years from last dose 
(whichever occurs 
later)
Overall survival
Time from date of W1D1 to death 
due to any cause
W1D1 through 5 years 
from first dose or 3 
years from last dose
(whichever occurs 
later)
Exploratory
Molecular and cellular 
markers in the bone 
marrow and/or in 
peripheral blood 
Evaluation of biomarkers that may 
potentially impact luspatercept 
efficacy, predict response or 
relapse, help to better understand 
MOA and/or provide further 
prognostic classification of MDS 
subtypes.
Molecular markers (eg, SF3B1) 
include evaluation of MDS-
associated gene mutations and their 
impact on drug efficacy, clinical 
response or relapse, disease 
progression, drug MOA and 
prognostication of MDS. 
Baseline through End 
of Treatment
Health-related quality 
of life (HRQoL)
 
Screening through End 
of Treatment
SARS-CoV-2 
Serology
Exploratory measurements of 
SARS-CoV-2 serology (anti-SARS-
CoV-2 total or IgG) from serum
Screening through EOT
ADA = antidrug antibodies; AE = adverse event; AML = acute myeloid leukemia; AUC = area under the 
concentration-time curve; Cmax = maximum plasma concentration of drug; 
 
 EOT = End of Treatment;
 – Anemia; Hgb = hemoglobin; HI-E = hematologic 
improvement – erythroid response; IgG = immunoglobulin G; IWG = International Working Group; MDS = 
myelodysplastic syndromes; MOA = mechanism of action; PK = pharmacokinetics; RBC = red blood cell; SARS-
CoV-2 = severe acute respiratory syndrome coronavirus 2; TI = transfusion independent/ independence; Tmax = time 
to maximum plasma concentration of drug; W1D1 = Week 1 Day 1.
2.0
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Approved
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EDMS Doc. Number: 25770028 - 22621913
Luspatercept (ACE-536)
Protocol ACE-536-MDS-003
Bristol-Myers Squibb K.K.
Confidential and Proprietary
36
ACE-536-MDS-003 Amendment 2.0 Final: 22 Nov 2021
3.
OVERALL STUDY DESIGN
3.1.
Study Design
The study will be conducted in compliance with the International Council for Harmonisation
(ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use/Good 
Clinical Practice (GCP) and applicable regulatory requirements.
This is a Phase 2, multicenter, single-arm study to evaluate the efficacy, safety and PK of 
luspatercept (ACE-536) for the treatment of anemia due to IPSS-R very low, low or intermediate 
risk MDS in Japanese subjects who are not requiring RBC transfusion.
The study is divided into the Screening Period, a Treatment Period and a Post-Treatment Follow-
up Period. See Figure 2 for more details and refer to Section 6 for a full list of study 
procedures/assessments.
Screening Period 
Upon giving written informed consent, subjects enter the Screening Period to determine 
eligibility. Subject screening procedures are to take place within 35 days prior to W1D1. During 
the Screening Period, subjects will undergo safety and other assessments to determine eligibility 
for the study.  Subjects deemed eligible for the study will be enrolled using integrated response 
technology (IRT).
Central review of bone marrow aspirate smear and peripheral blood smear will be used to
confirm MDS diagnosis according to the WHO 2016 classification (Appendix B) and to 
determine the baseline IPSS-R riskclassification (Greenberg, 2012).  A bone marrow biopsy will 
be collected only when adequate aspirate is not attainable.
The sponsor may review key eligibility criteria as well as relevant data (eg, central laboratory 
reports and cytomorphology/cytogenetic reports) and communicate as necessary with the 
investigator prior to enrolment of a subject.
Treatment Period
The first dose of IP should be administered on the same day after, but at the latest within 3 days 
of enrollment.  
Subjects will receive IP every 3 weeks (21 days) (ie, at the Week 1 Day 1 (W1D1) Visit, W4D1 
Visit; W7D1 Visit, etc.).
Details on IP administration and intra-individual dose titration are outlined in Section 7.
Best supportive care (BSC) may be used in combination with study treatment when clinically 
indicated per investigator.  BSC includes, but is not limited to, treatment with transfusions, 
antibiotic, antiviral and/or antifungal therapy, and nutritional support as needed.  BSC forthis 
study excludes the use of ESAs.  Please refer to Section 8 for more details on permitted and 
prohibited concomitant medications and procedures.
Subjects should receive IP through to a minimum of the 24-week MDS Disease Assessment Visit 
scheduled for Day 169, unless the subject experiences unacceptable toxicities, withdraws
consent, or meets any other treatment discontinuation criteria.
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EDMS Doc. Number: 25770028 - 22621913
Luspatercept (ACE-536)
Protocol ACE-536-MDS-003
Bristol-Myers Squibb K.K.
Confidential and Proprietary
37
ACE-536-MDS-003 Amendment 2.0 Final: 22 Nov 2021
The MDS Disease Assessment (Section 6.4.2) performed on Day 169 (and every 24 weeks 
thereafter [ie, Day 337, Day 505, etc.] consists of the investigator’s assessment of clinical benefit 
from IP and status of underlying disease.  For subjects to remain on treatment beyond this 
timepoint both of the following criteria must be confirmed in each subject:

Evidence of clinical benefit defined by either one of the following two criteria:

HI-E based on IWG (Cheson, 2006) (Appendix D) (Hgb increase of ≥ 1.5 g/dL 
for 8 weeks within 12 weeks immediately preceding Day 169 and every 24 weeks 
thereafter [ie, Day 337, Day 505, etc.])

Maintain RBC transfusion independence

Absence of disease progression per IWG criteria for altering natural history of 
MDS (Cheson, 2006) (Appendix E) based on central morphological assessment of 
bone marrow, peripheral blood and cytogenetics results.
Based on the outcome of these assessments, subjects will either be discontinued from treatment 
with IP and enter the Post-Treatment Follow-up Period or continue the treatment as long as the 
above criteria continue to be met or until the subject experiences unacceptable toxicities, 
withdraws consent, or meets any other discontinuation criteria.
For subjects to continue the treatment with IP, scheduled MDS disease assessments will be 
repeated at the 48-Week MDS Disease Assessment Visit (ie. Day 337) and every 24 weeks 
thereafter (see Section 6.4.2 for details) to confirm continued clinical benefit and absence of
disease progression as per above criteria.
Serial measurements of safety and efficacy will occur at scheduled study visits as outlined in 
Table 3.  Laboratory analyses will be performed centrally.  Local laboratories are allowed in 
cases when timely results are needed (eg, pre-dose Hgb assessments, study treatment dosing 
decisions, hematology assessments between clinic visits, adverse event).  In these circumstances, 
a split sample should still be collected and sent to the central laboratory for analysis.  Where 
discrepancies are present, results of the central laboratory will be used to determine response 
assessments.
An End of Treatment (EOT) evaluation will be performed for subjects who are withdrawn from 
treatment for any reason as soon as possible after the decision to permanently discontinue 
treatment has been made (Section 6.2.2).
Post-Treatment Follow-up Period
The Post-Treatment Follow-up Period consist of the 42-Day Safety Follow-up (Section 6.3.1), 
which includes (but is not limited to) the collection of adverse events (AEs), concomitant drugs 
and RBC-transfusion data, and the Long-term Follow-up (Section 6.3.2). 
The transfusion data collection will continue until 8 weeks from the date of last dose of IP or 
from the date of the EOT Visit (whichever is later).
In addition, continuation of monitoring for other malignancies/pre-malignances and progression 
to AML will occur in the Long-term Post-Treatment Follow-up Period along with data collection 
of subsequent MDS therapies, and overall survival for 5 years from the date of the first dose of 
IP, or 3 years from the last dose (whichever occurs later) unless the subject withdraws consent 
2.0
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EDMS Doc. Number: 25770028 - 22621913
Luspatercept (ACE-536)
Protocol ACE-536-MDS-003
Bristol-Myers Squibb K.K.
Confidential and Proprietary
38
ACE-536-MDS-003 Amendment 2.0 Final: 22 Nov 2021
from the study, dies or is lost to follow-up.  For that purpose, visits (which may consist of 
telephone contacts from the site) will be conducted every 12 weeks for the first 3 years from the 
date of last dose of IP and every 6 months thereafter, if applicable.
An antidrug antibodies (ADA) sample(s) may be required in the Post-Treatment Follow-up 
Period for subjects who terminate the Treatment Period with less than 1 year of ADA monitoring 
if a subject is ADA positive at the time of treatment discontinuation.
2.0
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Approved
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EDMS Doc. Number: 25770028 - 22621913
Luspatercept (ACE-536)
Protocol ACE-536-MDS-003
Bristol-Myers Squibb K.K.
Confidential and Proprietary
39
ACE-536-MDS-003 Amendment 2.0 Final: 22 Nov 2021
Figure 2:
Overall Study Design
AE = adverse event; AML = acute myeloid leukemia; EOT = End of Treatment; IP = investigational product; MDS 
= myelodysplastic syndromes; Q3W = every 3 weeks; SC = subcutaneous.
Screening
Eligibility Check
Luspatercept
(ACE-536)
1.0 mg/kg s.c.Q3W
titration up to max 1.75 mg/kg
Continuation of
Treatment
MDS Disease Status Assessment 
every 24 weeks
MDS Disease Status Assessment
Day 169 Visit: 169 days after first dose, regardless of dose delays
Study Discontinuation
Post-Treatment Follow-Up
42 Day Follow-up: AE Reporting until 42 days post last dose of IP
Collection of Transfusion data: for at least 8 weeks after last dose of IP or until EOT
(whichever is later)
Long Term Follow-up: Monitoring for other malignancies/pre-malignancies, progression to AML, 
subsequent MDS therapies and survival for 5 years from the date of the first dose of IP, or 3 years from 
the last dose (whichever occurs later), unless the subject withdraws consent from the study, dies or is 
lost to follow-up
End of Treatment (EOT)
Continue treatment unless discontinued early for evidence 
of progression, death, unacceptable toxicity, 
subject/physician decision, or withdrawal of consent.
2.0
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EDMS Doc. Number: 25770028 - 22621913
Luspatercept (ACE-536)
Protocol ACE-536-MDS-003
Bristol-Myers Squibb K.K.
Confidential and Proprietary
40
ACE-536-MDS-003 Amendment 2.0 Final: 22 Nov 2021
3.2.
Study Duration for Subjects
The duration of participation for subjects who complete the study will be approximately 6 years 
(and may be shorter or longer for individual subjects) consisting of the following phases: 

Screening Period: up to 35 days prior to W1D1

Treatment Period: at least up to the 24-week MDS Disease Assessment (ie, Day 169) 
unless the subject experiences unacceptable toxicities, withdrawsconsent, or meets 
any other treatment discontinuation criteria (eg, absence of clinical benefit, or disease 
progression per IWG criteria for altering natural history of MDS (Cheson, 2006)
(Appendix E)

Post-Treatment Follow-up Period:  5 years from the date of the first dose of IP, or 3 
years from the last dose (whichever occurs later), unless the subject withdraws 
consent from the study, dies or is lost to follow-up. Long-term Follow-up visits may 
be conducted as telephone contacts from the site.
3.3.
End of Trial
The End of Trial is defined as either the date of the last visit of the last subject to complete the 
post-treatment follow-up, or the date of receipt of the last data point from the last subject that is 
required for primary, secondary and/or exploratory analysis, as prespecified in the protocol, 
whichever is the later date.
The sponsor may end the trial when all key endpoints and objectives of the study have been 
analyzed and the availability of a roll-over protocol exists into which subjects remaining on 
study may be consented and continue to receive access to luspatercept and/or complete long-term 
follow-up. Such a protocol would be written for a compound that would not yet be 
commercially available.  
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EDMS Doc. Number: 25770028 - 22621913
Luspatercept (ACE-536)
Protocol ACE-536-MDS-003
Bristol-Myers Squibb K.K.
Confidential and Proprietary
41
ACE-536-MDS-003 Amendment 2.0 Final: 22 Nov 2021
4.
STUDY POPULATION
4.1.
Number of Subjects 
Approximately 20 subjects with anemia due to IPSS-R very low, low, or intermediate risk MDS 
who are not requiring RBC transfusion will be enrolled into the study.
4.2.
Inclusion Criteria
Subjects must satisfy the following criteria to be enrolled in the study:
1. Subject is ≥ 20 years of age the time of signing the informed consent form (ICF) 
2. Subject must understand and voluntarily sign an ICF prior to any study-related 
assessments/procedures being conducted. 
3. Subject is willing and able to adhere to the study visit schedule and other protocol 
requirements.
4. Subject has a documented diagnosis of MDS according to WHO 2016 classification 
(Section 6.1.1, Appendix B) that meets IPSS-R classification (Greenberg, 2012) of very 
low, low, or intermediate risk disease, and:

< 5% blasts in bone marrow
5. Subject has symptomatic anemia with mean Hgb concentration < 10.0 g/dL from 2 
measurements (one performed within 1 day prior to W1D1 and the other performed 7 to 
35 days prior to W1D1) that does not require RBC transfusion.  If more than one
measurement exists in the period of 7 to 35 days prior to W1D1, the most recent value
will be used.
6. Subject must be TI, as documented by the following criteria:

No RBC transfusion administered within 16 weeks prior to W1D1 (except 
transfusions due to blood loss or infection that occurred between 16 and 8 weeks prior 
to W1D1)
7. Subject has Eastern Cooperative Oncology Group (ECOG) score of 0, 1, or 2 
8. Females of childbearing potential (FCBP), defined as a sexually mature woman who: 
1) has achieved menarche at some point, 2) not undergone a hysterectomy or bilateral 
oophorectomy, or 3) has not been naturallypostmenopausal (amenorrhea following
cancer therapy or amenorrhea due to other medical reasons does not rule out childbearing
potential) for at least 24 consecutive months (ie, has had menses at any time in the
preceding 24 consecutive months), must:

Have two negative pregnancy tests as verified by the investigator prior to starting 
study therapy (unless the screening pregnancy test was done within 72 hours of 
W1D1).  Refer to Section 6.1.14 for additional details.  She must agree to ongoing 
pregnancy testing during the course of the study, and after end of study treatment.
This applies even if the subject practices true abstinence1 from heterosexual contact.
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EDMS Doc. Number: 25770028 - 22621913
Luspatercept (ACE-536)
Protocol ACE-536-MDS-003
Bristol-Myers Squibb K.K.
Confidential and Proprietary
42
ACE-536-MDS-003 Amendment 2.0 Final: 22 Nov 2021

Either commit to true abstinence1 from heterosexual contact (which must be reviewed 
on a monthly basis and source documented) or agree to use, and be able to comply 
with, highly effective contraception2 without interruption, 5 weeks prior to starting 
investigational product, during the study therapy (including dose interruptions), and 
for 12 weeks after discontinuation of study therapy. 

If breastfeeding, agree to stop breastfeeding prior to the participation in the study and 
not to resume breastfeeding after treatment discontinuation.
9. Male subjects must:

Practice true abstinence1 (which must be reviewed prior to each IP administration or 
on a monthly basis [eg, in the event of dose delays]) or agree to use a condom (latex 
or non-latex, but not made out of natural [animal] membrane) during sexual contact 
with a pregnant female or a female of childbearing potential while participating in the 
study, during dose interruptions and for at least 12 weeks following investigational 
product discontinuation, even if he has undergone a successful vasectomy. 
4.3.
Exclusion Criteria
The presence of any of the following will exclude a subject from enrollment:
1. Subject with the any of the following prior treatments for underlying disease:

Disease modifying agents (eg, immune-modulatory drug [IMiDs such as 
lenalidomide])

Except if the subject received ≤ 1 week of treatment with a disease modifying 
agent ≥ 8 weeks from W1D1, at the investigator’s discretion.  

Hypomethylating agents 

Subjects may be enrolled at the investigator’s discretion contingent that the 
subject received no more than 2 injections of HMA. The last dose must be ≥ 8 
weeks from the date of W1D1.  

Luspatercept (ACE-536) or sotatercept (ACE-011)

Allogeneic and/or autologous hematopoietic cell transplant
2. Subject with myelodysplastic/myeloproliferative neoplasms (MDS/MPN) according to 
WHO 2016 classification (ie, chronic myelomonocytic leukemia (CMML), atypical 
chronic myeloid leukemia (aCML), BCR-ABL12, juvenile myelomonocytic leukemia
(JMML), MDS/MPN unclassifiable.
                                               
1 True abstinence is acceptable when this is in line with the preferred and usual lifestyle of the subject. (Periodic 
abstinence [eg, calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable 
methods of contraception). 
2 Highly effective contraception is defined in this protocol as the following (information will also appear in the 
ICF): Hormonal contraception (ie, birth control pills); intrauterine device (IUD); tubal ligation (tying your tubes); 
or a partner with a successful vasectomy.
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EDMS Doc. Number: 25770028 - 22621913
Luspatercept (ACE-536)
Protocol ACE-536-MDS-003
Bristol-Myers Squibb K.K.
Confidential and Proprietary
43
ACE-536-MDS-003 Amendment 2.0 Final: 22 Nov 2021
3. Subject with secondary MDS, ie, MDS that is known to have arisen as the result of 
chemical injury or treatment with chemotherapy and/or radiation for other diseases.
4. Subject with known clinically significant anemia due to iron, vitamin B12, or folate 
deficiencies, or autoimmune or hereditary hemolytic anemia, or hypothyroidism, or any 
type of known clinically significant bleeding or sequestration.  Subject with drug induced 
anemia (eg, mycophenolate).  

Iron deficiency to be determined by serum ferritin < 100 µg/L and additional testing 
if clinically indicated (eg, calculated transferrin saturation [iron/total iron binding 
capacity ≤ 20%] or bone marrow aspirate stain for iron).
5. Subject with known history of diagnosis of AML
6. Subject receiving any of the following treatment within 8 weeks prior to W1D1:

Anticancer cytotoxic chemotherapeutic agent or treatment 

ESAs

Granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-
stimulating factor (GM-CSF), unless given for treatment of febrile neutropenia

Immunosuppressive therapy for MDS

Systemic corticosteroid, except for subjects on a stable or decreasing dose for 
≥1 week prior to W1D1 for medical conditions other than MDS

Other RBC hematopoietic growth factors (eg, Interleukin-3)

Androgens, unless to treat hypogonadism

Hydroxyurea, anagrelide

Oral retinoids 

Arsenic trioxide

Interferon and interleukins

Investigational drug or device, or approved therapy for investigational use (if 5 times 
the half-life of the previous investigational drug exceeds 8 weeks, then the time of 
exclusion should be extended up to 5 times the half-life of the investigational drug)
7. Subject with uncontrolled hypertension, defined as repeated elevations of systolic blood 
pressure (SBP) of ≥ 150 mmHg and/or diastolic blood pressure (DBP) ≥ 100 mmHg 
despite adequate treatment, or with a history of hypertensive crisis or hypertensive 
encephalopathy.   
8. Subject with any of the following laboratory abnormalities:

Absolute neutrophil count (ANC) < 500/μL (0.5 x 109/L)

Platelet count < 30,000/μL (30 x 109/L) (Exclude subjects that may be at risk of 
bleeding regardless of platelet counts.  This includes [but is not limited to] subjects
currently using aspirin or heparin, immediately after surgery, or easily causes 
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EDMS Doc. Number: 25770028 - 22621913
Luspatercept (ACE-536)
Protocol ACE-536-MDS-003
Bristol-Myers Squibb K.K.
Confidential and Proprietary
44
ACE-536-MDS-003 Amendment 2.0 Final: 22 Nov 2021
bleeding such as nasal bleeding or subcutaneous bleeding or previous episode of 
major bleeding where the cause was not effectively treated.)

Estimated glomerular filtration rate (eGFR) < 40 mL/min/1.73 m2 (via the 4-variable 
modification of diet in renal disease [MDRD] formula, Appendix G)

Serum aspartate aminotransferase/serum glutamic oxaloacetic transaminase 
(AST/SGOT) or alanine aminotransferase/serum glutamic pyruvic transaminase 
(ALT/SGPT) ≥ 3.0 x upper limit of normal (ULN)

Total bilirubin ≥ 2.0 x ULN. 

Higher levels are acceptable if these can be attributed to active red blood cell 
precursor destruction within the bone marrow (ie, ineffective erythropoiesis) or in 
the presence of known history of Gilbert Syndrome. 
9. Subject with prior history of malignancies, other than MDS, unless the subject has been 
free of the disease for ≥ 5 years.
However, subjects with the following 
history/concurrent conditions are allowed if considered as curatively treated:

Basal or squamous cell carcinoma of the skin

Carcinoma in situ of the cervix

Carcinoma in situ of the breast

Incidental histologic finding of prostate cancer (T1a or T1b using the tumor, nodes, 
metastasis [TNM] clinical staging system)
10. Subject with major surgery within 8 weeks prior to W1D1. Subjects must have 
completely recovered from any previous surgery prior to W1D1
11. Subject with history of cerebrovascular accident (including ischemic, embolic, and 
hemorrhagic cerebrovascular accident), transient ischemic attack, deep venous 
thrombosis (DVT; including proximal and distal), pulmonary or arterial embolism, 
arterial thrombosis or other venous thrombosis within 6 months prior to W1D1
Note: prior superficial thrombophlebitis is not an exclusion criterion.
12. Subject with the following cardiac conditions within 6 months prior to W1D1: 
myocardial infarction, uncontrolled angina, acute decompensated cardiac failure or New 
York Heart Association (NYHA) Class III-IV heart failure, or uncontrolled cardiac 
arrhythmia as determined by the investigator.  Subjects with a known ejection fraction ˂ 
35%, confirmed by a local echocardiogram (ECHO) or multi-gated acquisition (MUGA) 
scan performed within 6 months prior to W1D1.
13. Subject with uncontrolled systemic fungal, bacterial, or viral infection (defined as 
ongoing signs/symptoms related to the infection without improvement despite 
appropriate antibiotics, antiviral therapy, and/or other treatment).
14. Subject with known human immunodeficiency virus (HIV), known evidence of active 
infectious hepatitis B, and/or known evidence of active hepatitis C. Local laboratory 
testing confirming HIV, hepatitis B, and hepatitis C status should not have been 
performed beyond 4 weeks prior to the date of ICF signature.
2.0
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EDMS Doc. Number: 25770028 - 22621913
Luspatercept (ACE-536)
Protocol ACE-536-MDS-003
Bristol-Myers Squibb K.K.
Confidential and Proprietary
45
ACE-536-MDS-003 Amendment 2.0 Final: 22 Nov 2021
15. Subject with history of severe allergic or anaphylactic reactions or hypersensitivity to 
recombinant proteins or excipients in luspatercept (see current IB).
16. Pregnant or breastfeeding females.
17. Subject has any significant medical condition, laboratory abnormality, psychiatric illness, 
or is considered vulnerable by local regulations (eg, imprisoned or institutionalized) that 
would prevent the subject from participating in the study.
18. Subject has any condition including the presence of laboratory abnormalities, which 
places the subject at unacceptable risk if he/she were to participate in the study.
19. Subject has any condition or receives concomitant medication that confounds the ability 
to interpret data from the study.
20. Subject has history of active SARS-CoV-2 infection within 4 weeks prior to screening, 
unless the subject has adequately recovered from COVID-19 symptoms and related 
complications as per investigator’s discretion and following a discussion with the 
Medical Monitor.  Use of a live COVID-19 vaccine is prohibited within 4 weeks prior to 
W1D1.
2.0
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Approved
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EDMS Doc. Number: 25770028 - 22621913
Luspatercept (ACE-536)
Protocol ACE-536-MDS-003
Bristol-Myers Squibb K.K.
Confidential and Proprietary
46
ACE-536-MDS-003 Amendment 2.0 Final: 22 Nov 2021
5.
TABLE OF EVENTS
Table 3:
Table of Events
Screening
Treatment Period
Post-treatment Follow-up
Efficacy 
Assessment
Independent of any 
dose delays
Section
Day -35
to -1
W1D1
Visit
W2D1
Visit
W3D1
Visit
3-wkly
Visits
W4D1
W7D1
W10D1
etc.
Other
Visits
24-Wk 
MDS 
Assess-
ment
Visit
D169
Every 
24 wks
D337
D505
etc.
EOT
Visita
42-Day 
Follow-
up
Long 
Term 
Follow-
up
End of 
Study
Section
6.2.2/11.1
6.3.1
6.3.2
11.2
Time window
±2 days
±2 days
±2 days
±2 days
±14daysb
±14daysb
+2 days
±7 days
Note: 
Weekly visits as displayed above represent visits as they are scheduled if dosing occurs without any dose delays.  In the event of dose delays (eg, due to adverse events) the next 
dosing visit (every 3 weeks for luspatercept) and associated assessments should be delayed accordingly.  Assessments to monitor the condition of the subject should be recorded 
as unscheduled visits.  Please note that efficacy assessments (MDS Disease assessments) always occur at the designated days after W1D1 as indicated above.  Dose delays do 
not affect the timing of these assessments.
Informed Consent
6.1
X
−
−
−
−
−
−
−
−
−
−
−
Inclusion/Exclusion 
Evaluation
6.1
X
−
−
−
−
−
−
−
−
−
−
−
Physical 
Examination
6.1.5
X
−
−
−
−
−
X
X
X
−
−
−
Demographics 
6.1.3
X
−
−
−
−
−
−
−
−
−
−
−
Medical History
6.1.4
X
−
−
−
−
−
−
−
−
−
−
−
HIV and Hep B/C 
Status
6.1.4.1
X
−
−
−
−
−
−
−
−
−
−
−
Prior RBC and 
Platelet 
Transfusions
6.1.2
X
−
−
−
−
−
−
−
−
−
−
−
2.0
Approved
930198598
4.0
v
Approved
1.0
v


EDMS Doc. Number: 25770028 - 22621913
Luspatercept (ACE-536)
Protocol ACE-536-MDS-003
Bristol-Myers Squibb K.K.
Confidential and Proprietary
47
ACE-536-MDS-003 Amendment 2.0 Final: 22 Nov 2021
Table 3:
Table of Events (Continued)
Screening
Treatment Period
Post-treatment Follow-up
Efficacy 
Assessment
Independent of any 
dose delays
Section
Day -35
to -1
W1D1
Visit
W2D1
Visit
W3D1
Visit
3-wkly
Visits
W4D1
W7D1
W10D1
etc.
Other
Visits
24-Wk 
MDS 
Assess-
ment
Visit
D169
Every 
24 wks
D337
D505
etc.
EOT
Visita
42-Day 
Follow-
up
Long 
Term 
Follow-
up
End of 
Study
Section
6.2.2/11.1
6.3.1
6.3.2
11.2
Time window
±2 days
±2 days
±2 days
±2 days
±14daysb
±14daysb
+2 days
±7 days
INVESTIGATIONAL PRODUCT (IP)
IP Administration 
and Accountability 
Luspatercept
7
–
X
–
–
X
–
–
–
–
–
–
–
SAFETY ASSESSMENTS
ECOG 
Performance 
Status 
6.1.7
X
X
–
–
X
–
X
X
X
–
–
–
Urinalysis
6.1.13
X
X
–
–
Every 12 
weeks 
ie, 
W13D1, 
W25D1, 
etc.
–
–
–
–
–
–
–
ECG (12-lead)
6.1.8
X
–
–
–
–
–
–
–
–
–
–
–
Pregnancy Test 
and Counseling
6.1.14
X
X
–
–
X
–
–
–
X
–
–
–
Adverse events 
6.1.19/10
Continuous, after signing informed consent until 42 days after last IP administration
–
–
2.0
Approved
930198598
4.0
v
Approved
1.0
v


EDMS Doc. Number: 25770028 - 22621913
Luspatercept (ACE-536)
Protocol ACE-536-MDS-003
Bristol-Myers Squibb K.K.
Confidential and Proprietary
48
ACE-536-MDS-003 Amendment 2.0 Final: 22 Nov 2021
Table 3:
Table of Events (Continued)
Screening
Treatment Period
Post-treatment Follow-up
Efficacy 
Assessment
Independent of any 
dose delays
Section
Day -35
to -1
W1D1
Visit
W2D1
Visit
W3D1
Visit
3-wkly
Visits
W4D1
W7D1
W10D1
etc.
Other
Visits
24-Wk 
MDS 
Assess-
ment
Visit
D169
Every 
24 wks
D337
D505
etc.
EOT
Visita
42-Day 
Follow-
up
Long 
Term 
Follow-
up
End of 
Study
Section
6.2.2/11.1
6.3.1
6.3.2
11.2
Time window
±2 days
±2 days
±2 days
±2 days
±14daysb
±14daysb
+2 days
±7 days
SAFETY ASSESSMENTS (Continued)
Prior and 
Concomitant 
medications/ 
procedures 
6.1.18/8
Continuous, 8 weeks prior to W1D1 until 42 days after last IP administration or until the EOT Visit, whichever occurs 
later
–
–
Vital Signs 
(Height to be 
measured only at 
screening)
6.1.6
X
X
X
X
X
–
X
X
X
–
–
–
Serum 
Chemistryc
6.1.10
X
X
–
–
X
–
X
X
X
–
–
–
2.0
Approved
930198598
4.0
v
Approved
1.0
v


EDMS Doc. Number: 25770028 - 22621913
Luspatercept (ACE-536)
Protocol ACE-536-MDS-003
Bristol-Myers Squibb K.K.
Confidential and Proprietary
49
ACE-536-MDS-003 Amendment 2.0 Final: 22 Nov 2021
Table 3:
Table of Events (Continued)
Screening
Treatment Period
Post-treatment Follow-up
Efficacy 
Assessment
Independent of any 
dose delays
Section
Day -
35
to -1
W1D1
Visit
W2D1
Visit
W3D1
Visit
3-wkly
Visits
W4D1
W7D1
W10D1
etc.
Other
Visits
24-Wk 
MDS 
Assess-
ment
Visit
D169
Every 
24 wks
D337
D505
etc.
EOT
Visita
42-Day 
Follow-
up
Long 
Term 
Follow-
up
End of 
Study
Section
6.2.2/11.1
6.3.1
6.3.2
11.2
Time window
±2 days
±2 days
±2 days
±2 days
±14daysb
±14daysb
+2 days
±7 days
EFFICACY ASSESSMENTS
Hematologyc
6.1.9
X
X
X
X
X
–
X
X
X
–
–
–
Serum EPO
6.1.11
X
–
–
–
Every 
6 weeks:
ie,
W7D1
W13D1
etc.
–
X
X
X
–
–
–
Serum Ferritin 
and other iron-
related markers
6.1.12
X
X
–
–
X
–
X
X
X
–
–
–
Transfusion Data 
Collection and 
Assessment
6.4.1
Assess and record on ongoing basis (prior to each dose of IP) until 8 weeks after last dose of IP or the End of 
Treatment Visit, whichever occurs later.  Clinical site staff must confirm (and document in the subject’s source 
record) if any transfusions were received by the subject (including any at outside local institutions in between study 
visits) prior to each IP administration. In addition to local procedures in place at the site to capture this information, 
a patient transfusion diary will be provided to subjects and will be reviewed by the site when/if returned by the 
subject.
–
–
MDS Disease 
Assessment
6.4.2
–
–
–
–
–
–
X
X
X
–
–
–
BMA and PB for 
Cytomorphology 
and Cytogenetic 
testingd, e
6.1.1
X
–
–
–
–
–
X
X
X
–
–
–
2.0
Approved
930198598
4.0
v
Approved
1.0
v


EDMS Doc. Number: 25770028 - 22621913
Luspatercept (ACE-536)
Protocol ACE-536-MDS-003
Bristol-Myers Squibb K.K.
Confidential and Proprietary
50
ACE-536-MDS-003 Amendment 2.0 Final: 22 Nov 2021
Table 3:
Table of Events (Continued)
Screening
Treatment Period
Post-treatment Follow-up
Efficacy 
Assessment
Independent of any 
dose delays
Section
Day -35
to -1
W1D1
Visit
W2D1
Visit
W3D1
Visit
3-wkly
Visits
W4D1
W7D1
W10D1
etc.
Other
Visits
24-Wk 
MDS 
Assess-
ment
Visit
D169
Every 
24 wks
D337
D505
etc.
EOT
Visita
42-Day 
Follow-
up
Long 
Term 
Follow-
up
End of 
Study
Section
6.2.2/11.1
6.3.1
6.3.2
11.2
Time window
±2 days
±2 days
±2 days
±2 days
±14daysb
±14daysb
+2 days
±7 days
EXPLORATORY/BIOMARKER ASSESSMENTS
PB for Exploratory 
Biomarkers 
(eg, soluble 
biomarkers, MDS-
associated 
molecular mutations 
and other markers 
of drug MOA)
6.1.1
6.7
X
–
–
X
W10D1
W34D1
only
–
X
X
X
–
–
–
BMA for 
Exploratory 
Biomarkers 
(eg, soluble 
biomarkers, MDS-
associated 
molecular 
mutations, erythroid 
differentiation and 
other markers of 
drug MOA)f
6.1.1
6.7
X
–
–
–
–
–
X
X
X
–
–
–
SARS-COV-2 
Serology testing
6.7
X
–
–
–
–
–
–
–
X
–
–
–
2.0
Approved
930198598
4.0
v
Approved
1.0
v


EDMS Doc. Number: 25770028 - 22621913
Luspatercept (ACE-536)
Protocol ACE-536-MDS-003
Bristol-Myers Squibb K.K.
Confidential and Proprietary
51
ACE-536-MDS-003 Amendment 2.0 Final: 22 Nov 2021
Table 3:
Table of Events (Continued)
Screening
Treatment Period
Post-treatment Follow-up
Efficacy 
Assessment
Independent of any 
dose delays
Section
Day -35
to -1
W1D1
Visit
W2D1
Visit
W3D1
Visit
3-wkly
Visits
W4D1
W7D1
W10D1
etc.
Other
Visits
24-Wk 
MDS 
Assess-
ment
Visit
D169
Every 
24 wks
D337
D505
etc.
EOT
Visita
42-Day 
Follow-
up
Long 
Term 
Follow-
up
End of 
Study
Section
6.2.2/11.1
6.3.1
6.3.2
11.2
Time window
±2 days
±2 days
±2 days
±2 days
±14daysb
±14daysb
+2 days
±7 days
PK/ADA ASSESSMENTS (cont.)
PK Sample 
Collection g
Should be 
collected prior to 
IP dosing on a 
dosing day 
6.5
–
X
X
X
W4D1
W10D1 
W16D1
W22D1
for all 
subjects
W13D1
W19D1
for 
dense 
PK 
subjects 
only
W1D3
W2D3
W17D1
W18D1
for dense 
PK 
subjects 
only
X
And every 12 weeks (± 14 days) from the 24-
Week MDS Assessment Visit for up to 1 
year from the first dose.  Once a subject has 
been discontinued from treatment, PK 
samples may no longer be collected as long 
as ADA are not detectable.
–
ADA Sample 
Collection
Should be 
collected prior to 
IP dosing on a 
dosing day 
6.6
–
X
–
–
W4D1
W10D1
W16D1
W22D1
only
–
X
And every 12 weeks (± 14 days) from the 24-
Week MDS Assessment Visit for up to 1 
year from the first dose.  If the subject was 
discontinued from study treatment earlier 
than 1 year from the first dose, additional 
samples will be collected if the last ADA is 
positive. 
–
2.0
Approved
930198598
4.0
v
Approved
1.0
v


EDMS Doc. Number: 25770028 - 22621913
Luspatercept (ACE-536)
Protocol ACE-536-MDS-003
Bristol-Myers Squibb K.K.
Confidential and Proprietary
52
ACE-536-MDS-003 Amendment 2.0 Final: 22 Nov 2021
Table 3:
Table of Events (Continued)
Screening
Treatment Period
Post-treatment Follow-up
Efficacy 
Assessment
Independent of any 
dose delays
Section
Day -35
to -1
W1D1
Visit
W2D1
Visit
W3D1
Visit
3-wkly
Visits
W4D1
W7D1
W10D1
etc.
Other
Visits
24-Wk 
MDS 
Assess-
ment
Visit
D169
Every 
24 wks
D337
D505
etc.
EOT
Visita
42-Day 
Follow-
up
Long 
Term 
Follow-
up
End of 
Study
Section
6.2.2/11.1
6.3.1
6.3.2
11.2
Time window
±2 days
±2 days
±2 days
±2 days
±14daysb
±14daysb
+2 days
±7 days
2.0
Approved
930198598
4.0
v
Approved
1.0
v


EDMS Doc. Number: 25770028 - 22621913
Luspatercept (ACE-536)
Protocol ACE-536-MDS-003
Bristol-Myers Squibb K.K.
Confidential and Proprietary
53
ACE-536-MDS-003 Amendment 2.0 Final: 22 Nov 2021
Table 3:
Table of Events (Continued)
Screening
Treatment Period
Post-treatment Follow-up
Efficacy 
Assessment
Independent of any 
dose delays
Section
Day -35
to -1
W1D1
Visit
W2D1
Visit
W3D1
Visit
3-wkly
Visits
W4D1
W7D1
W10D1
etc.
Other
Visits
24-Wk 
MDS 
Assess-
ment
Visit
D169
Every 
24 wks
D337
D505
etc.
EOT
Visita
42-Day 
Follow-
up
Long 
Term 
Follow-
up
End of 
Study
Section
6.2.2/11.1
6.3.1
6.3.2
11.2
Time window
±2 days
±2 days
±2 days
±2 days
±14daysb
±14daysb
+2 days
±7 days
FOLLOW UP
Monitoring for 
progression to 
AML and other 
malignancies/pre-
malignancies
6.1.20
6.3.2
10.5
After signing ICF and until 5 years from the first dose of IP, or 3 years from the last dose (whichever occurs later), or until death, lost to 
follow-up, withdrawal of consent for further data collection
Posttreatment 
MDS therapies
6.3.2
–
–
–
–
–
–
–
–
–
X
X
X
Survival Follow-
up
6.3.2
–
–
–
–
–
–
–
–
–
X
X
X
ADA = antidrug antibodies; AML = acute myeloid leukemia; BMA = bone marrow aspirate; BMB = bone marrow biopsy; D = day; ECG = electrocardiogram; ECOG = Eastern 
Cooperative Oncology Group; 
; EOT = End of Treatment; EPO 
= erythropoietin;
 – Anemia; Hep = hepatitis; HIV = human immunodeficiency virus; ICF = informed consent form; IP = 
investigational product; MDS = myelodysplastic syndromes; MOA = mechanism of action; PB = peripheral blood; PK = pharmacokinetics; RBC = red blood cell; RS = ring 
sideroblast; SARS-COV-2 = severe acute respiratory syndrome coronavirus 2; W = week; wkly = weekly.
a End of Treatment (EOT) Visit procedures/assessments may not need to be repeated if previously performed within -7 days of EOT Visit.  If a subject is discontinued during a 
regular scheduled visit, all EOT procedures should be completed at that visit.  End of Treatment (EOT) Visit procedures/assessments may occur at 42-Day Follow-up assessment 
if subject is discontinued within ±7 days of 42-Day Follow-up assessment.
b As central laboratory results from bone marrow and peripheral blood samples (ie, cytomorphology, cytogenetic analysis) are required as part of the MDS Disease Assessment, a 
14-day window is allowed for the 24-Week MDS Disease Assessment Visit (ie, Day 169 ± 14 days) in order to account for sample collection and turnaround time of results.
Please see Section 6.4.2 for details. 
c If screening assessments are performed within 2 days of W1D1, assessments of serum chemistry and hematology do not need to be repeated on W1D1.
d In the event a local BM assessment for MDS diagnosis was made no more than 8 weeks before ICF signature, local BM samples/reports may be allowed for central “over read” 
after consultation with the sponsor and provided the central lab can confirm the diagnosis using the local samples/reports.
2.0
Approved
930198598
4.0
v
Approved
1.0
v


EDMS Doc. Number: 25770028 - 22621913
Luspatercept (ACE-536)
Protocol ACE-536-MDS-003
Bristol-Myers Squibb K.K.
Confidential and Proprietary
54
ACE-536-MDS-003 Amendment 2.0 Final: 22 Nov 2021
e Collection of a BMB is only required when adequate aspirate is not attainable.  To allow for cytomorphology assessment and cytogenetic analysis of the BMB please follow 
guidance for processing the sample provided in the study’s Central Laboratory Manual.
f Remaining BMA (after quantity sufficient is allocated towards cytomorphology and cytogenetics analysis) will be used for exploratory biomarker studies.  An additional bone 
marrow procedure should not be performed for these samples.  Refer to the central laboratory manual for additional information related to sample collection.
g If a PK sample is drawn on a dosing day, the PK sample should be drawn prior to luspatercept dosing.  All PK samples should be collected along the protocol defined “weekly” 
visits adapting to dose delays.
h Questionnaires should be completed by the subject prior to IP administration.
2.0
Approved
930198598
4.0
v
Approved
1.0
v


EDMS Doc. Number: 25770028 - 22621913
Luspatercept (ACE-536)
Protocol ACE-536-MDS-003
Bristol-Myers Squibb K.K.
Confidential and Proprietary
55
ACE-536-MDS-003 Amendment 2.0 Final: 22 Nov 2021
6.
PROCEDURES
Questions regarding the protocol should be directed to the Celgene Medical Monitor or designee.
All of the protocol required assessments are listed in Table 3, with an “X” indicating at which 
visits the assessments are to be performed.  All data obtained from these assessments must be 
recorded in the subject’s source documentation.
Refer to the electronic case report form (eCRF) completion guidelines for additional information 
related to data entry requirements of local laboratories.
Sample collection, processing, storage, and shipment procedures will be provided in the study’s
Central Laboratory Manual.
6.1.
Screening Period
Upon giving written informed consent, subjects enter the Screening Period to determine 
eligibility.  Screening evaluations will be performed for all subjects to determine study 
eligibility. These evaluations must be completed within 35 days of W1D1 unless noted 
otherwise below. All inclusion/exclusion criteria must be met in order for subjects to be enrolled 
in the study. Waivers to the protocol will not be granted during the conduct of this trial.  
Subjects who do not meet the eligibility criteria will be considered screening failures and will not 
be eligible for enrollment.  Subjects who fail screening may undergo rescreening.
Safety laboratory analyses and all laboratory assessments will be performed centrally unless 
noted otherwise. Screening laboratory values must demonstrate subject eligibility, but may be 
repeated within the screening window, if necessary.
The following assessments will be performed during screening as specified in the Table of 
Events (Table 3), after informed consent has been obtained.
The sponsor may review key eligibility criteria as well as relevant data (eg, central laboratory 
reports and cytomorphology/cytogenetic reports) and communicate as necessary with the 
investigator prior to enrollment of a subject.
6.1.1.
Bone Marrow and Peripheral Blood Samples
Diagnosis of MDS, WHO classification (Appendix B), and IPSS risk classification (Appendix C) 
will be prospectively determined by independent central pathology and cytogenetics review, and 
applicable central laboratory results.  The screening bone marrow aspirate sample together with
peripheral blood should be collected within the protocol screening window or 5 weeks prior to 
W1D1.  Samples should be collected, if possible, no later than 14 days prior to the planned 
W1D1 in order to allow sufficient time for central review and a repeat bone marrow assessment, 
if necessary.
The collection of a bone marrow biopsy is only required when an adequate aspirate is not 
attainable.  To allow for cytomorphology assessment and cytogenetic analysis of the bone 
marrow biopsy please follow the guidance for processing the sample provided in the study’s 
Central Laboratory Manual.
2.0
Approved
930198598
4.0
v
Approved
1.0
v


EDMS Doc. Number: 25770028 - 22621913
Luspatercept (ACE-536)
Protocol ACE-536-MDS-003
Bristol-Myers Squibb K.K.
Confidential and Proprietary
56
ACE-536-MDS-003 Amendment 2.0 Final: 22 Nov 2021
If a subject is rescreened (eg, due to retesting of another lab), repeat bone marrow samples do not 
need to be collected contingent that initial samples were adequate for cytomorphology/ 
cytogenetic assessment by the central laboratory and were done within 8 weeks before ICF 
signature.

Cytomorphology Assessment:
Bone marrow and peripheral blood samples will be prepared locally and sent to the
central laboratory for analysis to confirm MDS diagnosis and baseline WHO 
classification (Appendix B) prior to W1D1.  If the central reviewer and local 
pathologist disagree on the diagnosis of a subject, a third reviewer at the central 
laboratory may be consulted to provide an adjudication assessment. The central 
laboratory may also request the site to send in samples reviewed by the local 
pathologist for further assessment. 

Cytogenetics Analysis:
The central laboratory will conduct cytogenetic analysis throughout the study. The 
central laboratory will provide standardized analysis and reporting for all subjects. 
Bone marrow samples will be sent to the central laboratory for processing and 
cytogenetic analysis prior to W1D1.
Every attempt should be made to send bone marrow and peripheral blood samples to the central 
laboratory for processing and analysis prior to the first dose of investigational product. In the 
event that cytomorphology/cytogenetic analysis is technical failing at the central laboratory prior 
to W1D1, local cytomorphology/cytogenetic analysis may suffice for the purposes after 
consultation with the sponsor. This will require a central “over read” of the local 
cytomorphology/cytogenetics report, slides and/or photographs bythe central laboratory prior to 
W1D1.
Additionally, in the event a local BM assessment for MDS diagnosis was made no more than 8 
weeks before ICF signature, local BM samples/reports may be allowed for central “over read”
after consultation with the sponsor and provided the central lab can confirm the diagnosis using 
the local samples/reports.  The sponsor must be consulted prior to enrolling a subject using 
cytogenetic results from a local laboratory.
Results from central laboratory analysis should be used to determine baseline IPSS-R 
category (Greenberg, 2012) (Appendix C).  In the event historical local BM samples/reports are 
being used for “over read”, local laboratory results obtained from the same date the BM was 
taken should be used to determine the baseline IPSS-R category, if possible.
The central laboratory will also assess bone marrow and peripheral blood samples during the 
Treatment Period of the study. During the course of the study, whenever a bone marrow sample 
is collected, a peripheral blood smear is also to be prepared.
Bone marrow aspirate and/or blood collected at prespecified study time points will also be used 
for central laboratory exploratory/biomarker analysis (eg, MDS-associated molecular mutations 
[eg, SF3B1, etc.] and soluble biomarkers).
Sample collection, processing, storage, and shipment procedures will be provided in the study’s 
Central Laboratory Manual.
2.0
Approved
930198598
4.0
v
Approved
1.0
v


EDMS Doc. Number: 25770028 - 22621913
Luspatercept (ACE-536)
Protocol ACE-536-MDS-003
Bristol-Myers Squibb K.K.
Confidential and Proprietary
57
ACE-536-MDS-003 Amendment 2.0 Final: 22 Nov 2021
6.1.2.
Prior Transfusion History
Transfusion history must be available for at least 16 weeks prior to W1D1. Red blood cell
transfusion history will be confirmed to determine the eligibility of an individual study subject.  
Thus, this information must be collected during the Screening window (prior to W1D1) 
(including any transfusions at outside local institutions).
For details on the required information to be collected and reported in the eCRF for transfusions 
please refer to Section 6.4.1.
6.1.3.
Demographics
The subject’s date of birth, sex, race, and ethnicity will be recorded on the appropriate eCRF - as
allowed by local regulations. 
6.1.4.
Medical History
All relevant medical conditions (including recent surgical history) diagnosed/ occurring prior to 
screening should be included and recorded in the eCRF.  This may include relevant information 
related to original MDS diagnosis (eg, date of original diagnosis, WHO and/or FAB 
classification at original diagnosis, prior treatments administered) and/or other past malignancies.
6.1.4.1.
Assessment of HIV/Hepatitis B/Hepatitis C Status
Local testing confirming HIV, hepatitis B, and hepatitis C status should not have been performed 
beyond 4 weeks prior to the date of ICF signature.  If beyond this window or if information is not 
available in the medical history, additional local testing is required.
6.1.5.
Physical Examination
Information about the physical examination must be present in the subject’ssource 
documentation.  Significant findings must be reported as AE on the respective eCRF.
Refer to Table 3 for timing of physical examinations during the study.
6.1.6.
Vital Signs, Height, and Weight
Vital signs including height (measured at screening only), weight, seated blood pressure 
(documented as mean of 2 readings obtained approximately 10 minutes apart with the subject 
seated for approximately 10 minutes prior to initial reading), temperature, and heart rate (HR) are 
to be reported in the subject’s source record and appropriate eCRF.
Subjects must have blood pressure and weight assessed prior to IP administration on days where 
dosing occurs at the site.  For more details, please refer to Section 7.2.1.
Refer to Table 3 for timing of vital signs during the study.
6.1.7.
Eastern Cooperative Oncology Group Performance Status
Performance status will be assessed by the investigator during Screening and at other timepoints
indicated on Table 3 using ECOG criteria provided in Appendix F. 
2.0
Approved
930198598
4.0
v
Approved
1.0
v


EDMS Doc. Number: 25770028 - 22621913
Luspatercept (ACE-536)
Protocol ACE-536-MDS-003
Bristol-Myers Squibb K.K.
Confidential and Proprietary
58
ACE-536-MDS-003 Amendment 2.0 Final: 22 Nov 2021
6.1.8.
Electrocardiogram
A 12-lead ECG is performed locally at the study site.  The following ECG parameters will be 
recorded on the respective eCRF(s): eg, HR, PR interval, QRS duration, QT. The investigator 
will review the results and assess as normal, abnormal - not clinically significant, or abnormal -
clinicallysignificant, and report the abnormal finding(s) on the appropriate eCRF.  If the ECG is 
abnormal, the investigator should consult a cardiologist if deemed appropriate.
Refer to Table 3 for timing of ECGs during the study.
6.1.9.
Hematology
Hematology assessment (eg, RBC count, complete blood count [CBC], white blood cell [WBC] 
with differential [including myeloblasts], hemoglobin, hematocrit, nucleated red blood cells 
[nRBC], reticulocytes, platelet count, mean corpuscular volume [MCV], mean corpuscular 
hemoglobin [MCH], mean corpuscular hemoglobin concentration [MCHC], and red blood cell 
distribution width [RDW]) will be performed by the central laboratory.  Sample collection, 
processing, storage, and shipment procedures are provided in the study’s Central Laboratory 
Manual.
Local laboratories are allowed in cases when timely results are needed (eg, pre-dose Hgb 
assessments, study treatment dosing decisions, hematology assessments between clinic visits, 
adverse event).  In these circumstances, a split sample should still be collected and sent to the 
central laboratory for analysis.  Where discrepancies are present, results of the central laboratory 
will be used to determine response assessments (Section 6.4).
For details regarding assessment of Hgb levels prior to IP dosing to ensure dose modification 
rules are followed please refer to Section 7.2.1.
Refer to Table 3 for timing of hematologyassessments during the study.
6.1.10.
Serum Chemistry
Serum chemistry (ie, sodium, potassium, calcium, phosphorus, creatinine,creatinine clearance 
and/or eGFR, glucose, albumin, alkaline phosphatase, total bilirubin, direct/indirect bilirubin, 
AST/SGOT or ALT/SGPT, lactatedehydrogenase [LDH]) will be analyzed by the central 
laboratory.  Sample collection, processing, storage, and shipment procedures are provided in the 
study’s Central Laboratory Manual.
Local laboratories are allowed in cases when timely results are needed (eg, adverse events).  In 
these circumstances, a split sample should still be collected and sent to the central laboratory for 
analysis.
Refer to Table 3 for timing of serum chemistry assessments during the study.
6.1.11.
Serum EPO Level
Serum EPO samples will be analyzed by the central laboratory.  Sample collection, processing, 
storage, and shipment procedures are provided in the study’s Central Laboratory Manual.
Refer to Table 3 for timing of serum EPO level testing duringthe study.
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Confidential and Proprietary
59
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6.1.12.
Serum Ferritin and Other Iron-Related Markers
Analysis of serum ferritin and other iron-related markers (ie, total serum iron, percent iron 
saturation, total iron binding capacity, unsaturated iron binding capacity) will be
performed/provided by the central laboratory.  Sample collection, processing, storage, and 
shipment procedures are provided in the study’s Central Laboratory Manual.
Refer to Table 3 for timing of serum ferritin testing during the study.
6.1.13.
Urinalysis
Urinalysis will be conducted by the central laboratory and includes macroscopic, microscopic
and quantitative analysis of urine (ie, albumin, protein, creatinine, albumin/creatinine ratio).
Sample collection, processing, storage, and shipment procedures are provided in the study’s 
Central Laboratory Manual.
Refer to Table 3 for timing of urinalysis sample collection during the study.
6.1.14.
Pregnancy Testing and Counseling
For the definition of females of childbearing potential (FCBP) please refer to Section 4.2
(Inclusion criterion 8).  The investigator will appraise a female subject of their FCBP status 
according to this definition.  Justification for the designation must be recorded in the eCRF and 
the source document.
A medically supervised serum pregnancy test (ie, a serum beta human chorionic gonadotropin
[β-hCG] test with a minimum sensitivity of 25 mIU/mL [conducted at the central laboratory or 
locally]) is to be obtained and verified negative for a FCBP at screening.  Pregnancy testing is not 
required for non-FCBP subjects.
Additional urine (or serum) pregnancy testing, to confirm negative results and to assess subject 
eligibility, will be performed within 72 hours prior to the administration of the first dose of IP, 
unless the screening serum pregnancy test was already performed and verified negative during 
this time frame.
During the Treatment Period urine or serum pregnancy testing is allowed.
For males and FCBP, counseling about pregnancy precautions and the potential risks of fetal 
exposure must be conducted prior to each IP administration or monthly (eg, in the event of dose 
delays).
Refer to Table 3 for timing of pregnancy testing and counseling during the study.
6.1.15.
Sample Collection for Exploratory Biomarker Assessments
Refer to Section 6.7 for more information. 
6.1.16.
Sample Collection for Pharmacokinetic Analysis and ADA Evaluation
Refer to Section 6.5 and Section 6.6 for more information on PK and ADA sampling, 
respectively.
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Protocol ACE-536-MDS-003
Bristol-Myers Squibb K.K.
Confidential and Proprietary
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6.1.18.
Concomitant Medications and Procedures
Information on prior and concomitant medications and procedures are to be reported on the 
appropriate eCRF starting 8 weeks prior to W1D1.  Any prior anticancer treatments should be 
recorded on the appropriate eCRF(s).
Refer to Section 8 for more information on permitted and prohibited medication.
6.1.19.
Adverse Event Evaluation
Ongoing evaluation and reporting of adverse events begins when the subject signs the informed 
consent form and must be documented on the appropriate eCRF.
Refer to Section 10 for more information.
6.1.20.
Monitoring for Progression to AML and Other Malignancies/Pre-malignancies
Progression to AML as per WHO classification (Arber, 2016) will be monitored and will be 
included as part of the safety assessment throughout the course of the study.  Progression to 
AML should be monitored from time of signing of informed consent through 5 years from the 
date of the first dose of IP, or 3 years from the last dose (whichever occurs later), or until death, 
lost to follow-up or withdrawal of consent from the study.  For that purpose, subjects will be 
followed post-treatment every 12 weeks for 3 years from the date of last dose of IP and every 6 
months thereafter, if applicable.
The occurrence of a new malignancy or pre-malignant lesion will be monitored as an event of 
interest and should be included as part of the assessment of AEs throughout the course of the 
study (please refer to Section 10.5 for details).  Investigators are to report the development of any 
new malignancy or pre-malignant lesion as a serious adverse event (SAE), regardless of causal 
relationship to IP (luspatercept or epoetin alfa), occurring at any time for the duration of the 
study, from the time of signing the ICF for up to and including long-term follow-up (ie, 5 years 
from the date of the first dose of IP, or 3 years from the last dose [whichever occurs later]), or 
until death, lost to follow-up, or withdrawal of consent for further data collection.
Documentation supporting the diagnosis of progression to AML and other malignancies/pre-
malignancies (eg, confirmatory histology or cytology results, etc.) may be requested.  
Appropriate information related to the diagnosis of AML and other malignancies/pre-
malignancies should be captured on the eCRF and in the subject’s source documents.
Refer to Section 10.5 and Section 10.6 for more information regarding reporting requirements.
6.1.21.
Information to be Collected on Screening Failures
For all subjects determined as screen failures the following information is to be captured in the 
subject’s source documents and eCRF page(s): the date ICF was signed, demographics, the 
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EDMS Doc. Number: 25770028 - 22621913
Luspatercept (ACE-536)
Protocol ACE-536-MDS-003
Bristol-Myers Squibb K.K.
Confidential and Proprietary
61
ACE-536-MDS-003 Amendment 2.0 Final: 22 Nov 2021
reason the subject did not qualify for the study, and the investigator’s signature for the eCRF 
pages. The adverse events experienced by screen failure subjects will be collected from the date 
of signing consent to the day the subject is confirmed as a screen failure. Relevant information 
will also be recorded on the Screening Log.
6.2.
Treatment Period
The subject must receive the first dose of investigational product (IP) within 3 days of 
enrollment at the latest and can be on the same day as enrollment.  For all subsequent visits, an 
administrative time window of ± 2 days is permitted if not indicated otherwise.  If screening 
assessments are performed within 3 days of W1D1, safety laboratory and physical examinations 
need not be repeated at W1D1.
Subjects will receive IP every 3 weeks (21 days) (ie, at W1D1 Visit, W4D1 Visit; W7D1 Visit, 
etc.).  For details regarding IP administration including dose adjustments and dose modifications 
please refer to Section 7.
The following evaluations will be performed at the frequency specified in the Table of Events 
(Table 3). The evaluations should be performed prior to dosing on the visit day, unless otherwise 
specified. 

Physical examination (as detailed in Section 6.1.5)

Administration and accountability of IP (as detailed in Section 7)

ECOG performance status (as detailed in Section 6.1.7)

Urinalysis (as detailed in Section 6.1.13)

Pregnancy testing and counseling (as detailed in Section 6.1.14)

Adverse event assessment and reporting on an ongoing basis (as detailed in
Section 10)

Concomitant medications and procedures on an ongoing basis (refer to Section 8 for 
more information on permitted and prohibited medications)

Vital signs and weight (as detailed in Section 6.1.6)

Serum chemistry (as detailed in Section 6.1.10)

Hematology assessments (as detailed in Section 6.1.9)

Serum EPO level (as detailed in Section 6.1.11)

Serum ferritin level (as detailed in Section 6.1.12)

Transfusion data collection and assessment (as detailed in Section 6.4.1)

Bone marrow aspirate and peripheral blood collection for cytomorphology and 
cytogenetic testing (as detailed in Section 6.1.1)

MDS Disease assessment (as detailed in Section 6.4.2)

Bone marrow aspirate and peripheral blood collection for exploratory Biomarker 
sample collection (as detailed in Section 6.7)
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EDMS Doc. Number: 25770028 - 22621913
Luspatercept (ACE-536)
Protocol ACE-536-MDS-003
Bristol-Myers Squibb K.K.
Confidential and Proprietary
62
ACE-536-MDS-003 Amendment 2.0 Final: 22 Nov 2021

PK and ADA sample collection (as detailed in Section 6.5 and Section 6.6, 
respectively.

 

Monitoring for progression to AML and other malignancies/pre-malignancies (as 
detailed in Section 6.1.20)
6.2.1.
Unscheduled Visits
Should it become necessary to repeat an evaluation (eg, laboratory tests or vital signs), the results 
of the repeated evaluation should be entered as an additional unscheduled visit in the eCRF.
Refer to the eCRF completion guidelines for detailed instructions related to eCRF data entry.
6.2.2.
End of Treatment
An End of Treatment (EOT) evaluation will be performed for subjects who are withdrawn from 
treatment for any reason as soon as possible after the decision to permanently discontinue 
treatment has been made. 
Evaluations will be performed as specified in the Table of Events (Table 3).
If a subject is discontinued during a regular scheduled visit, all EOT procedures should be 
completed at that visit.
If a procedure had been performed within 7 days of the EOT Visit, it does not need to be 
repeated unless clinically indicated as per investigator’s discretion (with the exception of blood 
pressure assessment and sample collection for hematology, chemistry, and urinalysis). A bone 
marrow assessment procedure should only be performed at EOT if a prior bone marrow 
assessment has been performed > 90 days apart.
End of Treatment (EOT) Visit procedures/ assessments may occur at the 42-Day Follow-up 
assessment if a subject is discontinued within ± 7 days of the 42-Day Follow-up assessment.
The reason for treatment discontinuation will be recorded in the subject’s eCRF and source 
document for all enrolled subjects, regardless of whether they have been dosed or not. Reasons 
for treatment discontinuation are provided in Section 11.1.
6.3.
Post-Treatment Follow-up Period
6.3.1.
Safety Follow-up (42-Day Follow-up)
All subjects will be followed for 42 days after the last dose of IP for AE reporting, as well as 
SAEs made known to the investigator at any time thereafter that are suspected of being related to 
IP, as described in Section 10.1.
Refer to Table 3 for additional assessments to be performed at the 42-Day Follow-up.
Females of childbearing potential must avoid becoming pregnant for 12 weeks after the last dose 
of IP and male subjects must avoid fathering a child for 12 weeks after the last dose of IP. Refer 
to Section 10.4 for additional details.
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EDMS Doc. Number: 25770028 - 22621913
Luspatercept (ACE-536)
Protocol ACE-536-MDS-003
Bristol-Myers Squibb K.K.
Confidential and Proprietary
63
ACE-536-MDS-003 Amendment 2.0 Final: 22 Nov 2021
In the case of dose delays that exceed 6 weeks (+2 days) and end in treatment discontinuation, 
the 42-Day Follow-up Visit will be omitted and replaced by the EOT Visit.
6.3.2.
Long-term Follow-up
Transfusion data collection will continue until 8 weeks from the date of last dose of IP or from 
the date of the EOT Visit (whichever is later) (Section 6.4.1).  Subjects should also be followed 
via telephone contact by the site to verify if transfusions were given outside of the investigative 
site.
Antidrug antibodies sample(s) may be required in the Post-Treatment Follow-up Period for 
subjects who terminate the Treatment Period with less than 1 year of ADA monitoring if a 
subject is ADA positive at the time of treatment discontinuation (Section 6.6).
All subjects discontinued from protocol-prescribed therapy for any reason should be followed for
the below events/therapies for 5 years from the date of the first dose of IP, or 3 years from the 
last dose (whichever occurs later), or until death, lost to follow-up or withdrawal of consent from 
the study. 

Progression to AML and other malignancies/pre-malignancies (please refer to 
Section 6.1.20 and Section 10.5 for details)

Survival (date and cause of death)

and subsequent MDS therapies
Subjects may be followed via telephone contact by the site for collection of the above data every 
12 weeks for the first 3 years from the date of last dose of IP and every 6 months thereafter (if 
applicable) until 5 years from the date of the first dose of IP, or 3 years from the last dose
(whichever occurs later), or until death, lost to follow-up or withdrawal of consent from the 
study. Refer to Table 3.
Data regarding subsequent MDS therapies, determination of AML progression and other 
malignancies/pre-malignancies, and date and cause of death will be recorded in the eCRF.  The 
investigator must make every effort to obtain information regarding the subject’s survival status 
before determining the subject is lost to follow-up.  If the subject is discontinued from Long-term 
Follow-up, the reason for discontinuation should be recorded on the End of Study eCRF.
Long-term follow-up may be conducted by record review (including public records if allowed by 
local regulations) and/or telephone contact with the subject, family, or the subject’s treating 
physician.
6.4.
Efficacy Assessment
Treatment response will be assessed locally by the investigator in accordance with IWG 2006 
criteria for MDS (Cheson, 2006), through assessment of administered RBC transfusions, 
hematology parameters, peripheral blood smears, bone marrow aspirates and/or biopsies, and 
cytogenetics.  Central lab, cytomorphology and cytogenetics results will be used for response 
assessment. Please refer to Section 6.4.1 and Section 6.4.2 below for details.
Other efficacy assessments will include health-related quality of life measurements.
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EDMS Doc. Number: 25770028 - 22621913
Luspatercept (ACE-536)
Protocol ACE-536-MDS-003
Bristol-Myers Squibb K.K.
Confidential and Proprietary
64
ACE-536-MDS-003 Amendment 2.0 Final: 22 Nov 2021
The timing of efficacy assessments (MDS disease assessments and health-related quality-of-life) 
as well as associated sampling and assessments (ie, bone marrow and peripheral blood samples, 
RBC transfusion assessment) are specified in the Table of Events (Table 3). Please refer to 
Section 6.1.1 for details on bone marrow aspirate samples for assessing treatment response.
6.4.1.
Transfusion Assessment
During the Treatment Phase transfusions will be assessed and recorded in the eCRF on an 
ongoing basis (prior to each dose of IP) until 8 weeks after last dose of IP or the End of 
Treatment Visit, whichever occurs later.  Clinical site staff must confirm (and document in the 
subject’s source record) if any transfusions were received by the subject (including any at outside 
local institutions in between study visits) prior to each IP administration. In addition to local 
procedures in place at the site to capture this information, a patient transfusion diary will be 
provided to subjects and will be reviewed by the site when/if returned by the subject.
The following information will be collected for RBC transfusions (and platelet transfusions if 
applicable) and reported in the eCRF: 

Type, number of units, reason and date of transfusion

The Hgb value for which any RBC transfusion is given, and the platelet value for 
which any platelet transfusion is given, (these Hgb and platelet values may be local or 
central laboratory measurements)
Please find recommendations for adequate source documentation of transfusion history as well as 
transfusions given during the treatment phase below:

Signed original or copy of single transfusion record including number of units 
administered and Hgb/platelet value prior to transfusion.

Signed record of multiple transfusions done at the same clinic.  For each transfusion, 
the units and dates are specified along with Hgb/platelet value prior to each 
transfusion.

If electronic record: signed print-out of administration record(s), specifying unit(s) on 
specified date(s), plus signed additional documentation of Hgb/platelet values(s) prior 
to transfusion.

Signed referral letter(s) specifying date(s) and number(s) of units administered with 
Hgb/platelet value(s) prior to transfusion(s).
6.4.2.
MDS Disease Assessment
The MDS Disease Assessment consists of the investigator’s assessment of clinical benefit from 
IP and status of underlying disease.
The 24-Week MDS Disease Assessment Visit should be completed 24 calendar weeks (ie, Day 
169) after W1D1, regardless of dose delays.
As central laboratory results from bone marrow and peripheral blood samples (ie, 
cytomorphology, cytogenetic analysis) are required as part of the MDS Disease Assessment, a 
14-day window is allowed for the 24-Week MDS Disease Assessment Visit (ie, Day 169 ± 
14 days) in order to account for sample collection and turnaround time of results.
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EDMS Doc. Number: 25770028 - 22621913
Luspatercept (ACE-536)
Protocol ACE-536-MDS-003
Bristol-Myers Squibb K.K.
Confidential and Proprietary
65
ACE-536-MDS-003 Amendment 2.0 Final: 22 Nov 2021
The MDS Disease Assessment by the investigator, associated with this visit to assess clinical 
benefit, should be completed no sooner than 24 calendar weeks (ie, 169 days) after W1D1 as it 
requires 24 weeks of transfusion information in addition to central laboratory results from bone 
marrow and peripheral blood samples (ie, cytomorphology, cytogenetic analysis).  Up to date 
information related to all transfusions received during the Treatment Period (including those 
received at outside institutions) must be available prior to completion of the clinical benefit 
component of the MDS Disease Assessment.
For subjects to remain on treatment beyond this timepoint both of the following criteria must be 
confirmed in each subject:

Evidence of clinical benefit defined by either one of the following two criteria:

HI-E based on IWG (Cheson, 2006) (Appendix D) (Hgb increase of ≥ 1.5 g/dL 
for the 8 weeks within the 12 weeks immediately preceding Day 169 and every 24 
weeks thereafter [ie, Day 337, Day 505, etc.])

Maintain RBC transfusion independence

Absence of disease progression per IWG criteria for altering natural history of 
MDS (Cheson, 2006) (Appendix E) based on central morphological assessment of 
bone marrow, peripheral blood and cytogenetics results.
Based on the outcome of these assessments, subjects will either be discontinued from treatment 
with IP and enter the Post-Treatment Follow-up Period or continue open-label treatment as long 
as above criteria continue to be met or until the subject experiences unacceptable toxicities, 
withdraws consent, or meets any other discontinuation criteria.
In circumstances where the next dose of IP is due to be scheduled prior to 
cytomorphology/cytogenetics results being available, dosing should not be delayed for this 
reason contingent that the investigator has confirmed absence of signs of disease progression 
based on review of peripheral blood parameters.  However, the investigator must complete the 
assessment of cytomorphology/cytogenetics results prior to the following IP administration.
For subjects to continue open-label treatment with IP, MDS disease assessments will be repeated 
at the 48-Week MDS Disease Assessment Visit and every 24 weeks thereafter (ie, Day 337, Day 
505 etc.; a ± 14-day time window to allowed for sample collection) to confirm continued clinical 
benefit and absence of disease progression as per above criteria.
6.5.
Pharmacokinetics
Blood samples will be collected to analyze luspatercept concentrations in serum in all subjects.  
At each PK time point, approximately 3 mL of peripheral blood will be collected and serum 
prepared as described in the in the study’s Central Laboratory Manual. Blood samples for PK 
will be taken at the following visits during the study (also see Table 3):

For the dense PK in the initial 10 subjects, W1D1 (must be collected before the first 
dose), W1D3, W2D1, W2D3, W3D1, W4D1, W10D1, W13D1, W16D1, W17D1, 
W18D1, W19D1, W22D1, 24-Week MDS Disease Assessment, and every 12 weeks 
from the 24-Week MDS Disease Assessment Visit for up to 1 year from the first dose.
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EDMS Doc. Number: 25770028 - 22621913
Luspatercept (ACE-536)
Protocol ACE-536-MDS-003
Bristol-Myers Squibb K.K.
Confidential and Proprietary
66
ACE-536-MDS-003 Amendment 2.0 Final: 22 Nov 2021

For the sparse PK in other 10 subjects, W1D1 (must be collected before the first dose), 
W2D1, W3D1, W4D1, W10D1, W16D1, W22D1, 24-Week MDS Disease Assessment
Visit, and every 12 weeks (± 14 days) from the 24-Week MDS Disease Assessment Visit 
for up to 1 year from the first dose.
If a PK sample is drawn on a dosing day, the PK sample should be drawn prior to luspatercept 
dosing.  All PK samples should be collected along the protocol defined “weekly” visits adapting 
to dose delays (see footnote g under Table 3). Once a subject has been discontinued from 
treatment, PK samples may no longer be collected as long as ADA are not detectable.
6.6.
Antidrug Antibody (ADA)
Blood samples will be collected to assess ADAs against luspatercept in serum.  At each ADA 
sampling time point, approximately 3 mL of peripheral blood will be collected and serum 
prepared as described in the study’s Central Laboratory Manual.  However, during the first year 
of treatment, an additional blood draw is not needed for the ADA test, as the ADA test will be 
conducted utilizing the PK samples obtained at the same visit.  Blood samples for ADA will be 
taken at the following visits during the study (also see Table 3):

W1D1 (must be collected before the first dose), W4D1, W10D1, W16D1, W22D1, 
24-Week MDS Disease Assessment Visit and every 12 weeks (± 14 days) from the 
24-Week MDS Disease Assessment Visit.
If an ADA sample is drawn on a dosing day, the ADA sample should be drawn prior to 
luspatercept dosing.  If the last available ADA result at the end of treatment is positive, the 
subject may be asked to return to the clinical site for additional long-term follow up every 12 
weeks (± 14 days) for up to one year after the first dose of luspatercept or until ADA are not 
detectable, whichever comes first.
The maximum ADA monitoring period will not exceed 1 year from the first luspatercept dose 
unless justified by safety reasons.  ADA sampling per investigator’s or sponsor’s discretion is 
allowed and should be recorded as an unscheduled visit.
6.7.
Biomarkers, Pharmacodynamics, Pharmacogenomics
Bone marrow aspirate and/or peripheral blood samples for evaluation of exploratory biomarkers 
such as myeloid-associated molecular mutations and activin receptor IIB ligands and other 
exploratory biomarkers will be collected at specified timepoints as indicated in the Table of 
Events (Table 3).  These measurements may include, but are not limited to, assessments of 
SARS-CoV-2 serologic status.  If required on study dosing days, samples should be taken prior 
to IP administration.
Bone marrow aspirate for evaluation of biomarkers will be collected at study time points when a 
bone marrow procedure is required for MDS disease assessment (eg, cytogenetics and 
cytomorphology analysis).  Please note that the remaining bone marrow aspirate (after sufficient 
quantity is allocated towards cytomorphology and cytogenetics analysis) will be used for 
exploratory biomarker studies.  An additional bone marrow procedure should not be performed 
for these samples.  Refer to the study’s Central Laboratory Manual for additional information 
related to sample collection.
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EDMS Doc. Number: 25770028 - 22621913
Luspatercept (ACE-536)
Protocol ACE-536-MDS-003
Bristol-Myers Squibb K.K.
Confidential and Proprietary
67
ACE-536-MDS-003 Amendment 2.0 Final: 22 Nov 2021
Activin Receptor IIB ligands and other exploratory biomarkers
Peripheral blood will be collected by the site and sent to central laboratories for analysis of 
soluble biomarkers.  Sample collection, storage and shipping procedures will be provided in the 
Central Laboratory Manual.  Refer to the Table of Events (Table 3) for timing of sample 
collection.
MDS-associated molecular mutations
Bone marrow aspirate will be collected by the site and sent to a central laboratory for analysis of 
molecular mutations such as SF3B1 and others.  If there is sufficient volume, an aliquot of bone 
marrow mononuclear cells will be stored frozen for future analysis, such as RNA expression 
profiling to allow us to develop a gene signature that predicts response.  Sample collection, 
storage and shipping procedures will be provided in the study’s Central Laboratory Manual.  
Refer to the Table of Events (Table 3) for timing of sample collection.
Terminal erythropoiesis
Bone marrow aspirate will be collected by the site and sent to central laboratories for analysis of 
terminal erythroid differentiation by flow cytometry.  Sample collection, storage and shipping 
procedures will be provided in the Central Laboratory Manual.  Refer to the Table of Events
(Table 3) for timing of sample collection.
SARS-Cov-2 serology testing
Blood will be collected at screening and EOT for possible measurements of SARS CoV-2 
serology (anti-SARS-CoV-2 IgG or total antibody).
The samples will be destroyed five years after the end of trial or earlier if required by law. If 
subjects decide to withdraw the consent, all previously retained identifiable samples be destroyed 
to prevent future testing. Since the results of genetic tests are not beneficial to the treatment of 
an individual subject, they will not be disclosed to the subjects.
6.8.
Additional and Optional Research
Additional and optional research as described below may be performed using left-over samples 
originally collected for another test required in this study or using samples collected specifically 
for biomarker testing. The research may involve genetic tests using DNA or RNA and may lead 
to the development of new diagnostic tests.
6.8.1.
Additional Research
Additional research related to the study drug and/or disease may be performed. The results of 
this additional research could help to improve the diagnosis and/or the treatment of this disease 
in the future.
6.8.2.
Optional Research
Optional research not related to the study drug or the subject’s disease may be performed. The 
subject’s decision to participate in this optional research will not impact their ability to 
participate in the main study.
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EDMS Doc. Number: 25770028 - 22621913
Luspatercept (ACE-536)
Protocol ACE-536-MDS-003
Bristol-Myers Squibb K.K.
Confidential and Proprietary
68
ACE-536-MDS-003 Amendment 2.0 Final: 22 Nov 2021
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EDMS Doc. Number: 25770028 - 22621913
Luspatercept (ACE-536)
Protocol ACE-536-MDS-003
Bristol-Myers Squibb K.K.
Confidential and Proprietary
69
ACE-536-MDS-003 Amendment 2.0 Final: 22 Nov 2021
7.
DESCRIPTION OF STUDY TREATMENTS
7.1.
Description of Investigational Products
Luspatercept will be provided by the sponsor. Luspatercept for injection is formulated as a 
sterile, preservative-free, lyophilized cake/powder. Luspatercept for injection is available in 25 
mg and 75 mg vials and when reconstituted, with water for injection, each consists of 50 mg/mL 
luspatercept in a 
 mM citrate buffer-based solution (
 mM citrate, pH 
, % sucrose, 
% 
polysorbate 80).
The recommended storage condition for luspatercept for injection (25 mg/vial and 75 mg/vial; 
lyophilized powder formulation) is 2°C to 8°C.  It is recommended that the reconstituted 
luspatercept for injection, at room temperature, be administered immediately.  However, it may 
be held for up to 24 hours at 2°C to 8°C.  If not used immediately, the total in-use time of the 
reconstituted luspatercept for injection, from reconstitution to administration, must not exceed 
24 hours.  Please refer to the pharmacy manual for more details.
Samples of luspatercept drug product, held at the recommended storage condition, have been 
shown to be stable through the labeled shelf-life.
7.2.
Treatment Administration and Schedule
7.2.1.
Luspatercept Administration and Schedule
Luspatercept will be administered as a subcutaneous injection every 3 week (21 days; Q3W), at 
an initial dose level of 1.0 mg/kg. Doses may be titrated up starting at dosing visit W7D1 (ie, 
Dose 3) as described in Section 7.2.2.
Luspatercept will be administered to subjects by the study staff at the clinical site and 
administration will be documented in the subject’s source record.  Subjects must have Hgb, 
blood pressure and weight assessed (changes of body weight of ≤± 5% do not require a dose 
adjustment) prior to each IP administration.
Subcutaneous injections will be given in the upper arm, thigh, and/or abdomen.  Calculated 
doses requiring reconstituted volume greater than 1.2 mL should be divided into separate similar
volume injections across separate sites using the same anatomical location but on opposite sides 
of the body (example left thigh and right thigh).  The maximum volume per subcutaneous
injection should not exceed 1.2 mL.
The injection sites can be rotated according to investigator judgment, and the injections can be 
given in the following order as needed, for example: 1) right upper arm, 2) left upper arm, 
3) right upper thigh, 4) left upper thigh.
Clinical site staff must also confirm (and document in the subject’s source record) if any 
transfusions were received by the subject (including any at outside local institutions in between 
study visits) prior to each IP administration. In addition to local procedures in place at the site to 
capture this information, a patient transfusion diary will be provided to subjects and will be 
reviewed by the site when/if returned by the subject.
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7.2.2.
Luspatercept Dose Adjustment and Dose Modification
Appropriate dose adjustments should be made to maintain hemoglobin concentrations within the 
target range of 10 g/dL to 12 g/dL (6.2 mmol/L to 7.5 mmol/L) independent of transfusions.  
Starting as soon as with dosing visit W7D1 (ie, Dose 3) of luspatercept, and assessed by the 
investigator prior to every subsequent luspatercept dosing, subjects may have the dose level 
increased in a stepwise manner beyond the starting dose of 1.0 mg/kg to 1.33 mg/kg, and up to a 
maximum of 1.75 mg/kg (Table 4), if all of the following criteria are met:

Subject Hgb levels are below the target range of 10 g/dL to 12 g/dL (6.2 mmol/L to 
7.5 mmol/L).

Subject Hgb level increase compared to the Hgb sample taken prior to the previous 
luspatercept dose is ≤ 1 g/dL.

The two most recent prior luspatercept administrations assessed must be at the same 
dose level.

Subject must not have met protocol dose delay and/or reduction criteria in the two 
most recent luspatercept administrations (exception of dose delay required due to 
influence of RBC transfusions).  Refer to Table 5.
If all criteria above are met, the dose may be increased by 1 dose level.  The dose level should be 
titrated individually for each subject and must not exceed 1.75 mg/kg.  Starting dose with dose 
increases and reductions are presented below for reference (Table 4).
Dose delay and/or reduction or discontinuation may be required due to increased hemoglobin or 
adverse events. For details on dose modification guidance for luspatercept please refer to
Table 5.
Table 4:
Luspatercept Starting Dose Level with Dose Reductions and Dose Titration
3rd Dose 
Reduction
2nd Dose 
Reduction
1st Dose 
Reduction
Starting Dose 
Level
1st Dose 
Titration 
Increase
2nd Dose 
Titration 
Increase
0.45 mg/kg
0.6 mg/kg
0.8 mg/kg
1.0 mg/kg
1.33 mg/kg
1.75 mg/kg
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Table 5:
Luspatercept Dose Modification: Dose Delay, Dose Reduction, and 
Discontinuation Guidelines
Event at the Day of Dosing
(Assessed prior to each IP administration at 
the respective visiti)
Action
Any suspected related AE ≥ Grade 3a,b
Dose delayc until resolved to ≤ Grade 1 or 
baseline, and then reduce dose by one dose level 
according to Table 4
> 3 dose reductions due to suspected related AEa
Discontinue treatment 
ΔHgb > 2.0 g/dL (not influenced by RBC 
transfusionsd) compared to pre-dose Hgb of the 
previous luspatercept administration  
Reduce dose by one dose level according to 
Table 4
Predose Hgb ≥12.0 g/dL 
Dose delay until Hgb < 11.0 g/dLd
≥ 50% increase in white blood cell count (WBC) 
compared to pre-dose WBC of previous treatment 
cycle and above upper limit of normal in the 
absence of an associated condition (eg, infection 
or concomitant corticosteroid use)
Dose delay; recheck complete blood count (CBC), 
including WBC, at least weekly during dose delay.
Treatment may be resumed if:
WBC values below upper limit of normale within 
2 weeks
If WBC remains above upper limit of normale for 
≥ 2 consecutive weeks in absence of an associated 
condition (eg, infection or concomitant 
corticosteroid use); continue dose delay and collect 
bone marrow/peripheral blood samples to assess 
MDS disease status. 
Treatment may be resumed if:
Absence of disease progression per IWG response 
criteria for altering natural history of 
MDS (Cheson, 2006) (Appendix E)
AND
WBC values return below upper limit of normal
Discontinue treatment if: 
Disease progression per IWG response criteria for 
altering natural history of MDS (Cheson, 2006)
(Appendix E)
OR
WBC remain above upper limit of normale
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EDMS Doc. Number: 25770028 - 22621913
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Table 5:
Luspatercept Dose Modification: Dose Delay, Dose Reduction, and 
Discontinuation Guidelines (Continued)
AE = adverse event; Hgb = hemoglobin; IP = investigational product; IWG = International Working Group; MDS = 
myelodysplastic syndromes; RBC = red blood cell.
a Possibly, probably or definitely related to IP.
b Includes systolic blood pressure ≥160 mmHg and diastolic blood pressure ≥100 mmHg.
c If dose delay is > 12 consecutive weeks (> 15 weeks from last dose administered), treatment should be 
discontinued.
d Predose Hgb value not being influenced by RBC transfusion (ie, Hgb result > 14 days after last RBC transfusion 
or within 3 days from next RBC transfusion); Hgb should be rechecked weekly during dose delay.
e Upper limit of normal >10,000 total WBC/µL or as defined by institutional standards.
f Peripheral blood smear should be prepared for central pathology lab assessment.
g At the investigator’s discretion, bone marrow samples may also be collected and analyzed centrally to assess MDS 
disease status (eg, cytomorphology) prior to making decision regarding treatment discontinuation.  The central 
laboratory must also confirm <5% bone marrow blasts prior to resumption of treatment. 
h The investigator may contact the Medical Monitor prior to making decision regarding treatment discontinuation.
i Every attempt should be taken to assess the blasts count in peripheral blood prior to dosing, however, in 
circumstances where results are not readily available at the time of planned dosing, the investigator may proceed 
with dosing provided there are no signs of clinical progression. In this case, results must be evaluated as soon as 
they become available (but no later than 3 days post dosing).  If presence of ≥ 1% blasts in peripheral blood is 
observed, actions described in table above must be followed immediately.
7.2.3.
Overdose 
On a per dose basis, an overdose for luspatercept is defined as the following amount over the 
protocol-specified dose of luspatercept assigned to a given subject, regardless of any associated 
adverse events or sequelae.
Event at the Day of Dosing
(Assessed prior to each IP administration at 
the respective visiti)
Action
Presence of ≥ 1% blasts in peripheral blood 
(based on either local or central laboratory 
hematology sample)
Dose interruption; immediately prepare peripheral 
blood smearf,g for cytomorphology assessment by 
central pathology laboratory. 

If central pathology laboratory 
cytomorphology assessment confirms 
≥1% blasts in the peripheral blood; 
discontinue treatmenth

If central pathology laboratory 
cytomorphology assessment determines 
< 1% peripheral blasts are present, repeat 
hematology assessment.  
-
If presence of < 1% blasts in 
peripheral blood, treatment can be 
resumed at next scheduled 
luspatercept administration.
-
If presence of ≥ 1% blasts in 
peripheral blood; discontinue 
treatmenth
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Subcutaneous injection 10% over the protocol-specified dose
On a schedule or frequency basis, an overdose is defined as anything more frequent than the 
protocol required schedule or frequency.  Complete data about drug administration, including 
any overdose, regardless of whether the overdose was accidental or intentional, should be 
reported in the eCRF.  See Section 10.1 for the reporting of adverse events associated with 
overdose.
7.3.
Method of Treatment Assignment
The subject’s enrollment will occur at the end of the Screening Period, once all required 
screening procedures have been completed and all inclusion and exclusion criteria have been 
assessed to determine eligibility of the subject.  Subjects deemed eligible for the study will be 
enrolled using IRT.
Designated research personnel at each investigational site will be assigned password protected, 
coded identification numbers which gives them the authorization to call into IRT to enroll 
subjects.
For drug assignment at dosing visits and in the event of any dose reduction or dose titration site 
staff must contact IRT to record the new dose level and obtain the new IP assignment.
7.4.
Packaging and Labeling
The label(s) for IP will include sponsor name, address and telephone number, the protocol 
number, IP name, dosage form and strength (where applicable), amount of IP per container, lot 
number, expiry date (where applicable), medication identification/kit number, dosing 
instructions, storage conditions, and required caution statements and/or regulatory statements as 
applicable. Additional information may be included on the label as applicable per regulations.
7.5.
Investigational Product Accountability and Disposal 
7.5.1.
Accountability Procedures
Accountability for IP that is administrated during the course of the study is the responsibility of 
the investigator or designee.  
Investigational clinical supplies must be received by a designated person at the clinical site and 
kept in a secure and temperature-controlled location.  The investigational site must maintain 
accurate records demonstrating dates and amounts of IP received, to whom it was administered 
(subject-by-subject accounting), and accounts of any IP accidentally or deliberately destroyed or 
returned.  
Accurate recording of all IP administration will be made in the appropriate section of the 
subject’s eCRF and source documents.  Unless otherwise notified, all vials of IP, both used and 
unused, must be saved for drug accountability.  The used vials may be discarded, per the 
institution’s standard practice, after drug accountability has been completed by the monitor.
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Confidential and Proprietary
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7.5.2.
Drug Disposal and Destruction
Celgene (or designee) will review with the investigator and relevant site personnel the process 
for investigational product return, disposal, and/or destruction including responsibilities for the 
site versus Celgene (or designee).
7.6.
Investigational Product Compliance
Luspatercept will be administered as a subcutaneous injection at the clinical site by the study 
staff.  Monitoring for subject compliance with the treatment regimen is therefore unnecessary.
The investigator or designee is responsible for accounting for all IP that is administered during 
the course of the study.
Accurate recording of all IP administration will be made in the appropriate section of the 
subject’s eCRF and source documents.
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8.
CONCOMITANT MEDICATIONS AND PROCEDURES
Over the course of this study, additional medications may be required to manage aspects of the 
disease state of the subjects, including side effects from trial treatments or disease progression. 
Supportive care may be administered at the discretion of the investigator.
All prior/ concomitant medications, used 8 weeks prior to W1D1 until 42 days after the last dose 
of IP (or until the EOT Visit, whichever occurs later), must be reported on the eCRF.  All prior 
procedures within the 8 weeks prior to W1D1 as well as concomitant procedures (including 
transfusions) will be recorded on the appropriate eCRF(s).
Prior anticancer treatments should be recorded on the appropriate eCRF(s) regardless of 
treatment discontinuation/procedure date.
Prior ESAs and G-CSF/GM-CSF should be recorded on the appropriate eCRF(s) regardless of 
treatment discontinuation date.
If a subject requires treatment with any new medications that are specifically excluded in 
Section 8.2, the subject will be discontinued from treatment and should complete the EOT visit 
and enter the Post-Treatment Follow-up Period of the study. The investigator should consult the 
medical monitor regarding any questions about whether a new medication or dosage of existing 
medication would require the subject to discontinue from the study.
For information regarding other drugs that may interact with IP and affect its metabolism, 
pharmacokinetics, or excretion, please see the IB and/or package insert.
8.1.
Permitted Concomitant Medications and Procedures
8.1.1.
RBC Transfusions
Concurrent treatment for anemia with blood transfusions is allowed, at the discretion of the 
investigator, for low hemoglobin levels, symptoms associated with anemia (eg, shortness of 
breath, fatigue etc.) or comorbidity.
For any RBC transfusions received during the study, hemoglobin values just prior to transfusion 
will be collected.  Please refer to Section 6.4.1 for details on required data collection.
8.1.2.
Corticosteroids
Concurrent systemic corticosteroids used for medical conditions other than MDS is allowed 
provided the subject is on a stable or decreasing dose for ≥ 1 week prior to W1D1.  Use of 
topical steroids is permitted.  Occasional use of corticosteroids before transfusions to prevent 
allergic reactions is permitted.
8.1.3.
Attenuated Vaccines
Administration of attenuated vaccines (eg, influenza vaccine) is allowed if clinically indicated, 
per investigator discretion with the exception of a live COVID-19 vaccine.
8.1.4.
Phlebotomy
Phlebotomy may be performed for emergency/urgency if excessively high Hgb levels occur.
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8.2.
Prohibited Concomitant Medications and Procedures
Best supportive care for this study specifically excludes cancer surgery, immunotherapy, 
biologic therapy, radiotherapy, and systemic chemotherapy where the goal is to eradicate or slow 
the progression of the disease.
The following concomitant medications are specifically excluded during the course of the study:

ESAs and other RBC hematopoietic growth factors (eg, Interleukin-3)

Granulocyte colony stimulating factors (ie, G-CSF, GM-CSF), except in cases of 
neutropenic fever or as clinically indicated per product label.

Cytotoxic, chemotherapeutic, targeted or investigational agents/therapies

Azacitidine, decitabine or other hypomethylating agents

Lenalidomide, thalidomide and other immunomodulating drugs (IMiDs)

Hydroxyurea, anagrelide

Androgens, unless to treat hypogonadism

Oral retinoids

Arsenic trioxide

Interferon and interleukins
Administration of a live COVID-19 vaccine is prohibited within 4 weeks prior to randomization. 
Live COVID-19 vaccines should not be used during the study, including the treatment period 
and until 42 days following the last dose of IP.
8.3.
Required Concomitant Medications and Procedures
Not applicable.
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9.
STATISTICAL CONSIDERATIONS
9.1.
Overview
This is a Phase 2, multicenter, single-arm study.  The primary objective of the study is to 
evaluate HI-E per IWG (Cheson, 2006) for the treatment of anemia due to IPSS-R very low, 
low, or intermediate risk MDS in Japanese subjects who are not requiring RBC transfusion.
The design of the study, including the proposed targeted subject population, study endpoints, and 
statistical plan, is discussed below.
9.2.
Study Population Definitions
Study populations to be analyzed are defined as follows:
Intent-to-treat (ITT): The ITT population will consist of all enrolled subjects regardless of 
whether or not the subject received IP.
Efficacy Evaluable (EE):  The EE population will consist of 1) all subjects who received at 
least one dose of IP and 2) have at least two hemoglobin assessments ≥ 8 weeks apart post-
treatment.
Safety: The safety population will consist of all subjects who were enrolled and received at least 
one dose of IP. Statistical methods to handle missing data will be described in the statistical 
analysis plan (SAP). The SAP will describe any predefined rules for including/excluding any 
subjects with data from any analyses (eg, time windows, visit by visit analysis, endpoint analysis, 
protocol violation).
9.3.
Sample Size and Power Considerations
For the primary efficacy endpoint, HI-E, the sample size is based on one sample binomial exact 
test. The null hypothesis to be tested is that the proportion of subjects achieving HI-E (defined as 
≥ 1.5 g/dL increase in Hgb over any consecutive 56-day period in the absence of RBC 
transfusions) is ≤ 10%; the alternative hypothesis is that the proportion of subjects achieving HI-
E is > 10%. With these hypotheses, a sample size of 20 subjects are required with a power of 
95% at a one-sided 0.025 alpha level if the expected proportion is 45%.  This criterion requires 
that the lower limit of the 95% confidence intervals for the HI-E rate is greater than 10%.
The selection of a null hypothesis of 10% HI-E rate is based on the results of ARCADE Phase 3 
study of darbepoetin, where the proportion of subjects achieving HI-E was reported as 14.7%
(95% CI: 8%–25%) (11/75) (Platzbecker, 2017c).  Based on the lower limit of 95% CI, the null 
hypothesis is assumed as 10%.  The expected proportion of 45% HI-E rate is based on the 
preliminary efficacy observed with luspatercept in the ex-Japan Phase 2 study (Platzbecker, 
2017a).  In the study, HI-E rate was 63% (95% CI: 48%–76%) (32/51 evaluable).  Based on the 
lower limit of 95% CI, the expected proportion is assumed as 45%.
9.4.
Background and Demographic Characteristics
Subjects’ age, height, weight, and baseline characteristics will be summarized using descriptive 
statistics, while gender and other categorical variables will be provided using frequency 
tabulations by dose cohort.  Medical history data will be summarized using frequency tabulations 
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by the Medical Dictionary for Regulatory Activities (MedDRA) system organ class and preferred 
term.  MDS diagnoses will be summarized using frequency tabulations.
9.5.
Subject Disposition
Subject disposition (analysis population allocation, entered, discontinued, along with primary 
reason for discontinuation) will be summarized using frequency and percent for both treatment 
and follow-up phases.  A summary of subjects enrolled by site will be provided. Protocol 
deviations will be summarized using frequency tabulations.
9.6.
Efficacy Analysis
9.6.1.
Primary Efficacy Analysis
The primary efficacy endpoint of HI-E per IWG (Cheson, 2006) within 24 weeks is defined as 
proportion of subjects meeting HI-E criteria of ≥ 1.5 g/dL increase in Hgb sustained over any 
consecutive 56-day period in the absence of RBC transfusions from W1D1 through Week 24.  
Subjects discontinued from the Treatment Period without achieving HI-E will be counted as non-
responders.
As the primary efficacy analysis, one sample binomial one sided exact test will be performed 
based on ITT population, to provide p-value (significance level: 0.025).  The statistical 
hypothesis will be as follows,
H0: p ≤ 10%,
Ha: p > 10%
where p denotes the true response rate.  The number and percentage of subjects who achieve the 
response and 95% CI will be presented based on the ITT population.  
Dose modification guidance for luspatercept in Section 7.2.2 defines that, if predose Hgb is
≥12.0 g/dL at the day of dosing, the dose should be delayed until Hgb is < 11.0 g/dL. For 
subjects who meet this criterion and then have their dose delayed, if their Hgb levels temporarily 
decrease to < 1.5 g/dL but achieve ≥ 1.5 g/dL again after treatment resumption, this period (ie, 
the time from dose delay to achieving a Hgb increase of ≥ 1.5 g/dL again) will be included as the 
period of sustained Hgb increase of ≥ 1.5 g/dL.  As a sensitivity analysis, the analysis results not 
applicable to this rule will also be calculated.
Additional details will be outlined in the SAP.
9.6.2.
Secondary Efficacy Analyses
The secondary variables will be analyzed descriptively, unless otherwise specified, and will be 
based on the ITT population and EE population. Kaplan-Meier methods will be used to estimate 
curves for time to event secondary variables. Counts and percentages will be used to describe 
categorical variables.  Response rate of HI-E per IWG (Cheson, 2006) within 24 weeks, based 
on the EE population, will be analyzed as a secondary endpoint.
Modified hematologic improvement - erythroid (mHI-E) per IWG (Cheson, 2006) is 
defined as proportion of subjects meeting mHI-E criteria of ≥ 1.5 g/dL mean increase in Hgb 
compared to baseline that is sustained over any consecutive 56-day period in the absence of RBC 
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transfusions from W1D1 through Week 24 (and W1D1 through Week 48) of the Treatment 
Period. Subjects discontinued from the Treatment Period without achieving a mean Hgb increase 
≥1.5 g/dL will be counted as non-responders.
HI-E per IWG (Cheson, 2006) within 48 weeks is defined as proportion of subjects meeting 
HI-E criteria of ≥ 1.5 g/dL increase in Hgb sustained over any consecutive 56-day period in the 
absence of RBC transfusions from W1D1 through Week 48 of the Treatment Period.  Subjects 
discontinued from the Treatment Period without achieving HI-E will be counted as non-
responders.
For subjects who have a dose delay meeting the dose modification criterion described in 
Section 9.6.1, if their Hgb levels temporarily decrease to < 1.5 g/dL but achieve ≥ 1.5 g/dL again 
after treatment resumption, this period (ie, the time from dose delay to achieving a Hgb increase 
of ≥ 1.5 g/dL again) will be included as the period of sustained Hgb increase of ≥ 1.5 g/dL.
Time to HI-E will be summarized only for subjects who achieve HI-E.  It is defined as time 
from W1D1 to first onset of achieving ≥ 1.5 g/dL increase in Hgb over any consecutive 56-day 
period in the absence of RBC transfusions.  It will be summarized separately for subjects who 
achieve HI-E within the first 24 weeks and 48 weeks from W1D1, respectively.
Time to mHI-E will be summarized only for subjects who achieve mHI-E.  It is defined as the 
time from W1D1 to first onset of achieving ≥ 1.5 g/dL mean increase in Hgb over any 
consecutive 56-day period in the absence of RBC transfusions.  It will be summarized separately 
for subjects who achieve mHI-E within the first 24 weeks and 48 weeks from W1D1, 
respectively.
Duration of HI-E will be determined only for subjects who achieve HI-E during the Treatment 
Period.  Duration of HI-E is defined as the maximum duration of achieving ≥1.5 g/dL increase 
in Hgb for subjects who achieve Hgb increase ≥ 56 days in the absence of RBC transfusions.  
Subjects who maintain HI-E through the end of the Treatment Period or time of analysis will be 
censored at the date of treatment discontinuation/time of analysis or death, whichever occurs 
first.
Duration of mHI-E will be determined only for subjects who achieve mHI-E during the 
Treatment Period.  Duration of mHI-E is defined as the maximum duration of achieving ≥ 1.5 
g/dL mean increase in Hgb for subjects who achieve a mean Hgb increase of ≥ 56 days in the 
absence of RBC transfusions.  Subjects who maintain mHI-E through the end of the Treatment 
Period or time of analysis will be censored at the date of treatment discontinuation/time of 
analysis or death, whichever occurs first.
Proportion of subjects who maintain RBC-TI is defined as proportion of subjects not being 
given any RBC transfusion during the Treatment Period and will be calculated at Week 24, 
Week 48, and Week 72.
Time to progression to AML is defined as the time between W1D1 and first diagnosis of AML 
as per WHO classification of ≥ 20% blasts in peripheral blood or bone marrow.  Subjects with 
diagnosis of AML will be considered to have had an event.  Subjects who have not progressed to 
AML at the time of analysis will be censored at the last assessment date which does not indicate 
progression to AML.
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Overall survival (OS) is defined as the time between W1D1 and death/censored date.  Subjects 
who die, regardless of the cause of death, will be considered to have had an event.  Subjects who 
are alive at the time of analysis will be censored at the last assessment date at which the subject 
was known to be alive. All subjects who were lost to follow-up will also be censored at the time 
of last contact.
Full analysis details will be included in the SAP.
9.7.
Safety Analysis
All safety analyses will be performed on the safety population. Full details will be included in 
the SAP.  Planned data presentations and analyses include the following:
Adverse events will be coded using MedDRA.  Adverse event listings will include the verbatim 
term and the MedDRA preferred term.  Treatment-emergent adverse events will be summarized 
by system organ class and preferred term.  Treatment-emergent adverse events leading to death 
or to discontinuation from treatment, treatment-emergent adverse events (TEAEs) classified as 
National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) 
(version 4.03) all grades or grade 3/4 TEAEs, related to investigational product, and serious 
TEAEs will be summarized separately.
Clinical laboratory results will be summarized descriptively.  Clinically significant hematologic 
and non-hematologic laboratory abnormalities will be listed and summarized according to the 
NCI CTCAE (version 4.03).  Additionally, frequency of ADAs will also be reported.
Physical examination data and vital sign measurements, including body weight, will be listed for 
each subject at each visit.  Descriptive statistics for vital signs, both observed values and changes 
from baseline, will be summarized.
9.8.
Interim Analysis
There is no planned interim analysis for this study.
9.9.
Other Topics
9.9.2.
Pharmacokinetic Analysis
PK parameters including, but not limited to area under the concentration time curve (AUC), 
maximum plasma concentration of drug (Cmax), time to maximum plasma concentration of drug 
(Tmax) will be estimated for each subject. Descriptive statistics will be provided for all 
concentration data and PK parameters.
Full details will be included in the SAP.
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9.9.3.
Exploratory Analysis
Descriptive statistics will also be provided for exploratory parameters (eg, GDF11, SF3B1, 
C-reactive protein, SARS-CoV-2 antibody, and other molecular markers). Statistical tests will 
be applied for these parameters if applicable.  Full details will be included in the SAP.
9.9.4.
Subgroup Analysis
Appropriate subgroup analyses by baseline endogenous EPO level of < 500 U/L versus ≥ 500 
U/L and other baseline characteristics for clinical activity may be conducted as exploratory 
analyses.  Full details will be included in the SAP.
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10.
ADVERSE EVENTS
10.1.
Monitoring, Recording and Reporting of Adverse Events
An AE is any noxious, unintended, or untoward medical occurrence that may appear or worsen 
in a subject during the course of a study. It may be a new intercurrent illness, a worsening 
concomitant illness, an injury, or any concomitant impairment of the subject’s health, including 
laboratory test values (as specified by the criteria in Section 10.3), regardless of etiology. Any 
worsening (ie, any clinically significant adverse change in the frequency or intensity of a pre-
existing condition) should be considered an AE.  A diagnosis or syndrome should be recorded on 
the AE page of the eCRF rather than the individual signs or symptoms of the diagnosis or 
syndrome. 
Abuse, withdrawal, sensitivity or toxicity to an investigational product should be reported as an 
AE. Overdose, accidental or intentional, whether or not it is associated with an AE should be 
reported on the overdose eCRF (See Section 7.2.3 for the definition of overdose). Any sequela 
of an accidental or intentional overdose of an investigational product which meets the definition 
of an adverse event, should be reported as an AE on the eCRF.  If the sequela of an overdose 
meets serious criteria, then it must be marked as serious on the eCRF. The overdose itself should 
not be reported as an AE.
In the event of overdose, the subject should be monitored as appropriate and should receive 
supportive measures as necessary.  There is no known specific antidote for luspatercept
overdose. Actual treatment should depend on the severity of the clinical situation and the 
judgment and experience of the treating physician. Phlebotomy may be performed if excessively 
high Hgb levels occur.
All subjects will be monitored for AEs during the study.  Assessments may include monitoring 
of any or all of the following parameters:  the subject’s clinical symptoms, laboratory, 
pathological, radiological or surgical findings, physical examination findings, or findings from 
other tests and/or procedures.
All AEs will be recorded by the investigator from the time the subject signs informed consent 
until 42 days after the last dose of IP as well as those SAEs made known to the investigator at 
any time thereafter that are suspected of being related to IP. All adverse events (serious/non-
serious) will be recorded on the eCRF and in the subject’s source documents.  Refer to Section 
10.5 for instructions on how to report SAEs to Drug Safety.
10.2.
Evaluation of Adverse Events
A qualified investigator will evaluate all adverse events as to: 
10.2.1.
Seriousness 
An SAE is any AE occurring at any dose that:

Results in death;

Is life-threatening (ie, in the opinion of the investigator, the subject is at immediate 
risk of death from the AE);
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
Requires inpatient hospitalization or prolongation of existing hospitalization 
(hospitalization is defined as an inpatient admission, regardless of length of stay);

Results in persistent or significant disability/incapacity (a substantial disruption of the 
subject’s ability to conduct normal life functions);

Is a congenital anomaly/birth defect;

Constitutes an important medical event.
Important medical events are defined as those occurrences that may not be immediately life-
threatening or result in death, hospitalization, or disability, but may jeopardize the subject or 
require medical or surgical intervention to prevent one of the other outcomes listed above.  
Medical and scientific judgment should be exercised in deciding whether such an AE should be 
considered serious.
Events not considered to be SAEs are hospitalizations for:

a standard procedure for protocol therapy administration.  However, hospitalization or 
prolonged hospitalization for a complication of therapy administration will be 
reported as an SAE. 

routine treatment or monitoring of the studied indication not associated with any 
deterioration in condition.

the administration of blood or platelet transfusion as routine treatment of studied 
indication.  However, hospitalization or prolonged hospitalization for a complication 
of such transfusion remains a reportable SAE.

a procedure for protocol/disease-related investigations (eg, surgery, scans, endoscopy, 
sampling for laboratory tests, bone marrow sampling).  However, hospitalization or 
prolonged hospitalization for a complication of such procedures remains a reportable 
SAE.

hospitalization or prolongation of hospitalization for technical, practical, or social 
reasons, in absence of an AE.

a procedure that is planned (ie, planned prior to start of treatment on study); must be 
documented in the source document and the eCRF.  Hospitalization or prolonged 
hospitalization for a complication remains a reportable SAE.

an elective treatment of or an elective procedure for a pre-existing condition, 
unrelated to the studied indication, that has not worsened from baseline. 

emergency outpatient treatment or observation that does not result in admission, 
unless fulfilling other seriousness criteria above.
For each AE, the investigator will provide information on severity, start and stop dates, 
relationship to the IP, action taken regarding the IP, and outcome.
10.2.2.
Severity/Intensity
For each AE, the investigator must assess the severity/ intensity of the event. 
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The severity/intensity of AEs will be graded based upon the subject’s symptoms according to the 
current active minor version of the Common Terminology Criteria for Adverse Events (CTCAE, 
Version 4.03).
AEs that are not defined in the CTCAE should be evaluated for severity/intensity according to 
the following scale:

Grade 1 = Mild – transient or mild discomfort; no limitation in activity; no medical 
intervention/therapy required

Grade 2 = Moderate – mild to moderate limitation in activity, some assistance may be 
needed; no or minimal medical intervention/therapy required

Grade 3 = Severe – marked limitation in activity, some assistance usually required; 
medical intervention/therapy required, hospitalization is possible

Grade 4 = Life-threatening – extreme limitation in activity, significant assistance 
required; significant medical intervention/therapy required, hospitalization or hospice 
care probable

Grade 5 = Death - the event results in death
The term “severe” is often used to describe the intensity of a specific event (as in mild, moderate 
or severe myocardial infarction); the event itself, however, may be of relatively minor medical 
significance (such as severe headache).  This criterion is not the same as “serious” which is 
based on subject/event outcome or action criteria associated with events that pose a threat to a 
subject’s life or functioning.  
Seriousness, not severity, serves as a guide for defining regulatory obligations.
10.2.3.
Causality
The investigator must determine the relationship between the administration of the IP and the 
occurrence of an AE as Not Suspected or Suspected as defined below:
Not suspected:
a causal relationship of the adverse event to IP administration is 
unlikely or remote, or other medications, therapeutic 
interventions, or underlying conditions provide a sufficient 
explanation for the observed event.
Suspected:
there is a reasonable possibility that the administration of IP 
caused the adverse event.  ‘Reasonable possibility’ means there 
is evidence to suggest a causal relationship between the IP and 
the adverse event.
Causality should be assessed and provided for each AE based on currently available information.  
Causality is to be reassessed and provided as additional information becomes available.
If an event is assessed as suspected of being related to a comparator, ancillary or additional IP 
that has not been manufactured or provided by Celgene, please provide the name of the 
manufacturer when reporting the event.
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10.2.4.
Duration
For each AE, the investigator will provide a record of the start and stop dates of the event.
10.2.5.
Action Taken
The investigator will report the action taken with IP as a result of each AE, as applicable (eg, 
discontinuation, interruption, or dose reduction of IP, as appropriate) and report if concomitant 
and/or additional treatments were given for the event. 
10.2.6.
Outcome
The investigator will report the outcome of the event for each AE.
All SAEs that have not resolved upon discontinuation of the subject’s participation in the study 
must be followed until recovered (returned to baseline, unless the subject experiences 
progression of MDS or any other malignancy), recovered with sequelae, or death (due to the 
SAE).
10.3.
Abnormal Laboratory Values
An abnormal laboratory value is considered to be an AE if the abnormality:

results in discontinuation from the study;

requires treatment, modification/ interruption of IP dose, or any other therapeutic 
intervention; or

is judged to be of significant clinical importance, eg, one that indicates a new disease 
process and/or organ toxicity, or is an exacerbation or worsening of an existing 
condition.
Regardless of severity grade, only laboratory abnormalities that fulfill a seriousness criterion 
need to be documented as a serious adverse event.
If a laboratory abnormality is one component of a diagnosis or syndrome, then only the diagnosis 
or syndrome should be recorded as the AE.  If the abnormality was not a part of a diagnosis or 
syndrome, then the laboratory abnormality should be recorded as the AE. If possible, the 
laboratory abnormality should be recorded as a medical term and not simply as an abnormal 
laboratory result (eg, record thrombocytopenia rather than decreased platelets).
10.4.
Pregnancy
All pregnancies or suspected pregnancies occurring in either a female subject of childbearing 
potential or female partner of a male subject are immediately reportable events.  For adequate 
measures of contraception please refer to Section 4.2.
10.4.1.
Females of Childbearing Potential
Pregnancies and suspected pregnancies (including elevated β-hCG or positive pregnancy test in a 
female subject of childbearing potential regardless of disease state) occurring while the subject is 
on IP, or within 12 weeks of the subject’s last dose of IP are considered immediately reportable 
events.  Investigational product is to be discontinued immediately and if applicable the subject 
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instructed to return any unused portion of the IP to the investigator. The pregnancy, suspected 
pregnancy, or positive pregnancy test must be reported to Celgene Drug Safety immediately by 
email, phone or facsimile, or other appropriate method, using the Pregnancy Initial Report Form, 
or approved equivalent form.
The female subject may be referred to an obstetrician-gynecologist or another appropriate 
healthcare professional for further evaluation.
The investigator will follow the female subject until completion of the pregnancy, and must 
notify Celgene Drug Safety immediately about the outcome of the pregnancy (normal or 
abnormal outcome) using the Pregnancy Follow-up Report Form, or approved equivalent form.
If the outcome of the pregnancy was abnormal (eg, spontaneous abortion), the investigator
should report the abnormal outcome as an AE.  If the abnormal outcome meets any of the serious 
criteria, it must be reported as an SAE to Celgene Drug Safety within 24 hours of the 
investigator’s knowledge of the event.
All neonatal deaths that occur within 28 days of birth should be reported, without regard to 
causality, as an SAE.  In addition, any infant death after 28 days that the investigator suspects is 
related to the in-utero exposure to the IP should also be reported as an SAE to Celgene Drug 
Safety within 24 hours of the investigator’s knowledge of the event.
10.4.2.
Male Subjects
If a female partner of a male subject taking IP becomes pregnant, the male subject taking IP 
should notify the investigator, and the pregnant female partner should be advised to call their 
healthcare provider immediately.  
10.5.
Other Malignancies/Pre-malignancies
Events of new malignancy, pre-malignant lesions (excluding benign tumors or benign neoplasia) 
are to be reported to Celgene Drug Safety within 24 hours of the investigator’s knowledge of the 
event; the exception being SAEs occurring prior to treatment (after signing the ICF).  All SAE 
criteria (eg, hospitalization) should be marked if applicable, and all events must be marked as an 
“Important Medical Event” even if no other serious criteria apply; these events must also be 
documented in the appropriate page(s) of the CRF and subject’s source documents.  
Documentation related to the diagnosis of malignancy must be provided at the time of reporting 
as a serious adverse event (eg, any confirmatory histology or cytology results, X-rays, computed 
tomography [CT] scans, etc.).
Malignancies or cancerous tumors are lesions capable of invading into adjacent tissues, and may 
be capable of spreading to distant tissues. A benign tumor has none of those properties.
Malignancy or cancer is characterized by anaplasia, invasiveness, and metastasis.  For the 
Myelodysplastic Syndrome (MDS) studies, these also include progression to high/very high risk 
of MDS (per IPSS-R; Greenberg, 2012); myeloproliferation (eg, clinically significant increases 
in blasts), progression to AML, etc.
Premalignant or precancerous lesions refer to a state of disordered morphology of cells that is 
associated with an increased risk of cancer. If left untreated, these conditions may lead to cancer. 
Such conditions are usually either dysplasia or benign neoplasia (and the dividing line between 
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those is sometimes blurry). Sometimes the term "precancer" is used to describe carcinoma in 
situ, which is a noninvasive cancer that has not progressed to an aggressive, invasive stage. Not 
all carcinoma in situ will progress to invasive disease.
Premalignant lesions are morphologically atypical tissue which appears abnormal under 
microscopic examination, and in which cancer is more likely to occur than in its apparently 
normal counterpart.
10.6.
Reporting of Serious Adverse Events
Any AE that meets any serious criterion requires reporting as an SAE within 24 hours of the 
investigator’s knowledge of the event.  This instruction pertains to initial SAE reports as well as 
any follow-up reports.
This requirement applies to all SAEs (regardless of relationship to IP) that occur during the study 
(from the time the subject signs informed consent until 42 days after the last dose of IP) or any 
SAEs made known to the investigator at any time thereafter that are suspected of being related to 
IP.  Serious adverse events occurring prior to treatment (after signing the ICF) are to be recorded 
within the eCRF, but do not require reporting to Celgene Drug Safety.
Where required by local legislation, the investigator is responsible for informing the Institutional 
Review Board/Ethics Committee (IRB/EC) of the SAE and providing them with all relevant 
initial and follow-up information about the event. The investigator must keep copies of all SAE 
information on file including correspondence with Celgene and the IRB/EC.
The SAE is recorded within the eCRF, and the data are transmitted electronically to Celgene 
Drug Safety. In the event electronic transmission is not available, a paper SAE Report Form will 
be completed and sent directly to Celgene Drug Safety, ensuring the event is recorded on the 
eCRF as well.
10.7.
Expedited Reporting of Adverse Events
For the purpose of regulatory reporting, Celgene Drug Safety will determine the expectedness of 
events suspected of being related to luspatercept based on the IB.
Celgene or its authorized representative shall notify the investigators and the heads of the 
institutes of the following information:

Any AE suspected of being related to the use of IP in this study or in other studies 
that is both serious and unexpected (ie, suspected unexpected serious adverse reaction 
[SUSAR]);

Any finding from tests in laboratory animals that suggests a significant risk for 
human subjects including reports of mutagenicity, teratogenicity, or carcinogenicity.

Other important safety information and periodic reports according to the local 
regulations.
Where required by legislation, the investigator shall notify his/her IRB/EC promptly of these 
new serious and unexpected AE(s) or significant risks to subjects.
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The investigator must keep copies of all pertinent safety information on file including 
correspondence with the IRB/EC (See Section 14.3 for record retention information).
10.8.
COVID-19 Reporting
The occurrence of a COVID-19 event will be monitored as part of the assessment of AEs 
throughout the course of the study.  Investigators are to report the occurrence of COVID-19 
events, regardless of casual relationship to IP, occurring at any time for the duration of treatment 
up to 42 days after the last dose.
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11.
DISCONTINUATIONS
11.1.
Treatment Discontinuation
The following events are considered sufficient reasons for discontinuing a subject from the 
investigational product:

Lack of Efficacy 

Adverse Event

Withdrawal by subject

Death

Lost to follow-up

Pregnancy

Protocol violation

Study terminated by the sponsor

Other (to be specified on the eCRF)
o
Including treatment discontinuation guidance related to dose modification 
Section 7.2.2.

Disease Progression as per IWG criteria for altering natural history of MDS (Cheson, 
2006) (Appendix E)
o
For subjects with 5 to 10% blasts, a second bone marrow sample should be 
collected within 4 weeks for clinical assessment (eg, cytomorphology, 
cytogenetics) to confirm progression before discontinuing subjects from 
treatment.
The reason for discontinuation of treatment should be recorded in the eCRF and in the source 
documents.
The decision to discontinue a subject from treatment remains the responsibility of the treating 
physician, which will not be delayed or refused by the sponsor.  However, prior to discontinuing 
a subject, the investigator may contact the Medical Monitor and forward appropriate supporting 
documents for review and discussion.
An EOT evaluation will be performed for all subjects who are withdrawn from treatment with IP 
for any reason as soon as possible after the decision to permanently discontinue treatment has 
been made (Section 6.2.2).  Subjects who received at least one dose of IP will enter the Post-
Treatment Follow-up Period (Section 6.3).
11.2.
Study Discontinuation
The following events are considered sufficient reasons for discontinuing a subject from the 
study:

Screen failure
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
Adverse event

Withdrawal by subject

Death

Lost to follow-up

Protocol violation

Study terminated by sponsor

Other (to be specified on the eCRF)
The reason for study discontinuation should be recorded in the End of Study eCRF and in the 
source documents. 
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12.
EMERGENCY PROCEDURES
12.1.
Emergency Contact
In emergency situations, the investigator should contact the responsible Clinical Research 
Physician/Medical Monitor or designee by telephone at the number(s) listed on the Emergency 
Contact Information page of the protocol (after title page).
In the unlikely event that the Clinical Research Physician/Medical Monitor or designee cannot be 
reached, please contact the global Emergency Call Center by telephone at the number listed on 
the Emergency Contact Information page of the protocol (after title page). This global 
Emergency Call Center is available 24 hours a day and 7 days a week. The representatives are 
responsible for obtaining your call-back information and contacting the on-call Celgene/contract 
research organization Medical Monitor, who will then contact you promptly.
Note: The back-up 24-hour global emergency contact call center should only be used if you are 
not able to reach the Clinical Research Physician(s) or Medical Monitor or designee for 
emergency calls. 
12.2.
Emergency Identification of Investigational Products
This is a single arm study.
13.
REGULATORY CONSIDERATIONS
13.1.
Good Clinical Practice
The procedures set out in this study protocol pertaining to the conduct, evaluation, and 
documentation of this study are designed to ensure that Celgene, its authorized representative, 
and investigator abide by Good Clinical Practice (GCP), as described in International Council for
Harmonisation (ICH) Guideline E6 and in accordance with the general ethical principles outlined 
in the Declaration of Helsinki. The study will receive approval from an IRB/EC prior to 
commencement. The investigator will conduct all aspects of this study in accordance with 
applicable national, prefectural, and local laws of the pertinent regulatory authorities.
13.2.
Investigator Responsibilities
Investigator responsibilities are set out in the ICH Guideline for Good Clinical Practice and in 
the local regulations.  Celgene staff or an authorized representative will evaluate and approve all 
investigators who in turn will select their staff.
The investigator should ensure that all persons assisting with the study are adequately informed 
about the protocol, amendments, study treatments, as well as study-related duties and functions, 
including obligations of confidentiality of Celgene information. The investigator should maintain 
a list of Sub-investigators and other appropriately qualified persons to whom he or she has 
delegated significant study-related duties.
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The investigator is responsible for keeping a record of all subjects who sign an informed consent 
form (ICF) and are screened for entry into the study.  Subjects who fail screening must have the 
reason(s) recorded in the subject’s source documents.
The investigator, or a designated member of the investigator’s staff, must be available during 
monitoring visits to review data, resolve queries and allow direct access to subject records (eg, 
medical records, office charts, hospital charts, and study-related charts) for source data 
verification.  The investigator must ensure timely and accurate completion of eCRFs and queries.
The information contained in the protocol and amendments (with the exception of the 
information provided by Celgene on public registry websites) is considered Celgene confidential 
information.  Only information that is previously disclosed by Celgene on a public registry 
website may be freely disclosed by the investigator or its institution, or as outlined in the Clinical 
Trial Agreement.  Celgene protocol, amendment and IB information is not to be made publicly 
available (for example on the investigator’s or their institution’s website) without express written 
approval from Celgene.  Information proposed for posting on the investigator’s or their 
institution’s website must be submitted to Celgene for review and approval, providing at least 5
business days for review.
At the time results of this study are made available to the public, Celgene will provide 
investigators with a summary of the results that is written for the lay person. The investigator is 
responsible for sharing these results with the subject and/or their caregiver as agreed by the 
subject.
13.3.
Subject Information and Informed Consent
The investigator must obtain informed consent of a subject and/or a subject’s legal representative 
prior to any study related procedures.
Documentation that informed consent occurred prior to the study subject’s entry into the study 
and of the informed consent process should be recorded in the study subject’s source documents 
including the date.  The original ICF signed and dated by the study subject and by the person 
consenting the study subject prior to the study subject’s entry into the study, must be maintained 
in the investigator’s study files and a copy given to the study subject.  In addition, if a protocol is 
amended and it impacts on the content of the informed consent, the ICF must be revised.  Study 
subjects participating in the study when the amended protocol is implemented must be re-
consented with the revised version of the ICF.  The revised ICF signed and dated by the study 
subject and by the person consenting the study subject must be maintained in the investigator’s 
study files and a copy given to the study subject.
13.4.
Confidentiality
Celgene affirms the subject's right to protection against invasion of privacy and to be in 
compliance with ICH and other local regulations (whichever is most stringent). Celgene requires 
the investigator to permit Celgene's representatives and, when necessary, representatives from 
regulatory authorities, to review and/or copy any medical records relevant to the study in 
accordance with local laws.
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Should direct access to medical records require a waiver or authorization separate from the 
subject’s signed ICF, it is the responsibility of the investigator to obtain such permission in 
writing from the appropriate individual.
13.5.
Protocol Amendments
Any amendment to this protocol must be approved by the Celgene Clinical Research 
Physician/Medical Monitor.  Amendments will be submitted to the IRB/EC for written approval.  
Written approval must be obtained before implementation of the amended version occurs.  The 
written signed approval from the IRB/EC should specifically reference the investigator name, 
protocol number, study title and amendment number(s) that is applicable. Amendments that are 
administrative in nature do not require IRB/IEC approval but will be submitted to the IRB/IEC 
for information purposes.
13.6.
Institutional Review Board/Independent Ethics Committee Review 
and Approval
Before the start of the study, the study protocol, ICF, and any other appropriate documents will 
be submitted to the IRB/EC with a cover letter or a form listing the documents submitted, their 
dates of issue, and the site (or region or area of jurisdiction, as applicable) for which approval is 
sought. If applicable, the documents will also be submitted to the authorities in accordance with 
local legal requirements.
IP can only be supplied to an investigator by Celgene or its authorized representative after 
documentation on all ethical and legal requirements for starting the study has been received by 
Celgene or its authorized representative. This documentation must also include a list of the 
members of the IRB/EC and their occupation and qualifications. If the IRB/EC will not disclose 
the names, occupations and qualifications of the committee members, it should be asked to issue 
a statement confirming that the composition of the committee is in accordance with GCP. For 
example, the IRB General Assurance Number may be accepted as a substitute for this list. 
Formal approval by the IRB/EC should mention the protocol title, number, amendment number 
(if applicable), study site (or region or area of jurisdiction, as applicable), and any other 
documents reviewed. It must mention the date on which the decision was made and must be 
officially signed by a committee member. Before the first subject is enrolled in the study, all 
ethical and legal requirements must be met.
The IRB/EC and, if applicable, the authorities, must be informed of all subsequent protocol 
amendments in accordance with local legal requirements. Amendments must be evaluated to 
determine whether formal approval must be sought and whether the ICF should also be revised.
The investigator must keep a record of all communication with the IRB/EC and, if applicable, 
between a coordinating investigator and the IRB/EC. This statement also applies to any 
communication between the investigator (or coordinating investigator, if applicable) and 
regulatory authorities.
Any advertisements used to recruit subjects for the study must be reviewed by Celgene and the 
IRB/EC prior to use.  
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Protocol ACE-536-MDS-003
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13.7.
Ongoing Information for Institutional Review Board/ Ethics 
Committee
If required by legislation or the IRB/EC, the investigator must submit to the IRB/EC:

Information on serious or unexpected adverse events as soon as possible; 

Periodic reports on the progress of the study;

Deviations from the protocol or anything that may involve added risk to subjects.
13.8.
Termination of the Study
Celgene reserves the right to terminate this study prematurely at any time for reasonable medical 
or administrative reasons. Any premature discontinuation will be appropriately documented 
according to local requirements (eg, IRB/EC, regulatory authorities, etc).
The sponsor may end the trial when all key endpoints and objectives of the study have been 
analyzed and the availability of a roll-over protocol exists into which subjects remaining on 
study may be consented and continue to receive access to luspatercept and/or complete long-term 
follow-up.  Such a protocol would be written for a compound that would not yet be 
commercially available.  
In addition, the investigator or Celgene has the right to discontinue a single site at any time 
during the study for medical or administrative reasons such as:

Unsatisfactory enrollment;

GCP noncompliance;

Inaccurate or incomplete data collection;

Falsification of records;

Failure to adhere to the study protocol.
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Protocol ACE-536-MDS-003
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Confidential and Proprietary
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ACE-536-MDS-003 Amendment 2.0 Final: 22 Nov 2021
14.
DATA HANDLING AND RECORDKEEPING 
14.1.
Data/Documents
The investigator must ensure that the records and documents pertaining to the conduct of the 
study and the distribution of the investigational product are complete, accurate, filed and 
retained.  Examples of source documents include: hospital records; clinic and office charts; 
laboratory notes; memoranda; subject’s diaries or evaluation checklists; dispensing records; 
recorded data from automated instruments; copies or transcriptions certified after verification as 
being accurate copies; microfiche; x-ray film and reports; and records kept at the pharmacy, and 
the laboratories, as well as copies of eCRFs or CD-ROM.
14.2.
Data Management
Data will be collected via eCRF and entered into the clinical database per Celgene standard 
operating procedures (SOPs). This data will be electronically verified through use of 
programmed edit checks specified by the clinical team.  Discrepancies in the data will be brought 
to the attention of the clinical team, and investigational site personnel, if necessary.  Resolutions 
to these issues will be reflected in the database.  An audit trail within the system will track all 
changes made to the data.
14.3.
Record Retention
Essential documents must be retained by the investigator according to the period of time outlined 
in the clinical trial agreement. The investigator must retain these documents for the time period 
described above or according to local laws or requirements, whichever is longer. Essential 
documents include, but are not limited to, the following:

Signed ICFs for all subjects;

Subject identification code list, screening log (if applicable), and enrollment log;

Record of all communications between the investigator and the IRB/EC;

Composition of the IRB/EC;

Record of all communications between the investigator, Celgene, and their authorized 
representative(s);

List of Sub-investigators and other appropriately qualified persons to whom the 
investigator has delegated significant study-related duties, together with their roles in 
the study, curriculum vitae, and their signatures;

Copies of CRFs (if paper) and of documentation of corrections for all subjects;

IP accountability records;

Record of any body fluids or tissue samples retained;

All other source documents (subject records, hospital records, laboratory records, 
etc.); 
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
All other documents as listed in Section 8 of the ICH consolidated guideline on GCP 
(Essential Documents for the Conduct of a Clinical Trial).
The investigator must notify Celgene if he/she wishes to assign the essential documents to 
someone else, remove them to another location or is unable to retain them for a specified period.  
The investigator must obtain approval in writing from Celgene prior to destruction of any 
records. If the investigator is unable to meet this obligation, the investigator must ask Celgene 
for permission to make alternative arrangements. Details of these arrangements should be 
documented.
All study documents should be made available if required by relevant health authorities. 
investigator or institution should take measures to prevent accidental or premature destruction of 
these documents.
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Bristol-Myers Squibb K.K.
Confidential and Proprietary
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ACE-536-MDS-003 Amendment 2.0 Final: 22 Nov 2021
15.
QUALITY CONTROL AND QUALITY ASSURANCE
All aspects of the study will be carefully monitored by Celgene or its authorized representative 
for compliance with applicable government regulations with respect to current GCP and SOPs.
15.1.
Study Monitoring and Source Data Verification
Celgene ensures that appropriate monitoring procedures are performed before, during and after 
the study.  All aspects of the study are reviewed with the investigator and the staff at a study 
initiation visit and/or at an investigators’ Meeting.  Prior to enrolling subjects into the study, a 
Celgene representative will review the protocol, eCRFs, procedures for obtaining informed 
consent, record keeping, and reporting of AEs/SAEs with the investigator.  Monitoring details 
describing strategy, including definition of study critical data items and processes (eg, risk-based 
initiatives in operations and quality such as risk management and mitigation strategies and 
analytical risk-based monitoring), methods, responsibilities, and requirements, including 
handling of noncompliance issues and monitoring techniques (central, remote, or on-site 
monitoring) are provided in the monitoring plan.
Accuracy will be checked by performing source data verification that is a direct comparison of 
the entries made onto the eCRFs against the appropriate source documentation.  Any resulting 
discrepancies will be reviewed with the investigator and/or his/her staff.  Any necessary 
corrections will be made directly to the eCRFs or via queries by the investigator and/or his/her 
staff. Monitoring procedures require that informed consents, adherence to inclusion/exclusion 
criteria and documentation of SAEs and their proper recording be verified.  Additional 
monitoring activities may be outlined in a study-specific monitoring plan.
15.2.
Audits and Inspections
In addition to the routine monitoring procedures, a Good Clinical Practice Quality Assurance 
unit exists within Celgene.  Representatives of this unit will conduct audits of clinical research 
activities in accordance with Celgene SOPs to evaluate compliance with Good Clinical Practice 
guidelines and regulations.
The investigator is required to permit direct access to the facilities where the study took place, 
source documents, eCRFs and applicable supporting records of study subject participation for 
audits and inspections by IRB/ECs, regulatory authorities (eg, Food and Drug Administration 
[FDA], European Medicines Agency [EMA], Health Canada) and company authorized 
representatives.  The investigator should make every effort to be available for the audits and/or 
inspections.  If the investigator is contacted by any regulatory authority regarding an inspection, 
he/she should contact Celgene immediately.
15.3.
Investigational Medicinal Product Quality Issues
Issues that call into question IP safety, purity, potency, quality and identity (eg, evidence of 
suspected tampering of product) must be reported as soon as possible to the study Clinical Trial 
Monitor and/or Clinical Trial Manager or designee. Report an issue or concern with all sponsor 
supplied IP suspected to have occurred before the product was transferred to the responsibility of 
the investigational site (eg, during manufacturing, packaging and labeling, storage, and/or 
distribution).
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Bristol-Myers Squibb K.K.
Confidential and Proprietary
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This includes suspected quality issues of components co-packaged with the drug, labelling, and 
IP device/drug combination products, and medical devices. 
In the event of a suspected product quality issue, the immediate action to be taken by site is to 
quarantine the affected product. Do not dispose of the product unless retention presents a risk to 
personnel (eg, cytotoxic, risk of injury from broken glass or sharps).
When reporting, provide as much product information as possible. Suspected IP quality issues 
will be investigated and a response will be provided back to the investigational site. 
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EDMS Doc. Number: 25770028 - 22621913
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Protocol ACE-536-MDS-003
Bristol-Myers Squibb K.K.
Confidential and Proprietary
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ACE-536-MDS-003 Amendment 2.0 Final: 22 Nov 2021
16.
PUBLICATIONS
As described in Section 13.2, all protocol- and amendment-related information, with the 
exception of the information provided by Celgene on public registry websites, is considered 
Celgene confidential information and is not to be used in any publications.  Celgene protocol-
related information proposed for use in a publication must be submitted to Celgene for review 
and approval, and should not be utilized in a publication without express written approval from 
Celgene, or as described in the Clinical Trial Agreement.
Celgene will ensure Celgene-sponsored studies are considered for publication in the scientific 
literature in a peer-reviewed journal, irrespective of the results.  At a minimum, this applies to 
results from all Phase 3 clinical studies, and any other study results of significant medical 
importance.  This also includes results relating to investigational medicines whose development 
programs have been discontinued.
Study results may also be presented at one or more medical congresses, and may be used for 
scientific exchange and teaching purposes.  Additionally, this study and its results may be 
submitted for inclusion in all appropriate health authority study registries, as well as publication 
on health authority study registry websites, as required by local health authority regulations.
Eligibility for external authorship, as well as selection of first authorship, will be based on 
several considerations, including, but not limited to, contribution to protocol development, study 
recruitment, data quality, participation in data analysis, participation in study steering committee 
(when applicable) and contribution to abstract, presentation and/or publication development.
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17.
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Medalist trial: Results of a phase 3, randomized, double-blind, placebo-controlled study of 
luspatercept to treat anemia in patients with very low-, low-, or intermediate-risk 
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transfusions. Presented at: 60th Annual Meeting and Exposition of the American Society of 
Hematology (ASH): 2018b; San Diego, CA, US. Abstract No. 1.
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Dec;23 Suppl 1:S15-9.
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IWG2006 response criteria: Results of a randomized study of epoetin alfa versus placebo in 
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Germing U, Lauseker M, Hildebrandt B, Symeonidis A, Cermak J, Fenaux P, et al. Survival, 
prognostic factors and rates of leukemic transformation in 381 untreated patients with MDS and 
del(5q): a multicenter study. Leukemia. 2012 Jun;26(6):1286-92.
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system for evaluating prognosis in myelodysplastic syndromes. Blood. 1997 Mar 15;89(6):2079-
88.
Greenberg PL, Tuechler H, Schanz J, Sanz G, Garcia-Manero G, Sole F, et al. Revised 
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20;120(12):2454-65.
Haferlach T, Nagata Y, Grossmann V, Okuno Y, Bacher U, Nagae G, et al. Landscape of genetic 
lesions in 944 patients with myelodysplastic syndromes. Leukemia. 2014 Feb;28(2):241-7.
Hellstrom-Lindberg E, Gulbrandsen N, Lindberg G, Ahlgren T, Dahl IM, Dybedal I, et al. A 
validated decision model for treating the anaemia of myelodysplastic syndromes with 
erythropoietin + granulocyte colony-stimulating factor: significant effects on quality of life. Br J 
Haematol. 2003 Mar;120(6):1037-46.
Hellstrom-Lindberg E, van de Loosdrecht A. Erythropoiesis stimulating agents and other growth 
factors in low-risk MDS. Best Pract Res Clin Haematol. 2013 Dec;26(4):401-10.
Hu J, Liu J, Xue F, Halverson G, Reid M, Guo A, et al. Isolation and functional characterization 
of human erythroblasts at distinct stages: implications for understanding of normal and 
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Jang JH, Harada H, Shibayama H, Shimazaki R, Kim HJ, Sawada K, et al. A randomized 
controlled trial comparing darbepoetin alfa doses in red blood cell transfusion-dependent patients 
with low- or intermediate-1 risk myelodysplastic syndromes. Int J Hematol. 2015 
Oct;102(4):401-12.
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Protocol ACE-536-MDS-003
Bristol-Myers Squibb K.K.
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Japanese Society of Hematology (JSH) Clinical Practice Guidelines in hematopoietic tumor: 
Myelodysplastic Syndromes; Version 2013. Available from: http://www.jshem.or.jp/gui-
hemali/1_6.html#soron
Jansen AJ, Essink-Bot ML, Beckers EA, Hop WC, Schipperus MR, Van Rhenen DJ. Quality of 
life measurement in patients with transfusion-dependent myelodysplastic syndromes. Br J 
Haematol. 2003 Apr;121(2):270-4.
Kao JM, McMillan A, Greenberg PL. International MDS risk analysis workshop (IMRAW)/IPSS 
reanalyzed: impact of cytopenias on clinical outcomes in myelodysplastic syndromes. Am J 
Hematol. 2008 Oct;83(10):765-70.
Malcovati L, Hellstrom-Lindberg E, Bowen D, Ades L, Cermak J, Del Canizo C, et al. Diagnosis 
and treatment of primary myelodysplastic syndromes in adults: recommendations from the 
European Leukemia Net. Blood. 2013 Oct 24;122(17):2943-64.
Malcovati L, Papaemmanuil E, Bowen DT, Boultwood J, Della Porta MG, Pascutto C, et al. 
Clinical significance of SF3B1 mutations in myelodysplastic syndromes and 
myelodysplastic/myeloproliferative neoplasms. Blood. 2011 Dec 08;118(24):6239-46.
Malcovati L, Porta MG, Pascutto C, Invernizzi R, Boni M, Travaglino E, et al. Prognostic factors 
and life expectancy in myelodysplastic syndromes classified according to WHO criteria: a basis 
for clinical decision making. J Clin Oncol. 2005 Oct 20;23(30):7594-603.
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(NCCN Guidelines®): Myelodysplastic Syndromes; Version 2. 2018. [Internet] National 
Comprehensive Cancer Network. 2018 Feb 15. Available from: 
https://www.nccn.org/professionals/physician_gls/pdf/mds.pdf.
Noel P, Solberg LA, Jr. Myelodysplastic syndromes. Pathogenesis, diagnosis and treatment. Crit 
Rev Oncol Hematol. 1992;12(3):193-215.
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and chronic myelomonocytic leukemia. 8th update. 2017 May. Available from: 
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0treatment%20of%20MDS%20and%20CMML_17.pdf.
Papaemmanuil E, Cazzola M, Boultwood J, Malcovati L, Vyas P, Bowen D, et al. Somatic 
SF3B1 mutation in myelodysplasia with ring sideroblasts. N Engl J Med. 2011 Oct 
13;365(15):1384-95.
Pellagatti A, Boultwood J. The molecular pathogenesis of the myelodysplastic syndromes. Eur J 
Haematol. 2015 Jul;95(1):3-15.
Platzbecker U, Germing U, Götze K, Kiewe P, Mayer K, Chromik J, et al. Luspatercept for the 
treatment of anaemia in patients with lower-risk myelodysplastic syndromes (PACE-MDS): a 
multicentre, open-label phase 2 dose-finding study with long-term extension study. Lancet 
Oncol. 2017a Oct;18(10):1338-47.
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Platzbecker U, Hofbauer LC, Ehninger G, Holig K. The clinical, quality of life, and economic 
consequences of chronic anemia and transfusion support in patients with myelodysplastic 
syndromes. Leuk Res. 2012 May;36(5):525-36.
Platzbecker U, Symeonidis A, Oliva EN, Goede JS, Delforge M, Mayer J, et al. A phase 3 
randomized placebo-controlled trial of darbepoetin alfa in patients with anemia and lower-risk 
myelodysplastic syndromes. Leukemia. 2017c Sep;31(9):1944-50.
Platzbecker U, Komrokji R, Fenaux P, Garcia-Manero G, Mufti G, Sekeres MA, et al. A phase 3, 
randomized, double-blind study of luspatercept (ACE536) in patients (pts) with Revised 
International Prognostic Scoring System (IPSS-R) Very Low- to Intermediate-risk 
myelodysplastic syndromes (MDS) with ring sideroblasts (RS) who require red blood cell (RBC) 
transfusions: The MEDALIST Trial. Poster Presented at: 2016 Annual Meeting of the American 
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Proposals for revised IWG 2018 hematological response criteria in patients with MDS included 
in clinical trials. Blood. 2019 Mar 7;133(10):1020-30.
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chelation therapy be administered in myelodysplastic syndromes? Best Pract Res Clin Haematol. 
2013 Dec;26(4):431-44.
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factor-beta superfamily ligand trap ACE-536 corrects anemia by promoting late-stage 
erythropoiesis. Nat Med. 2014 Apr;20(4):408-14.
Suzuki T, Oh I, Ohmine K, Meguro A, Mori M, Fujiwara S, et al. Distribution of serum 
erythropoietin levels in Japanese patients with myelodysplastic syndromes. Int J Hematol. 2015 
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revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute 
leukemia: rationale and important changes. Blood. 2009 Jul 30;114(5):937-51.
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Zeidan AM, Linhares Y, Gore SD. Current therapy of myelodysplastic syndromes. Blood Rev. 
2013 Sep;27(5):243-59.
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18.
APPENDICES
APPENDIX A. TABLE OF ABBREVIATIONS
Table 6:
Abbreviations and Specialist Terms
Abbreviation or 
Specialist Term
Explanation
aCML
Atypical chronic myeloid leukemia 
ActRIIB
Activin receptor type IIB
ADA
Antidrug antibodies
AE
Adverse event
ALT
Alanine aminotransferase (SGPT)
AML
Acute myeloid leukemia
ANC
Absolute neutrophil count
AST
Aspartate aminotransferase (SGOT)
AUC
Area under the concentration-time curve
β-hCG
β-subunit of human chorionic gonadotropin
BM
Bone marrow
BMP6
Bone morphogenetic protein 6
BMP9
Bone morphogenetic protein 9
BSC
Best supportive care
BUN
Blood urea nitrogen
CBC
Complete blood count
CI
Confidence interval
CL/F
Apparent clearance of drug from plasma after extravascular administration
Cmax
Maximum plasma concentration of drug
CMML
Chronic myelomonocytic leukemia
COVID-19
Coronavirus disease 2019
CT
Computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
DAR
Darbopoetin
DBP
Diastolic blood pressure
DNA
Deoxyribonucleic acid
DVT
Deep venous thrombosis
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Abbreviation or 
Specialist Term
Explanation
EC
Ethics Committee
ECD
Extracellular domain
ECG
Electrocardiogram
ECHO
Echocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic case report form
EE
Efficacy evaluable
EEA
European Economic Area
eGFR
Estimated glomerular filtration rate
ELN
European Leukemia Net
EOT
End of treatment
EPO
Erythropoietin
ESA
Erythropoiesis stimulating agent
ESMO
European Society for Medical Oncology
EU
European Union
FAB
French-American-British (FAB) classification
FCBP
Females of childbearing potential
GCP
Good clinical practice
G-CSF
Granulocyte-colony stimulating factor
GDF11
Growth differentiation factor 11
GM-CSF
Granulocyte-macrophage colony-stimulating factor
Hgb
Hemoglobin
HI-E
Hematologic improvement – erythroid response
HIV
Human immunodeficiency virus
HMA
Hypomethylating agent
HR
Heart rate
HRQoL
Health-related quality-of-life
IB
Investigator’s Brochure
ICF
Informed consent form
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Abbreviation or 
Specialist Term
Explanation
ICH
International Council for Harmonisation
IgG1-Fc
Immunoglobulin G1 - Fragment crystallizable
IMiD
Immune-modulatory drug
IP
Investigational product
IPSS
International prognostic scoring system
IPSS-R
International prognostic scoring system-Revised
IRB
Institutional review board
IRT
Integrated response technology
ITT
Intent-to-treat
IUD
Intrauterine device
IWG
International Working Group
JMML
Juvenile myelomonocytic leukemia
JSH
Japanese Society of Hematology
LDH
Lactatedehydrogenase
MCH
Mean corpuscular hemoglobin
MCHC
Mean corpuscular hemoglobin concentration
MCV
Mean corpuscular volume
MedDRA
Medical dictionary for regulatory activities
MDRD
Modification of diet in renal disease
MDS
Myelodysplastic syndromes
MDS/MPN
Myelodysplastic/myeloproliferative neoplasms
mHI-E
modified HI-E
MOA
Mechanism of action 
MUGA
Multi-gated acquisition
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute
nRBC
Nucleated red blood cells
NYHA
New York Heart Association
OS
Overall survival
PBO
Placebo
PD
Pharmacodynamic
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Abbreviation or 
Specialist Term
Explanation
PK
Pharmacokinetics
PQC
Product Quality Complaint
Q3W
Every 3 weeks 
QoL
Quality-of-life 
RA
Refractory anemia
RAEB
Refractory anemia with excess blasts
RAEB-T
Refractory anemia with excess blasts in transformation
RARS
Refractory anemia with ringed sideroblasts
RBC
Red blood cell
RBC-TD
Red blood cell transfusion dependence
RBC-TI
Red blood cell transfusion independence
RDW
Red blood cell distribution width
RNA
Ribonucleic acid
RS
Ring sideroblast
SAE
Serious adverse event
SAP
Statistical analysis plan
SARS-CoV-2
Severe acute respiratory syndrome coronavirus 2
SBP
Systolic blood pressure
sEPO
Serum erythropoietin
SGOT
Serum glutamic oxaloacetic transaminase 
SGPT
Serum glutamic pyruvic transaminase
SOP
Standard operating procedure
SUSAR
Suspected unexpected serious adverse reaction
TEAE
Treatment-emergent adverse events
TD
Transfusion dependent/dependence
TGF-β 
Transforming growth factor-beta
TI
Transfusion independent/ independence
Tmax
Time to maximum plasma concentration of drug
TNM 
Tumor nodes metastasis
t1/2
Terminal elimination half-life
ULN
Upper limit of normal
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Abbreviation or 
Specialist Term
Explanation
US
United States
V/F
Apparent volume of distribution during the terminal phase after 
extravascular administration
W1D1
Week 1 Day 1
WBC
White blood cell
WHO
World Health Organization
WPSS
WHO prognostic scoring system
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APPENDIX B. MYELODYSPLASTIC SYNDROMES WORLD HEALTH 
ORGANIZATION CLASSIFICATION SYSTEM (2016)
Peripheral Blood and BM Findings and Cytogenetics of Myelodysplastic Syndromes (MDS)
Name
Dysplastic
lineages
Cytopeniasa
Ring sideroblasts as 
% of marrow 
erythroid elements
Bone marrow (BM) 
and peripheral 
blood (PB) blasts
Cytogenetics by 
Conventional karyotype 
analysis
MDS with single 
lineage dysplasia 
(MDS-SLD)
1
1 or 2
<15% / <5%b
BM <5%, PB <1%, 
no Auer rods
Any, unless fulfills all criteria 
for MDS with isolated del(5q)
MDS with 
multilineage dysplasia 
(MDS-MLD) 
2 or 3
1-3
<15% / <5% b
BM <5%, PB <1%, 
no Auer rods
Any, unless fulfills all criteria 
for MDS with isolated del(5q)
MDS with ring 
sideroblasts
(MDS-RS)
MDS-RS with 
single lineage 
dysplasia 
(MDS-RS-SLD) 
MDS-RS with
multilineage 
dysplasia 
(MDS-RS-MLD)
1
2 or 3 
1 or 2
1-3
≥15% / ≥5% b
≥15% / ≥5% b
BM <5%, PB <1%, 
no Auer rods
BM <5%, PB <1%,
No Auer rods
Any, unless fulfills all criteria 
for MDS with isolated del(5q)
Any, unless fulfills all criteria 
for MDS with isolated del(5q)
MDS with isolated 
del(5q)
1-3
1-2
None or any
BM <5%, PB <1%, 
no Auer rods
del(5q) alone or with 1 
additional abnormality except -
7 or del(7q)
MDS with excess 
blasts (MDSEB)
MDS-EB-1  
MDS-EB-2
0-3
0-3
1-3
1-3
None or any
None or any
BM 5-9% or PB 2-
4%, no Auer rods
BM 10-19% or PB 5-
19% or Auer rods
Any
Any
MDS, unclassifiable 
(MDS-U)

with 1% blood 
blasts

with single lineage 
dysplasia and 
pancytopenia

based on defining 
cytogenetic 
abnormality
1-3
1
0
1-3
3
1-3
None or any
None or any
<15%d
BM <5%, PB=1%c, 
no Auer rods
BM <5%, PB <1%, 
no Auer rods
BM <5%, PB <1%, 
no Auer rods
Any
Any
MDS-defining abnormality
Refractory cytopenia 
of childhood
1-3
1-3
None
BM <5%, PB <2%
Any
a Cytopenias defined as haemoglobin <10 g/dL, platelet count <100 x 109/L, and absolute neutrophil count <1.8 x 109/L; rarely, 
MDS may present with mild anaemia or thrombocytopenia above these levels.  PB monocytes must be <1 x 109/L.
b If SF3B1 mutation is present.
c 1% PB blasts must be recorded on at least two separate occasions.
d Cases with ≥15% ring sideroblasts by definition have significant erythroid dysplasia, and are classified as MDS-RS-SLD.
Sources: Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM, et al.  The 2016 revision to the World Health 
Organization (WHO) classification of myeloid neoplasms and acute leukemia. Blood 2016;127(20):2391-405.
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APPENDIX C. INTERNATIONAL PROGNOSTIC SCORING SYSTEM 
SCORE - REVISED
IPSS-R Cytogenetic Risk Groups*,**
Cytogenetic Prognostic 
Subgroups
Cytogenetic Abnormalities
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 or double independent clones
Poor
-7, inv(3)/t(3q)/del(3q), double including -7/del(7q), Complex: 3 abnormalities
Very poor
Complex: >3 abnormalities
IPSS-R Prognostic Score Values*
Prognostic Variable
0
0.5
1
1.5
2
3
4
Cytogenetics
Very 
Good
-
Good
-
Intermediate
Poor
Very Poor
BM Blasts (%)
≤2
-
> 2 - < 5
-
5 - 10
> 10
-
Hemoglobin (g/dL)
≥10
-
8 - < 10
<8
-
-
-
Platelets (x 109/L)
≥100
50 - < 100
< 50
-
-
-
-
ANC (x 109/L)
≥0.8
< 0.8
-
-
-
-
-
IPSS-R Prognostic Risk Categories/Scores*
Risk Category
Risk Score
Very Low
≤1.5
Low
> 1.5 - 3
Intermediate
> 3 - 4.5
High
> 4.5 - 6
Very High
> 6
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APPENDIX C. INTERNATIONAL PROGNOSTIC SCORING SYSTEM 
SCORE – REVISED (CONT.)
IPSS-R: Prognostic Risk Category Clinical Outcomes*
No. pts
Very Low
Low
Intermediate
High
Very High
Subjects (%)
7012
19%
38%
20%
13%
10%
Survival***
-
8.8
5.3
3.0
1.6
0.8
AML/25%***,^
-
NR
10.8
3.2
1.4
0.7
*Greenberg PL, Tuechler H, Schanz J, Sanz G, Garcia-Manero G, Solé F, et al. Revised international prognostic 
scoring system for myelodysplastic syndromes. Blood 2012;120(12):2454-65.
***Medians, years.
^ Median time to 25% AML evolution.
Schanz J, Tüchler H, Solé F, Mallo M, Luño E, Cervera J, et al. New comprehensive cytogenetic scoring system for 
primary myelodysplastic syndromes (MDS) and oligoblastic acute myeloid leukemia after MDS derived from an 
international database merge. J Clin Oncol 2012;30(8):820-9.
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APPENDIX D. INTERNATIONAL WORKING GROUP RESPONSE 
CRITERIA FOR HEMATOLOGIC IMPROVEMENT
Hematologic improvement*
(Cheson, 2006)
Response criteria (responses must last at least 8 wk)
Erythroid response
(pretreatment, < 11 g/dL)
Hgb increase by ≥1.5 g/dL
Relevant reduction of units of RBC transfusions by an absolute 
number of at least 4 RBC transfusions/8 wk compared with the 
pretreatment transfusion number in the previous 8 wk. Only RBC 
transfusions given for a Hgb of ≤9.0 g/dL pretreatment will count 
in the RBC transfusion response evaluation
Platelet response
(pretreatment, < 100 × 109/L)
Absolute increase of ≥30 × 109/L for patients starting with > 20 ×
109/L platelets
Increase from < 20 × 109/L to > 20 × 109/L and by at least 100%
Neutrophil response
(pretreatment, < 1.0 × 109/L)
At least 100% increase and an absolute increase > 0.5 × 109/L
Progression or relapse after HI‡
At least 1 of the following:
At least 50% decrement from maximum response levels in 
granulocytes or platelets
Reduction in Hgb by ≥1.5 g/dL
Transfusion dependence
Hgb indicates hemoglobin; RBC: red blood cell; HI: hematologic improvement.
*Pretreatment counts averages of at least 2 measurements (not influenced by transfusions) ≥1 week apart 
(modification).
‡In the absence of another explanation, such as acute infection, repeated courses of chemotherapy (modification), 
gastrointestinal bleeding, hemolysis, and so forth. It is recommended that the 2 kinds of erythroid and platelet 
responses be reported overall as well as by the individual response pattern.
Notes: Deletions to IWG criteria are not shown. To convert hemoglobin from grams per deciliter to grams per liter, 
multiply grams per deciliter by 10.
Source: Cheson, BD, Greenberg PL, Bennett JM, Lowenberg B, Wijermans PW, Nimer SD, et al. Clinical 
application and proposal for modification of the International Working Group (IWG) response criteria in 
myelodysplasia. Blood 2006;108 (2):419-25.
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APPENDIX E. INTERNATIONAL WORKING GROUP RESPONSE 
CRITERIA FOR MYELODYSPLASTIC SYNDROMES
Altering Natural History of MDS According to IWG Criteria for MDS (Cheson, 2006)
Category
Response Criteria (responses must last at least 4 weeks)
Complete Remission (CR) c
Bone marrow: ≤ 5% myeloblasts with normal maturation of all cell linesa Persistent dysplasia 
will be noteda,b
Peripheral bloodc 
-
Hgb ≥ 11 g/dL
-
Platelets ≥ 100 X 109/L
-
Neutrophils ≥ 1.0 X 109/Lb Blasts 0%
Partial Remission (PR) c
All CR criteria if abnormal before treatment except:
-
Bone marrow blasts decreased by ≥ 50% over pre-treatment but still > 5%
-
Cellularity and morphology not relevant
Marrow CR
b,c
Bone marrow: ≤ 5% myeloblasts and decrease by ≥ 50% over pre-treatmentb
Peripheral blood:  if HI responses, they will be noted in addition to marrow CRb.
Stable Disease (SD)
Failure to achieve at least PR, but no evidence of progression for > 8 wks
Failurec
Death during treatment or disease progression characterized by worsening of cytopenias,
increase in percentage of bone marrow blasts, or progression to a more advanced MDS FAB
subtype thanpre-treatment.
Relapse After CR or PRc
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 
plateletsc
-
Reduction in Hgb concentration by ≥ 1.5 g/dL or transfusion dependence
Cytogenetic Responsec
Complete:
-
Disappearance of the chromosomal abnormality without appearance of new ones
Partial:
-
At least 50% reduction of the chromosomal abnormality
Disease Progression
For subjects 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% blastsd:
≥ 50% increase to > 30% blasts 
Any of the following:
-
≥ 50% decrease from maximum remission/response in granulocytes or plateletsc
-
Reduction in Hgb by ≥ 2 g/dL
-
Transfusion dependence
Survivalc
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
KEY: CR = complete remission; FAB = French-American-British; Hgb = hemoglobin; HI = hematologic improvement; IWG = 
International Working Group; MDS = myelodysplastic syndromes; PR = partial remission; PFS= progression-free survival; 
DFS= disease-free survival.
a Dysplastic changes should consider the normal range of dysplastic changes (modification).
b Modification to IWG (2000) response criteria.
c Criteria not applicable for ACE-536-MDS-003 subject population.  
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d 20 – 30% blasts is considered AML according to WHO classification (Vardiman, 2009).
Notes: Deletions to IWG criteria are not shown. To convert hemoglobin from grams per deciliter to grams per liter, multiply 
grams per deciliter by 10.
Source: Cheson, BD, Greenberg PL, Bennett JM, Lowenberg B, Wijermans PW, Nimer SD, et al. Clinical application and 
proposal for modification of the International Working Group (IWG) response criteria in myelodysplasia. Blood 2006;108 
(2):419-25.
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APPENDIX F.
EASTERN COOPERATIVE ONCOLOGY GROUP 
(ECOG) PERFORMANCE STATUS
Eastern Cooperative Oncology Group (ECOG) Performance Status
Grade
ECOG
0
Fully active, able to carry on all pre-disease performance without restriction.
1
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or 
sedentary nature, eg, light house work, office work.
2
Ambulatory and capable of all selfcare but unable to carry out any work activities.  Up and about 
more than 50% of waking hours.
3
Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours.
4
Completely disabled.  Cannot carry on any selfcare.  Totally confined to bed or chair.
5
Dead.
Source:  Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity and response 
criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982;5(6):649-55.
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APPENDIX G. FOUR-VARIABLE MDRD GFR EQUATION
For Serum Creatinine in mg/dL: 
GFR (mL/min/1.73 m²) = 175 × (Scr)-1.154 × (Age)-0.203 × (0.742 if female) × (1.212 if 
African American) (conventional units)
Creatinine levels in μmol/L can be converted to mg/dL by dividing them by 88.4
Source: 
Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF, 3rd, Feldman HI, et al. A new equation to estimate 
glomerular filtration rate. Ann Intern Med. 2009;150(9):604-12.
Levey AS, Coresh J, Greene T, Stevens LA, Zhang YL, Hendriksen S, Kusek JW, Van Lente F; Chronic Kidney 
Disease Epidemiology Collaboration. Using standardized serum creatinine values in the modification of diet in renal 
disease study equation for estimating glomerular filtration rate. Ann Intern Med. 2006 Aug 15;145(4):247-54.
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Celgene Signing Page
This is a representation of an electronic record that was signed electronically in Livelink.
This page is the manifestation of the electronic signature(s) used in compliance with
the organizations electronic signature policies and procedures.
UserName: 
Title:  
Date: Tuesday, 23 November 2021, 02:32 PM   Eastern Daylight Time
Meaning: Approved, no changes necessary.
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Summary of Changes ACE-536-MDS-003
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1.
JUSTIFICATION FOR AMENDMENT
Significant changes included in this amendment are summarized below:

Clarification of the definition for the primary efficacy endpoint of hematologic 
improvement – erythroid response (HI-E) per International Working Group (IWG)
2006 criteria and related secondary endpoints
 
 
 
herefore, 
in the ACE-536-MDS-003 study, for subjects who have a dose delay meeting the dose 
interruption criterion of predose hemoglobin (Hgb) ≥ 12.0 g/dL, if their Hgb levels temporarily 
decrease to < 1.5 g/dL but achieve ≥ 1.5 g/dL again after treatment resumption, this period (ie, 
the time from dose delay to achieving a Hgb increase of ≥ 1.5 g/dL again) will be included as the 
period of sustained Hgb increase of ≥ 1.5 g/dL for HI-E 2006 evaluation. The secondary 
endpoints of HI-E per IWG 2006 criteria within 48 weeks, time to HI-E and duration of HI-E
will use this definition.
Revised sections: Protocol Summary; Section 1.1.1.1 (Erythropoiesis Stimulating Agents); 
Section 1.3.2.2 (Rationale for Study Endpoints); Section 9.6.1 (Primary Efficacy Analysis); 
Section 9.6.2 (Secondary Efficacy Analyses)

Addition of the secondary endpoints of modified HI-E (mHI-E) per IWG 2006 
criteria
The ARCADE Phase 3 study for darbepoetin (DAR) defined HI-E per IWG 2006 criteria as 
≥1.5 g/dL increase from baseline in Hgb with a mean rise of ≥1.5 g/dL for 8 weeks without 
transfusions. To ensure better comparison of efficacy data between luspatercept and DAR, 
mHI-E per IWG 2006 criteria defined as “≥ 1.5 g/dL mean increase in Hgb compared to baseline 
over any consecutive 56-day period in the absence of red blood cell (RBC) transfusions” was
added in the secondary endpoints. The secondary endpoints of the time to mHI-E and duration of 
mHI-E were also added. With this modification, the endpoint of “Mean Hgb increase ≥ 1.5 g/dL 
(defined as proportion of subjects with ≥ 1.5 g/dL mean increase in Hgb compared to baseline 
that is sustained over a 24-week period from Week 1 Day 1 (W1D1) through Week 24 (and 
W1D1 through Week 48) of the Treatment Period in the absence of RBC transfusions)” was 
removed.
Revised sections: Protocol Summary; Section 1.1.1.1 (Erythropoiesis Stimulating Agents); 
Section 1.3.2.2 (Rationale for Study Endpoints); Section 2 (Table 1 Study Objectives and Table
2 Study Endpoints); Section 9.6.2 (Secondary Efficacy Analyses)

Addition of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) testing
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EDMS Doc. Number: 25770028 - 22964360
Luspatercept (ACE-536)
Summary of Changes ACE-536-MDS-003
Bristol-Myers Squibb K.K.
Confidential and Proprietary
5
ACE-536-MDS-003 Amendment 2.0 Final: 22 Nov 2021
SARS-CoV-2 testing was added for subjects at baseline, Day (D)169, D337 and End of 
Treatment (EOT) to determine exposure to this virus and to evaluate the safety of luspatercept in 
SARS-CoV-2 antibody positive subjects.  Language to address use of coronavirus disease 2019 
(COVID-19) vaccines was also added to the protocol.
Revised sections: Section 1.3.4 (Rationale for Exploratory Biomarkers); Section 2 (Table 1 
Study Objectives and Table 2 Study Endpoints); Section 4.3 (Exclusion Criteria); Section 5 
(Table of Events); Section 6.7 (Biomarkers, Pharmacodynamics, Pharmacogenomics); Section 
8.1.3 (Attenuated Vaccines); Section 8.2 (Prohibited Concomitant Medications and Procedures); 
Section 9.9.3 (Exploratory Analysis); Section 10.8 (COVID-19 Reporting).

Modification of the Long-term Follow-up Period
Update to amend the reference point for the Long-term Follow-up Period from “3 years from the 
last dose” to “5 years from the date of the first dose of investigational product (IP), or 3 years 
from the last dose (whichever occurs later)”. This modification is to ensure the same reference 
point for the Long-term Follow-up Period is used across the luspatercept program. In the Long-
term Follow-up Period, visits or telephone contacts will be conducted every 12 weeks for the 
first 3 years from the date of last dose of IP and every 6 months thereafter, if applicable. The 
expected duration of the study and duration of participation for subjects are updated to 
approximately 8 years and 6 years, respectively.
Revised sections: Protocol Summary; Section 2 (Table 2 Study Endpoints); Section 3.1 (Study 
Design, and Figure 2 Overall Study Design); Section 3.2 (Study Duration for Subjects); Section 
5 (Table 3 Table of Events); Section 6.1.20 (Monitoring for Progression to AML and Other 
Malignancies/Pre-malignancies); Section 6.3.2 (Long-term Follow-up)

Clarification on the assessment of the status of human immunodeficiency virus 
(HIV), hepatitis B, and/or hepatitis C active infection
Update to the protocol to implement a time frame for local laboratory assessments (within 4 
weeks prior to the date of informed consent form [ICF] signature) to be acceptable to determine 
the status of HIV, hepatitis B, and/or hepatitis C active infection at Screening to align with other 
luspatercept studies (eg, ACE-536-MDS-002 study [COMMANDS trial]).
Revised sections: Section 4.3 (Exclusion Criteria); Section 5 (Table 3 Table of Events); Section 
6.1.4.1 (Assessment of HIV/Hepatitis B/Hepatitis C Status)
 
 
Revised sections: Protocol Summary; Section 7.2.1 (Luspatercept Administration and Schedule); 
Section 7.2.2 (Luspatercept Dose Adjustment and Dose Modification).
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EDMS Doc. Number: 25770028 - 22964360
Luspatercept (ACE-536)
Summary of Changes ACE-536-MDS-003
Bristol-Myers Squibb K.K.
Confidential and Proprietary
6
ACE-536-MDS-003 Amendment 2.0 Final: 22 Nov 2021

Inclusion of subjects with myelodysplastic/myeloproliferative neoplasms 
(MDS/MPN) with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T) in the 
study
Exclusion criterion 2 was modified to remove subjects with MDS/MPN-RS-T in alignment with 
other luspatercept studies (ie, COMMANDS).  Subjects with MDS/MPN-RS-T are eligible for 
the study with this modification. A subgroup analysis showed benefit in this population and this 
led to incorporation of this population in the United States  label for luspatercept in lower risk 
MDS.
Revised sections: Section 4.3 (Exclusion Criteria)
The amendment also includes several other minor clarifications and corrections:

 
 

Update/correction to Section 1.2.3.1 (Potential Risks of Human Use) to clarify that
male and female subjects of childbearing potential must be willing to abstain from 
sexual intercourse or use adequate contraception during the treatment period of the 
study and for at least 12 weeks after discontinuation of study therapy.

Updates to the protocol to include minor clarifications/corrections regarding 
pharmacodynamic and predictive biomarkers in alignment with other luspatercept 
studies (eg, COMMANDS).
Revised sections: Section 1.3.4 (Rationale for Exploratory Biomarkers); Section 2 
(Table 2 Study Endpoints); Section 5 (Table 3 Table of Events); Section 6.1.1 (Bone 
Marrow and Peripheral Blood Samples); Section 6.7 (Biomarkers, 
Pharmacodynamics, Pharmacogenomics).

Update to Section 4.3 (Exclusion Criteria) and Section 8.2 (Prohibited Concomitant 
Medications and Procedures) not to use anagrelide within 8 weeks prior to W1D1 and 
during the course of the study.

Update/correction to Section 5 (Table of Events) to replace “Day -35 to 
Randomization” with “Day -35 to -1”.

 
 
 
 

Update to Section 5 (Table of Events) and Section 8 (Concomitant Medications And 
Procedures) to clarify that concomitant medications must be reported on the
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EDMS Doc. Number: 25770028 - 22964360
Luspatercept (ACE-536)
Summary of Changes ACE-536-MDS-003
Bristol-Myers Squibb K.K.
Confidential and Proprietary
7
ACE-536-MDS-003 Amendment 2.0 Final: 22 Nov 2021
electronic case report form (eCRF) until 42 days after the last dose of IP or the EOT 
Visit, whichever occurs later.

Update to the protocol to reflect mandatory confirmation with the subject (and 
documentation in the subject’s source record) whether or not transfusions were 
received at outside local institutions prior to each IP administration at the site as well 
as the use of the study patient transfusion diary in alignment with other luspatercept 
studies (eg, COMMANDS).
Revised sections: Section 5 (Table of Events); Section 6.4.1 (Transfusion 
Assessment); Section 7.2.1 (Luspatercept Administration and Schedule)

Update/correction to Section 6.1.9 (Hematology) to add “reticulocytes” to the list of 
hematology assessments to ensure consistency with the study’s Central Laboratory 
Manual.

Update to the protocol to clarify a window for Pharmacokinetics (PK) and antidrug 
antibodies (ADA) sampling after the 24-Week MDS Disease Assessment Visit. This 
window allows the sites the ability to schedule this assessment during a dosing or 
other visit. Language was also added in these sections to clarify PK and ADA 
sampling timing.
Revised sections: Section 5 (Table 3 Table of Events); Section 6.5
(Pharmacokinetics); Section 6.6 (Antidrug Antibody [ADA]).

Update to Section 6.1.1 (Bone Marrow and Peripheral Blood Samples) to include 
guidance on laboratory values to be used to determine the baseline International 
Prognostic Scoring System - Revised (IPSS-R) category in case historical local bone 
marrow (BM) samples/reports are being used for “over read”.

Update to Section 6.3.1 (Safety Follow-up [42-Day Follow-up]) to add language 
clarifying the replacement of the 42-Day Follow-up Visit with the EOT Visit in cases 
of dose delays exceeding 6 weeks (+2 days).

Update/correction to Section 6.6 (Antidrug Antibody [ADA]) to include the 24-Week 
MDS Disease Assessment Visit as time point for ADA sampling (consistent with 
Section 5 [Table 3 Table of Events]).

Update to Section 7.1 (Description of Investigational Products) to include change of 
both the held for and total in-use time of reconstituted luspatercept from 10 hours at 
2°C to 8°C to 24 hours at 2°C to 8°C.  A reference to the pharmacy manual is 
included for more details. 

Update to Section 7.2.1 (Luspatercept Administration and Schedule) to change the 
allowance for no dose adjustment in cases of changes in body weight from < ± 5% to
≤ ± 5% in alignment with other luspatercept studies (eg, COMMANDS).

Update to Section 7.2 (Luspatercept Dose Adjustment and Dose Modification) to 
clarify that the subject Hgb levels should be assessed for dose modifications 
independently from any transfusions.
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EDMS Doc. Number: 25770028 - 22964360
Luspatercept (ACE-536)
Summary of Changes ACE-536-MDS-003
Bristol-Myers Squibb K.K.
Confidential and Proprietary
8
ACE-536-MDS-003 Amendment 2.0 Final: 22 Nov 2021

Update to Section 7.2.2 (Table 5 Luspatercept Dose Modification: Dose Delay, Dose 
Reduction, and Discontinuation Guidelines) to clarify that treatment should be 
discontinued, if dose delay is > 15 weeks from last dose administered in case of dose 
delay caused by any suspected related adverse events ≥ Grade 3 and that footnote “d”
is applicable if predose Hgb is ≥ 12.0 g/dL.

Update to Section 7.2.2 (Table 5 Luspatercept Dose Modification: Dose Delay, Dose 
Reduction, and Discontinuation Guidelines) to allow to proceed with dosing of IP in 
circumstances where results from the blast count assessment in peripheral blood are 
not readily available at the time of planned dosing, provided results are evaluated as 
soon as they become available (but within 3 days post dosing) and actions described 
in Table 5 are followed immediately in case a presence of ≥ 1% blasts in peripheral 
blood is observed.

Update to Section 8.1.4 (Phlebotomy) to clarify that the treatment of excessively high 
Hgb levels using phlebotomy should only be performed in emergency/urgency 
situations in alignment with other luspatercept studies (eg, COMMANDS).

Updated to Section 9.7 (Safety Analysis) to state that frequency of ADA will also be 
reported.

 

Update to Section 10.2.6 (Outcome) to clarify that progression of MDS or any other 
malignancy does not need to be followed until recovery, as recovery is not expected 
for these events in alignment with other luspatercept studies (eg, COMMANDS).

Update to Section 17 (References) to include new literature references.

Update to Section 18 (Appendix A Table of Abbreviations) to include new 
abbreviations in Table 6 Abbreviations and Specialist Terms.

Update to Section 18 (Appendix E International Working Group Response Criteria 
for Myelodysplastic Syndromes) to clarify the only categories that are applicable to 
this study are Stable Disease and Disease Progression in alignment with other 
luspatercept studies (eg, COMMANDS).

Update of language throughout the protocol to align with the current protocol 
template.
Revised sections: Section 4.2 (Inclusion Criteria); Section 6.8 (Additional and 
Optional Research); Section 6.8.1 (Additional Research); Section 6.8.2 (Optional 
Research); Section 10.1 (Monitoring, Recording and Reporting of Adverse Events); 
Section 10.2.1 (Seriousness) to Section 10.2.6 (Outcome); Section 10.3 (Abnormal 
Laboratory Values); Section 10.4.1 (Females of Childbearing Potential); Section 10.5 
(Other Malignancies/Pre-malignancies) to Section 10.7 (Expedited Reporting of 
Adverse Events); Section 15.1 (Study Monitoring and Source Data Verification) to 
Section 15.3 (Investigational Medicinal Product Quality Issues).
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EDMS Doc. Number: 25770028 - 22964360
Luspatercept (ACE-536)
Summary of Changes ACE-536-MDS-003
Bristol-Myers Squibb K.K.
Confidential and Proprietary
9
ACE-536-MDS-003 Amendment 2.0 Final: 22 Nov 2021

Minor editorial and formatting changes (spelling, grammatical error corrections, etc.) 
were also made throughout the document.
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EDMS Doc. Number: 22966860 - 22964360
Luspatercept (ACE-536)
Summary of Changes ACE-536-MDS-003
Celgene K.K.
Confidential and Proprietary
4
ACE-536-MDS-003 Amendment 1.0 Final: 29 Aug 2018
1.
JUSTIFICATION FOR AMENDMENT
Significant changes included in this amendment are summarized below:
 

Modification of Inclusion Criterion 8 on Females of Childbearing Potential
Update to the protocol to amend the Inclusion Criterion 8 on females of childbearing potential in
line with the Supplement to Protocol ACE-536-MDS-002 (ACE-536-MDS-002 Protocol 
Supplement JP, Version 1: 21 August 2018).  The definition of natural menopause is revised to 
also exclude amenorrhea due to other medical reasons in addition to amenorrhea after cancer 
therapy.  Also, the condition of breastfeeding women for the study enrollment is additionally 
included in the Inclusion Criterion 8, that is breastfeeding women must agree to stop 
breastfeeding prior to the participation in the study and not to resume breastfeeding after 
treatment discontinuation.
Regarding the Footnote 1 on highly effective contraception, update to the protocol to delete 
unapproved hormonal contraception in Japan, which are injection, implant, transdermal patch,
and vaginal ring.
Revised section: Section 4.2 Inclusion Criteria

Modification of Exclusion Criterion 7 on Hypertension
Update to the protocol to amend the Exclusion Criterion 7 on hypertension in line with the 
Supplement to Protocol ACE-536-MDS-002 (ACE-536-MDS-002 Protocol Supplement JP, 
Version 1: 21 August 2018).  It is revised to also exclude subjects with a history of hypertensive 
crisis or hypertensive encephalopathy in addition to subjects with uncontrolled hypertension.
Revised section: Section 4.3 Exclusion Criteria

Modification of Section 6.7. Biomarkers, Pharmacodynamics, Pharmacogenomics
Update to the protocol to include the additional information on biomarkers, pharmacodynamics, 
pharmacogenomics in line with the Supplement to Protocol ACE-536-MDS-002 (ACE-536-
MDS-002 Protocol Supplement JP, Version 1: 21 August 2018).  The section is revised to 
include the information on the rules of the storage period of and the disposal of bio-samples, the 
actions to be taken upon consent withdrawal, and the disclosure of genetic testing results to the 
subject, that is “The samples will be destroyed five years after the end of trial or earlier if 
required by law in each country. If subjects decide to withdraw the consent, all previously 
retained identifiable samples be destroyed to prevent future testing. Since the results of genetic 
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EDMS Doc. Number: 22966860 - 22964360
Luspatercept (ACE-536)
Summary of Changes ACE-536-MDS-003
Celgene K.K.
Confidential and Proprietary
5
ACE-536-MDS-003 Amendment 1.0 Final: 29 Aug 2018
tests are not beneficial to the treatment of an individual subject, they will not be disclosed to the 
subjects.”
Revised section: Section 6.7. Biomarkers, Pharmacodynamics, Pharmacogenomics
 
 
  
 
 
 
 
 
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