Clinical trial NCT01736683
Conditions: Anemia Myelodysplastic Syndromes Chronic Myelomonocytic Leukemia Low to Intermediate-1 MDS Myelodysplastic Syndromes (MDS) Chronic Myelomonocytic Leukemia (CMML)
Keywords: ACE-011 anemia dose-ranging intermediate-1 risk myelodysplastic syndromes low risk myelodysplastic syndromes (MDS) multicenter open-label parallel phase 2 randomized Sotatercept Non-proliferative chronic myelomonocytic leukemia (CMML) hemoglobin transfusions
Sponsor: Merck Sharp & Dohme LLC
Start date: 2012-11-28; Completion date: 2018-04-30
Enrollment: 74 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective of this study is to determine a safe, tolerable and effective dose of sotatercept that results in the greatest frequency of improvement of anemia in patients diagnosed with low- or intermediate-1 risk myelodysplastic syndromes (MDS) or non-proliferative chronic myelomonocytic leukemia (CMML).

Detailed description:

Arms: arm 1: Sotatercept 0.1 mg/kg arm 2: Sotatercept 0.3 mg/kg arm 3: Sotatercept 0.5 mg/kg arm 4: Sotatercept 1.0 mg/kg arm 5: Sotatercept 1.5 mg/kg arm 6: Sotatercept 2.0 mg/kg
Interventions: intervention 1: Sotatercept
Intervention descriptions: intervention 1: Sotatercept is supplied as a lyophilized powder that is reconstituted using Water for Injection (WFI) and administered as a subcutaneous injection (SC) injection by the study staff at the clinical site.

Protocol documents:
Prot_000.pdf: 
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Sotatercept (ACE-011)
Protocol ACE-011-MDS-001
Celgene Corporation
Confidential and Proprietary
1
ACE-011-MDS-001 Amendment 4 Final: 04 Aug 2015
TITLE PAGE
AN OPEN-LABEL, RANDOMIZED, PHASE 2, PARALLEL, 
DOSE-RANGING, MULTICENTER STUDY OF SOTATERCEPT 
FOR THE TREATMENT OF PATIENTS WITH ANEMIA AND 
LOW- OR INTERMEDIATE-1 RISK MYELODYSPLASTIC 
SYNDROMES OR NON-PROLIFERATIVE CHRONIC 
MYELOMONOCYTIC LEUKEMIA (CMML)
INVESTIGATIONAL PRODUCT (IP):
Sotatercept
STUDY NUMBER:
ACE-011-MDS-001
DATE FINAL:
12 Jun 2012
AMENDMENT No. 1 DATE FINAL:
13 Sep 2012
AMENDMENT No. 2 DATE FINAL:
13 Feb 2013
AMENDMENT No. 3 DATE FINAL
05 Aug 2013
AMENDMENT No. 4 DATE FINAL
04 Aug 2015
EudraCT NUMBER:
2012-002601-22
IND NUMBER:
103362
SPONSOR NAME / ADDRESS:
Celgene Corporation
86 Morris Avenue
Summit, NJ 07901
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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Sotatercept (ACE-011)
Protocol ACE-011-MDS-001
Celgene Corporation
Confidential and Proprietary
2
ACE-011-MDS-001 Amendment 4 Final: 04 Aug 2015
MEDICAL MONITOR / EMERGENCY CONTACT INFORMATION
Contact Information:
Name:
 
Title:
Address:86 Morris Avenue, Summit, NJ 07901
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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Sotatercept (ACE-011)
Protocol ACE-011-MDS-001
Celgene Corporation
Confidential and Proprietary
3
ACE-011-MDS-001 Amendment 4 Final: 04 Aug 2015
CELGENE THERAPEUTIC AREA HEAD SIGNATURE PAGE
{See appended electronic signature page}
Signature of Celgene Therapeutic Area Head
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By my signature, I indicate I have reviewed this protocol and find its content to be 
acceptable.  
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Sotatercept (ACE-011)
Protocol ACE-011-MDS-001
Celgene Corporation
Confidential and Proprietary
4
ACE-011-MDS-001 Amendment 4 Final: 04 Aug 2015
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 Conference on 
Harmonisation (ICH) Good Clinical Practices Guidelines, and local regulations 
governing the conduct of clinical studies.
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Sotatercept (ACE-011)
Protocol ACE-011-MDS-001
Celgene Corporation
Confidential and Proprietary
5
ACE-011-MDS-001 Amendment 4 Final: 04 Aug 2015
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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Sotatercept (ACE-011)
Protocol ACE-011-MDS-001
Celgene Corporation
Confidential and Proprietary
6
ACE-011-MDS-001 Amendment 4 Final: 04 Aug 2015
PROTOCOL SUMMARY
Title of Study
An open-label, randomized, Phase 2, parallel, dose-ranging, multicenter study of sotatercept for 
the treatment of patients with anemia and low- or intermediate-1 risk myelodysplastic syndromes
or non-proliferative chronic myelomonocytic leukemia (CMML)
Indication
Low- and intermediate-1 (int-1) risk myelodysplastic syndromes (MDS) or non-proliferative 
CMML by International Prognostic Scoring System (IPSS, Appendix B) with anemia 
(hemoglobin [Hgb] ≤9.0 g/dL)
Objectives
The primary objective of this study is to determine a safe, tolerable, and effective dose of 
sotatercept that results in the greatest frequency of erythroid hematological improvement (HI-E) 
in patients with anemia and low- or int-1 risk MDS or non-proliferative CMML.
The secondary objectives of this study are to evaluate the:
1. Safety of sotatercept
2. Rate of red blood cell (RBC) transfusion independence in transfusion-dependent subjects
3. Time to HI-E
4. Duration of HI-E
5. Time to progression to acute myeloid leukemia (AML)
6. Time to progression to events of higher risk MDS (ie, int-2 or high-risk IPSS)
7. Progression-free survival (PFS)
8. Overall survival (OS)
9. Pharmacokinetics (PK) of sotatercept
Study Design
This is an open-label, randomized, Phase 2, parallel, dose-ranging, multicenter study of 
sotatercept for the treatment of patients with low- and int-1 risk MDS or non-proliferative 
CMML, (IPSS, Appendix B), with anemia requiring a transfusion (subjects should have received 
at least 2 units of RBCs within 84 days prior to study enrollment).
The study is comprised of 2 parts:
Part 1
Subjects will be stratified by concentration of serum erythropoietin (EPO, < 500 versus
≥500 mIU/mL) and by number of transfusions within 56 days prior to study enrollment (< 4 
units of RBCs versus ≥4 units of RBCs), and assigned randomly to one of two treatment groups,
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Sotatercept (ACE-011)
Protocol ACE-011-MDS-001
Celgene Corporation
Confidential and Proprietary
7
ACE-011-MDS-001 Amendment 4 Final: 04 Aug 2015
wherein they will be administered sotatercept subcutaneously (SC) 0.1 mg/kg or 0.3 mg/kg once
every 3 weeks (Q3W).
Enrollment will continue without hiatus beyond randomization of five subjects into each of the 
0.1 mg/kg and 0.3 mg/kg treatment groups.  Following treatment of five subjects in each of the 
0.1 mg/kg and 0.3 mg/kg treatment groups (with the last subject for each group having 
completed at least one cycle of 21 days), all available safety and efficacy data will be assessed by 
a Steering Committee (Section 4.4).  Based upon the occurrence of dose-limiting toxicity (DLT) 
(Section 4.1.1) in ≤1/5 subjects in Cycle 1 in the 0.1 mg/kg and 0.3 mg/kg treatment groups, the 
0.5 mg/kg treatment group will begin inclusion in the randomization scheme.
Following treatment of at least six subjects in the 0.5 mg/kg treatment group (with at least six 
subjects having completed at least three cycles of 21 days each), all available safety and efficacy 
data will be assessed by a Steering Committee from all dose levels.  Based upon the occurrence 
of DLT in ≤ 1/6 subjects in Cycle 1 in the 0.5 mg/kg treatment group and an acceptable safety 
profile from all dose levels, the 1.0 mg/kg treatment group will begin inclusion in the 
randomization scheme.  
Following treatment of at least six subjects in the 1.0 mg/kg treatment group (with at least six
subjects having completed at least three cycles of 21 days each), all available safety and efficacy 
data will be assessed by a Steering Committee from all dose levels.  Based upon the occurrence 
of DLT in ≤ 1/6 subjects in Cycle 1 in the 1.0 mg/kg treatment group and an acceptable safety 
profile from all dose levels, the 2.0 mg/kg treatment group will begin inclusion in the 
randomization scheme.  The 2.0 mg/kg sotatercept dose was reduced to 1.5 mg/kg for ongoing 
and newly enrolled subjects (Amendment 4).
Intermediate cohorts (not to exceed 2.0 mg/kg) may be added at the time of dose escalation up to 
1.0 mg/kg and up to 2.0 mg/kg (eg, 0.75 mg/kg or 1.5 mg/kg respectively) based on assessment 
by the Steering Committee of available safety and efficacy data when at least six subjects have at 
least three cycles of treatment in the current dose level.  Enrollment will continue beyond 
randomization in all dose levels (unless dose level[s] is closed due to safety reasons or lack of 
efficacy as recommended by the Steering Committee) until up to a total of 20 subjects in each 
dose level.  
Meetings of the Steering Committee are planned periodically throughout the study to review all 
available safety and efficacy data.  For any treatment group, if ≥40% of the subjects (minimum 
four subjects experiencing an event) experience a DLT of related (suspected) adverse event (AE)
≥Grade 2 (other than Hgb or hypertension DLT as defined in Section 4.1.1), the Steering 
Committee may recommend the closure of the treatment group.
In addition, if > 33% of the subjects (minimum two subjects experiencing an event) experience 
Hgb > 12 g/dL (not influenced by transfusions) sustained for ≥7 days, confirmed by two
assessments ≥1 week apart, the Steering Committee may recommend the closure of the 
treatment group.
Moreover, if > 33% of the subjects (minimum two subjects experiencing an event) experience a 
hypertension DLT (Refer to Section 4.1.1) confirmed by the investigator by two readings 
obtained 5 minutes apart, the Steering Committee may recommend the closure of the treatment 
group.  In order to harmonize DLT assessment for hypertension across the study, additional 
guidance must be followed as defined in Section 4.1.1). 
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Sotatercept (ACE-011)
Protocol ACE-011-MDS-001
Celgene Corporation
Confidential and Proprietary
8
ACE-011-MDS-001 Amendment 4 Final: 04 Aug 2015
Additionally, for any treatment group that accrues a minimum of 10 subjects or less if 
recommended by the Steering Committee (with the last subject having received at least one 
complete cycle of 21 days), in the absence of any sign of efficacy (defined as an increase of Hgb 
> 1 g/dL in the absence of transfusion or at least a 50% reduction in the transfusion requirements
if the reduction observed is less than 4 units), the Steering Committee may recommend the 
closure of the treatment group.
Upon completion of up to 20 evaluable subjects in each of the treatment groups, analyses will be 
conducted in order to evaluate the safety profile of sotatercept and identify the dose that results 
in the greatest frequency of HI-E.
Part 2
Following the assessment of efficacy and safety parameters in Part 1, 15 additional evaluable 
subjects will be enrolled in Part 2 (Expansion Cohort) and complete treatment at the dose level of 
sotatercept that demonstrates the greatest frequency of HI-E.
Steering Committee Recommendation
Based on the 02 Mar 2015 Steering Committee’s review of safety, efficacy and pharmacokinetic 
data of subjects enrolled in the Part 1 dose levels, including the sotatercept 2.0 mg/kg cohort 
level:
Part 1 - The sotatercept 2.0 mg/kg cohort was closed.  Ongoing and newly enrolled subjects are 
to be dose reduced to sotatercept 1.5 mg/kg.
Part 2 - Subjects enrolled into Part 2 (Expansion Cohort) will receive sotatercept at 1.0 mg/kg. 
This update is reflected in Amendment 4.
Total Number of Subjects: Up to approximately 75-115 evaluable subjects
Study Population
This is a study of patients with low- and int-1 risk MDS or non-proliferative CMML, with 
anemia.  Subjects will be aged ! 18 years and have documented diagnosis of MDS or non-
proliferative CMML (white blood cell [WBC] count ≤13,000 /mm3,World Health Organization
[WHO], Vardiman, 2009) that meets IPSS (Appendix B) criteria for low- or int-1 risk MDS or 
non-proliferative CMML.  Anemia is defined as patients requiring at least 2 units of RBCs 
within 84 days of enrollment for Hgb ≤9.0 g/dL.  Subjects will have had no response or loss of 
response to prior treatment with rHu EPO (≥40,000 U/wk x 8), or darbepoetin alpha (≥500 mcg 
Q3W x 4), or low chance of response to erythroid-stimulating factors reflected by endogenous 
serum EPO concentration > 500 mIU/mL.
Length of Study
The study is comprised of the following periods:
Screening – Assessments to be performed up to 28 days prior to enrollment (Day 1).
Treatment – Comprised of five complete cycles of 21 days each of treatment on a schedule of 
once Q3W.  Subjects who have a sustained Hgb increase or a decreased transfusion burden by 
end of Cycle 5, but for a period less than or equal to 8 consecutive weeks (potential late 
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Sotatercept (ACE-011)
Protocol ACE-011-MDS-001
Celgene Corporation
Confidential and Proprietary
9
ACE-011-MDS-001 Amendment 4 Final: 04 Aug 2015
responders) may continue treatment for up to an additional three cycles (Cycles 6-8) for the 
purpose of meeting response criteria.
End of Treatment – Assessments to be conducted upon:
Completion (≥ 5 cycles) of participation in the Treatment Period of the study, prior to the first 
dose of sotatercept in the Extension Period.
Early (< 5 cycles) termination of participation in the Treatment Period of the study, after last 
dose of sotatercept.
Extension – After completing 5 cycles of treatment (or up to 8 cycles for potential late 
responders), subjects who qualify for the Extension Period (refer to Section 4.1.2) may enter the 
Extension Period and continue treatment, subject to Rules for Delay, Reduction, and 
Discontinuation of Treatment (Section 8.2.1), until disease progression (PD), treatment failure, 
or other reason, as appropriate, listed in Section 12, Discontinuations.  Visits will be once Q3W
to coincide with the schedule of treatment administration.
End of Extension – Assessments to be conducted upon completion of participation in the 
Extension Period of the study.
Follow-up – Following the End of Treatment (last dose of sotatercept administered) in the
Treatment Period or the Extension Period, follow-up will include a pregnancy test approximately
28 days after the last treatment; assessment of efficacy (ie, Hgb levels, transfusions) 
approximately 28 days after the last treatment and repeated once per month until 3 months after 
the last treatment or until the start of the next treatment for MDS, whichever is first; assessment 
of PK at a single time point 3 months after the last treatment; assessment of antidrug antibody 
(ADA) repeated every 3 months until 1 year after the last treatment; and assessment of 
progression to AML and OS every 6 months up to 2 years following the subject’s first 
administration of sotatercept.
The End of Trial is defined as either the date of the last visit of the last subject to complete the
study, or the date of receipt of the last data point from the last subject that is required for
primary, secondary 
 analysis, as pre-specified in the protocol and/or the
Statistical Analysis Plan, whichever is the later date.
The sponsor may decide to 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 any subjects that 
remain on study may be consented and continue to receive treatment with IP.  It must be the 
opinion of the investigator that the remaining subject(s) continue to receive benefit from 
treatment with IP.  
Study Treatments
In Part 1, subjects will be randomized to one of up to five treatment groups (contingent on 
number of treatment groups open at time of randomization) to be administered sotatercept
0.1 mg/kg, 0.3 mg/kg, 0.5 mg/kg, 1.0 mg/kg, or 2.0 mg/kg by SC injection once Q3W for a total
of 5-8 complete cycles of 21 days each in the Treatment Period.  Subjects may continue to 
receive treatment at the same dose and frequency in the Extension Period if protocol-defined 
criteria are met (refer to Section 4.1.2).  
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treatment;
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52


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Intermediate cohorts (not to exceed 2.0 mg/kg) may be added at the time of dose escalation up to 
1.0 mg/kg and up to 2.0 mg/kg (eg, 0.75 mg/kg or 1.5 mg/kg respectively) based on assessment 
by the Steering Committee of available safety and efficacy data when at least six subjects have at 
least three cycles of treatment in the current dose level. Based on the Steering Committee 
assessment of efficacy, safety and PK data in Part 1, the sotatercept 2.0 mg/kg cohort was closed 
with ongoing and newly enrolled subjects dose reduced to 1.5 mg/kg in Part 1; 15 additional 
evaluable subjects will be enrolled in Part 2 (Expansion Cohort)at the 1.0 mg/kg dose level of 
sotatercept (Amendment 4).
In both Part 1 and Part 2, after completing five cycles of treatment (or up to eight cycles for 
potential late responders), subjects who qualify for the Extension Period (refer to Section 4.1.2)
may enter the Extension Period and continue treatment, subject to Rules for Delay, Reduction, 
and Discontinuation of Treatment (Section 8.2.1), until PD, treatment failure, or other reason, as 
appropriate, listed in Section 12, Discontinuations.
Overview of Procedures
Procedures to be conducted in this study include, but are not limited to, medical history, height, 
record of prior medications and treatments, MDS disease history (including diagnostic, 
karyotype, cytogenetics, and historic mutational analysis information [ie,SF3B1, and other 
MDS-related molecular mutations]), baseline assessments and prior MDS therapy (ie, prior 
ESAs, non-ESA therapy), transfusion log (for collection of all prior transfusions [ie, red blood 
cell, platelets, whole blood, etc]) from at least 12 weeks prior to enrollment, up through 3 months 
post last dose of sotatercept and associated pre-transfusion Hgb levels at closest time prior to 
RBC transfusions, if available, record of prior/current therapies/procedures, record of AEs, 
physical examination, vital signs, weight, blood pressure, electrocardiogram (ECG), Eastern 
Cooperative Oncology Group (ECOG) performance status, hematology, serum chemistry, 
 
, serum erythropoietin, urinalysis, pregnancy testing, PK, ADA, MDS response 
assessment, bone marrow aspirate, smear of peripheral blood, bone marrow biopsy,
.
4.1.2
4.1.2)
ducti
duction, 
on, 
her reason, 
her reason,
med
edical
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S
prior 
rior MDS 
M
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tra
prior to enro
rior to enro
sion 
sio Hgb le
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pressure,
pressure el
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s, pregnan
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r of periph
pi


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TABLE OF CONTENTS
TITLE PAGE..............................................................................................................................1
PROTOCOL SUMMARY ..........................................................................................................6
1.
INTRODUCTION..................................................................................................17
1.1.
Sotatercept for Treatment of Anemia in Lower (Low- or Intermediate-1) 
Risk MDS...............................................................................................................17
1.2.
Sotatercept..............................................................................................................19
1.2.1.
Pharmacology Studies.............................................................................................19
1.3.
Summary of Clinical Experience ............................................................................22
1.3.1.
A011-01:  A Phase 1a Study in Healthy Postmenopausal Women (Single-
Dose)......................................................................................................................22
1.3.2.
A011-02:  A Phase 1b Study in Healthy Postmenopausal Women (Multiple 
Doses) ....................................................................................................................23
1.3.3.
A011-04:  A Phase 2a Study in Patients with Osteolytic Lesions of Multiple 
Myeloma ................................................................................................................25
1.3.4.
A011-08: A Phase 2 Study in Women with Metastatic Breast Cancer with 
Chemotherapy-induced Anemia..............................................................................29
 
1.5.
Rationale for Study.................................................................................................38
1.6.
Summary................................................................................................................38
2.
STUDY OBJECTIVES...........................................................................................41
2.1.
Primary Objective...................................................................................................41
2.2.
Secondary Objectives .............................................................................................41
3.
STUDY ENDPOINTS............................................................................................43
3.1.
Primary Endpoint....................................................................................................43
3.2.
Secondary Endpoints ..............................................................................................43
4.
OVERALL DESIGN OF THE STUDY..................................................................45
4.1.
Design of Study......................................................................................................45
4.1.1.
Dose-limiting Toxicity............................................................................................48
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4.1.2.
Study Periods..........................................................................................................49
4.2.
Rationale for the Design of the Study......................................................................50
4.3.
Duration of the Study..............................................................................................51
4.4.
Steering Committee ................................................................................................51
5.
TABLE OF EVENTS.............................................................................................54
6.
PROCEDURES......................................................................................................59
7.
STUDY POPULATION.........................................................................................65
7.1.
Number of Subjects and Sites .................................................................................65
7.2.
Inclusion Criteria....................................................................................................65
7.3.
Exclusion Criteria...................................................................................................66
8.
DESCRIPTION OF STUDY TREATMENTS........................................................69
8.2.
Treatment Administration and Schedule .................................................................69
8.2.1.
Rules for Delay, Reduction, and Discontinuation of Treatment...............................70
8.3.
Method of Treatment Assignment...........................................................................73
8.3.1.
Part 1......................................................................................................................73
8.3.2.
Part 2......................................................................................................................74
8.4.
Packaging and Labeling..........................................................................................74
8.5.
Investigational Product Accountability and Disposal ..............................................74
8.6.
Investigational Product Compliance........................................................................75
8.7.
Overdose ................................................................................................................75
9.
CONCOMITANT MEDICATIONS AND PROCEDURES....................................76
9.1.
Permitted Concomitant Medications and Procedures...............................................76
9.1.1.
Medications............................................................................................................76
9.1.2.
RBC Transfusions ..................................................................................................76
9.2.
Prohibited Concomitant Medications and Procedures..............................................76
9.3.
Required Concomitant Medications and Procedures................................................76
10.
STATISTICAL ANALYSES..................................................................................77
10.1.
Overview................................................................................................................77
10.2.
Definitions of Study Populations ............................................................................78
10.3.
Sample Size and Power Considerations...................................................................78
10.4.
Background and Demographic Characteristics........................................................79
10.5.
Subject Disposition.................................................................................................79
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10.6.
Analysis of Efficacy ...............................................................................................79
10.7.
Analysis of Safety...................................................................................................81
10.8.
Interim Analysis .....................................................................................................81
10.9.
Pharmacokinetics....................................................................................................82
10.10.
Other Topics...........................................................................................................82
11.
ADVERSE EVENTS..............................................................................................83
11.1.
Monitoring, Recording and Reporting of Adverse Events .......................................83
11.2.
Evaluation of Adverse Events.................................................................................83
11.2.1.
Seriousness.............................................................................................................83
11.2.2.
Severity / Intensity..................................................................................................84
11.2.3.
Causality ................................................................................................................85
11.2.4.
Duration .................................................................................................................85
11.2.5.
Action Taken..........................................................................................................85
11.2.6.
Outcome.................................................................................................................86
11.3.
Abnormal Laboratory Values..................................................................................86
11.4.
Pregnancy...............................................................................................................86
11.4.1.
Females of Childbearing Potential ..........................................................................86
11.4.2.
Male Subjects.........................................................................................................87
11.5.
Reporting of Serious Adverse Events......................................................................87
11.5.1.
Safety Queries ........................................................................................................87
11.6.
Expedited Reporting of Adverse Events..................................................................87
12.
DISCONTINUATIONS .........................................................................................89
13.
EMERGENCY PROCEDURES.............................................................................90
13.1.
Emergency Contact.................................................................................................90
13.2.
Emergency Identification of Investigational Products .............................................90
14.
REGULATORY CONSIDERATIONS...................................................................91
14.1.
Good Clinical Practice............................................................................................91
14.2.
Investigator Responsibilities ...................................................................................91
14.3.
Subject Information and Informed Consent.............................................................91
14.4.
Confidentiality........................................................................................................92
14.5.
Protocol Amendments.............................................................................................92
14.6.
Institutional Review Board/Independent Ethics Committee Review and 
Approval ................................................................................................................92
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4.4.


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14.7.
Ongoing Information for Institutional Review Board / Ethics Committee................93
14.8.
Closure of the Study ...............................................................................................93
15.
DATA HANDLING AND RECORDKEEPING.....................................................94
15.1.
Data/Documents .....................................................................................................94
15.2.
Data Management...................................................................................................94
15.3.
Record Retention....................................................................................................94
16.
QUALITY CONTROL AND QUALITY ASSURANCE........................................96
16.1.
Study Monitoring and Source Data Verification......................................................96
16.2.
Audits and Inspections............................................................................................96
17.
PUBLICATIONS ...................................................................................................97
18.
REFERENCES.......................................................................................................98
19.
APPENDICES......................................................................................................101
Appendix A:
The World Health Organization (WHO) Classification of the Myeloid 
Neoplasms and Leukemia (Vardiman, 2009).........................................................101
Appendix B:
International Prognostic Scoring System for MDS (Greenberg, 1997)..............102
Appendix C:
International Working Group (IWG) Response Criteria in Myelodysplasia 
(Cheson, 2006) .....................................................................................................103
Appendix D:
ECOG Performance Status Scale .....................................................................105
Appendix E:
New York Heart Association ∀Classification of Heart Failure.........................106
Appendix F:
National Cancer Institute (NCI) Common Terminology Criteria for 
Adverse Events (CTCAE) Version 4.0..................................................................107
Appendix H:
Cockcroft-Gault Estimation Of Creatinine Clearance (Crcl).............................109
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LIST OF TABLES
Table 1:
Hemoglobin, Mean Change from Baseline (Study A011-02, a Phase 1b 
Study in Healthy Postmenopausal Women).............................................................24
Table 2:
Adverse Events Reported in ≥ 5 % Percent of Subjects Overall (Study A011-
04)..........................................................................................................................27
Table 4:
Number of Subjects with an Increase in Hgb from Baseline at Any Time and 
Sustained for ≥ 28 Days (Study A011-04)...............................................................28
Table 5:
Primary Efficacy Analysis: Subjects with Hemoglobin Increase from 
Baseline of at Least 1 g/dL for 28 Consecutive Days – Per Protocol Set, 
Central Laboratory Results (Study A011-08) ..........................................................30
Table 7:
Schedule of Assessments........................................................................................54
Table 8:
Rules for Delay, Reduction, and Discontinuation of Treatment...............................71
Table 9:
Sotatercept Dose Reduction Levels.........................................................................72
Table 10:
95% Confidence Intervals for Selected Sample Sizes and Response Rates ..............78
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LIST OF FIGURES
 
 
 
 
 
Figure 4:
Design of Study......................................................................................................46
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1.
INTRODUCTION
Myelodysplastic syndromes (MDS) are a spectrum of hematologic malignancies characterized 
pathologically by presence of morphologic dysplasia and clinically by bone marrow failure 
resulting in persistent and progressive cytopenias. There is considerable variation in both the 
clinical manifestation and severity of individual disorders within this group, ranging from the 
relatively mild and painless condition of refractory anemia (RA) to the much more severe 
refractory anemia with an excess of blasts (RAEB) that often progresses to acute leukemia 
(Heaney, 1999).  The current treatment algorithm is based dominantly on risk stratification using 
the International Prognostic Scoring System (IPSS, Appendix B, Greenberg, 1997). In patients 
with low- or intermediate-1 (int-1) risk groups by IPSS the goal of treatment is alleviation of 
cytopenias (Komrokji, 2011).
More than 90% of patients diagnosed with MDS will have anemia during their course of disease; 
and 30%-50% of patients will be transfusion-dependent. Red blood cell (RBC) transfusion 
dependence is an independent adverse prognostic factor in MDS (Komrokji, 2011).  Anemia in 
MDS results from ineffective erythropoiesis. Accelerated apoptosis is the hallmark of early 
disease, while up-regulation of survival signals and clonal evolution are features of higher risk 
disease. Impaired clonogenic growth of primitive erythroid progenitors and impaired 
erythropoietin receptor signaling are major causes of anemia. Inflammatory cytokines and 
immune suppression within the microenvironment amplify accelerated apoptosis and the inherent 
defective erythroid maturation. Options for treating anemia in low- or int-1 risk MDS are 
limited. Erythroid-stimulating agents (ESAs) offer response rates of 20%-40%. Lenalidomide,
in non-deletion (5q) (non-del [5q]), lower risk MDS transfusion independence (TI), response 
rates are 26% with TI response duration less than a year (Raza, 2008). Azacitidine and 
decitabine yield hematological improvements in approximately 40% of patients; however, most 
patients’ responses are typically of short duration. Although bone marrow transplantation 
(BMT) can cure low and int-1 risk MDS, given the advanced age and greater incidence of co-
morbidities in patients with MDS the significant morbidity and mortality associated with BMT 
does not allow such treatment in the majority of patients.  The vast majority of patients with low-
or int-1 risk MDS will remain RBC transfusion-dependent and succumb from complications of 
the disease or iron overload rather than progression of the disease. There is an unmet need to 
develop novel agents for treating anemia in lower risk non-del (5q) MDS (Komrokji, 2011).
1.1.
Sotatercept for Treatment of Anemia in Lower (Low- or
Intermediate-1) Risk MDS
Treatment with sotatercept resulted in increased hematocrit (HCT), hemoglobin (Hgb), and 
absolute RBC number in both nonclinical and clinical studies.  The rapid and sustained increases 
in Hgb and HCT were observed in two Phase 1 studies in healthy volunteers, a Phase 2a study in 
subjects with multiple myeloma (MM), and a Phase 2 study in subjects with breast cancer. The 
ability for sotatercept to increase rapidly and sustain Hgb in subjects with anemia supports the 
clinical development of sotatercept for the treatment of anemia associated with lower risk MDS.
In Phase 1 single-dose and multiple-dose studies of sotatercept in postmenopausal women 
(Studies A011-01 and A011-02, respectively), a Phase 2 study in subjects with osteolytic lesions 
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associated with MM that examined concurrent administration of sotatercept with melphalan, 
prednisolone, and thalidomide (MPT) anti-myeloma therapy (Study A011-04), and a Phase 2 
study in subjects with breast cancer, increases in Hgb, RBC count, and HCT were observed 
following treatment with sotatercept, and these increases remained detectable throughout the 
course of study.  The observed Hgb, RBC count, and HCT effects of sotatercept were dose-
dependent and time-dependent.  These Phase 1 and Phase 2 clinical data are consistent with the 
increased hematologic parameters observed in nonclinical studies. Results from the four 
completed clinical studies A011-01, A011-02, A011-04, and A011-08 are summarized in the
Section 1.3, Summary of Clinical Experience.
Although the mechanism(s) underlying the stimulatory effect of sotatercept on erythropoiesis is
not fully understood, the result of clinical experience in healthy subjects showed a rapid and 
sustainable increase in mature erythrocytes released into circulation, suggesting that this impacts 
late stages of erythropoeisis.  
 
 
  
 
 
Activin Receptor Signaling
The activins (A-E) are a group of proteins that form dimers and heterodimers.  All are part of the 
superfamily of transforming growth factor-β (TGF-β) proteins.  The activin first described, 
activin A was initially identified as a gonadal differentiation factor involved in modulating 
secretion of follicle-stimulating hormone (FSH) from the pituitary (Ying, 1988).  Subsequently, 
the pleiotropic nature of activin A has become more apparent (Woodruff, 1998).  There is a 
growing body of data suggesting a role for activins in bone remodeling, specifically as a negative 
regulator of bone growth (Perrien, 2007).  Before the two molecules were shown to be identical 
(Rivier, 1985), activin A was also described as erythroid differentiation factor (EDF), effecting 
the maturation and differentiation of RBCs (Murata, 1988).  The mechanism(s) by which activin 
A influences erythropoiesis remains under investigation and, in fact, there are data from in vitro 
and in vivo studies that support erythropoiesis-stimulatory (Shiozaki, 1992; Shiozaki, 1989) and 
erythropoiesis-inhibitory effects (Nakao, 1991).
The high-affinity activin type II receptor (ActRIIA) binds a number of ligands in the TGF-β
superfamily including activins A and B, myostatin, and other growth differentiation factors 
(GDFs), as well as a number of the bone morphogenetic protein (BMP) family members.  The 
ligand-bound ActRIIA then recruits the low-affinity Type I receptor (ActRIA or ALK-4) and 
then the receptor heterocomplex, through its cytoplasmic protein kinase activity, activates the 
SMAD signaling cascade to eventually influence nuclear transcriptional factors (Chen, 2002; 
Mathews, 1994).  The competitive binding of activin receptor ligands in the blood and tissues by 
the sotatercept soluble fusion protein can result in inhibition of the ActRIIA receptor 
 
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1.2.
Sotatercept
Sotatercept (ActRIIA-IgG1Fc) is a fusion protein consisting of the extracellular domain (ECD) 
of activin receptor IIA (ActRIIA) fused to the human IgG1 Fc domain, which includes the heavy 
chain hinge and constant domains CH2 and CH3.  The ECD sequence of ActRIIA is completely 
conserved among numerous species including mouse, rat, cynomolgus monkey, and humans;
thus mouse, rat, and cynomolgus monkeys have been considered relevant species for nonclinical 
evaluation of sotatercept. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
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ACE-011-MDS-001 Amendment 4 Final: 04 Aug 2015
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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ACE-011-MDS-001 Amendment 4 Final: 04 Aug 2015
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
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ACE-011-MDS-001 Amendment 4 Final: 04 Aug 2015
 
 
 
 
 
 
 
 
1.3.
Summary of Clinical Experience
1.3.1.
A011-01:  A Phase 1a Study in Healthy Postmenopausal Women (Single-Dose)
Sotatercept was first studied in a Phase 1a, single center, randomized, double-blind, placebo-
controlled, single-dose, dose-escalation study in healthy, postmenopausal women (Ruckle, 
2009).  Sotatercept was diluted in normal saline was administered as an IV infusion (over 
approximately 1 hour) or as a SC injection on Day 1.  Dose levels were 0.01, 0.03, 0.1, 0.3, 1.0, 
and 3.0 mg/kg IV and 0.03 and 0.1 mg/kg SC.  A total of 48 subjects were enrolled; five active 
and one placebo subject at each of the IV and SC dose levels.  All subjects were followed for 4
months following a single-dose administration.  
The pharmacokinetic (PK) profile of sotatercept was linear.  The overall mean exposure (AUC) 
was proportional to doses (0.01 to 3.0 mg/kg IV, and 0.03 and 0.1 mg/kg SC).  Across IV doses 
ranging from 0.1 through 3.0 mg/kg, the mean CL ranged from 0.092 to 0.128 mL/h/kg, the 
volume of distribution ranged from 73.7 to 110 mL/kg, and the mean terminal half-life in serum 
(t1/2, z) ranged from 23.7 to 31.8 days, with no apparent dependence on dose.  After SC 
administration of 0.03 and 0.1 mg/kg, sotatercept was completely absorbed, and the mean t1/2, z 
was approximately 30 days, with no apparent dependence on dose.
The most commonly occurring (ie, those occurring in more than 1 subject in any treatment 
group) treatment-emergent adverse events (AEs) were headache, infusion site reaction, injection 
site hemorrhage, and toothache.  The majority of the injection site reactions and injection site 
hemorrhages were in the first IV cohort and were related to infiltration of the IV site.  The 
majorities of treatment-emergent AEs were mild in severity and were judged to be unrelated to 
sotatercept.  No death, serious AE (SAE), or AE leading to discontinuation was reported.  
Changes in RBCs, Hgb, reticulocytes, liver function tests, glucose, uric acid, amylase, and lipase 
occurred in some subjects.  Mild, transient elevations in pancreatic enzymes, liver enzymes, or 
glucose were reported as AEs in five subjects.  
There were no clinically significant changes from baseline in vital signs, physical examination, 
endocrine function, or electrocardiogram (ECG).  Preservation of adrenal cortical function was 
monitored through evaluation of serum electrolytes (sodium and potassium) and through cortisol 
response to adrenocorticotropic hormone (ACTH) stimulation.  
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Sotatercept (ACE-011)
Protocol ACE-011-MDS-001
Celgene Corporation
Confidential and Proprietary
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ACE-011-MDS-001 Amendment 4 Final: 04 Aug 2015
No clinically significant finding was observed at doses up to 3.0 mg/kg IV, and sotatercept was 
well tolerated in healthy, postmenopausal women in single doses up to 0.1 mg/kg SC and 3.0 
mg/kg IV, the highest dose tested in this study.  
1.3.2.
A011-02:  A Phase 1b Study in Healthy Postmenopausal Women (Multiple 
Doses)
Study A011-02 was a Phase 1b, single-center, randomized, double-blind, placebo-controlled, 
multi-dose, dose-escalation study to evaluate the safety, tolerability and pharmacodynamics of 
sotatercept in healthy postmenopausal women.  Four cohorts of 10 subjects each were planned at 
the following doses: 0.1, 0.3, 1.0, and 2.0 mg/kg administered SC.  Within each cohort, subjects 
were to be randomized to either active or placebo treatment in an 8:2 ratio.  Subjects were to 
receive one SC injection of sotatercept or placebo every 28 days for a total of four doses.  All 
subjects were to be followed for 12 weeks after the last dose.
The treatment phase of the study was terminated early after a treatment-related SAE was 
attributed to a dose-limiting pharmacodynamic effect.  While on study, one subject in the 
1.0 mg/kg cohort experienced an SAE of progressive and persistent hypertension that was 
attributed to a rapid and significant increase in both Hgb (up to 20 g/dL) and HCT (up to 57.3%).  
Due to symptoms of headache, nausea, eye pain, dizziness, and vomiting approximately 1 week 
following the second dose, the subject was hospitalized for monitoring and evaluation of Grade 2 
hypertension.  Head magnetic resonance imaging (MRI), fundoscopy, and ECG were performed 
and were reported as normal. The hypertension was monitored and initially managed with 
antihypertensive medication.  The headache resolved following corrective treatment by 
phlebotomy.  The SAE resolved on Day 3 after the detection of hypertension and the subject was 
discharged from the hospital the following day.  The hypertension resolved by the end of the
study without need of antihypertensive medication.  For headaches, the subject received aspirin 
prophylactically until the end of the study and continued taking ibuprofen as needed.  Further 
details can be found in the Investigator’s Brochure. In addition, two subjects who were treated 
with sotatercept 1.0 mg/kg showed increases in Hgb but were asymptomatic at the time of the 
consultation and underwent prophylactic phlebotomies.
Based on the magnitude of the hematopoietic response, the Sponsor suspended dose escalation to 
the 2.0 mg/kg dose and further dosing in all cohorts as a result of this dose-limiting SAE of 
hypertension, attributed to a pharmacodynamic effect at the 1.0 mg/kg dose level.  A total of 31 
subjects were enrolled and treated.  Doses of sotatercept administered included 0.1, 0.3, and 1.0 
mg/kg (Cohorts 1, 2, and 3 respectively).  All subjects randomized to active treatment in Cohort 
1 received all four planned doses of sotatercept.  Due to early discontinuation of IP, subjects 
randomized to active treatment in Cohort 2 received three doses of sotatercept, and subjects 
randomized to active treatment in Cohort 3 received two doses of sotatercept.  Subjects 
randomized to placebo treatment received between one to four doses of study treatment. 
Following administration of the first dose, dose- and time- dependent increases in Hgb, HCT, 
and RBCs were observed (see Table 1 below for changes in Hgb):
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Sotatercept (ACE-011)
Protocol ACE-011-MDS-001
Celgene Corporation
Confidential and Proprietary
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ACE-011-MDS-001 Amendment 4 Final: 04 Aug 2015
Table 1:
Hemoglobin, Mean Change from Baseline (Study A011-02, a Phase 1b Study 
in Healthy Postmenopausal Women)
Evaluation Time Point
Mean Change from Baseline (g/dL)
Placebo
(N=7)a
Sotatercept
0.1 mg/kg
(N=8)
Sotatercept
0.3 mg/kg
(N=8)
Sotatercept
1.0 mg/kg
(N=8)
Baseline Mean, pre-Dose 1
13.20
13.11
13.30
12.71
Day 8
0.17
0.68
0.85
1.21
Day 15
-0.27
0.43
0.44
1.75
Day 29
0.27
0.61
1.21
2.68b
Day 36
0.56
0.64
1.89
2.96
Day 43
-0.02
0.89
1.21
2.85
Day 57
0.27
1.28
1.64b
2.09
Day 64
0.53
1.11
2.49
2.21
Day 71
-0.10
1.34
2.09
1.66
Day 85
0.38
1.18b
2.55
1.86
Day 92
0.00c
1.04
1.60c
3.80c
Day 99
-0.20
1.21
3.20c
1.28c
Day 113
-0.02
1.30
1.29
1.04
Day 141
0.30
0.95
0.34
2.30
Day 169
0.20c
0.06
-
2.00c
a The number of placebo subjects with data decreases over time as a result of the early termination of the study (ie, 
there were placebo subjects in each dosing cohort).  There were seven placebo subjects with data at baseline, Days 
8, 15, and 36; six subjects with data at Days 29, 43, 57, and 85; five subjects with data on Days 71 and 113; four 
subjects with data on Day 64; three subjects with data on Day 141; two subjects with data on Day 99; and one 
subject with data on Days 92 and 169.
b Number of doses administered per treatment group:  0.1 mg/kg, four doses; 0.3 mg/kg, three doses; 1.0 mg/kg, two 
doses.  Data beyond this study day were considered follow-up results.
c n=1.
- Data not available.
Source: CSR A011-02 in-text Table 9.
Other than the SAE of Hgb increase, no life-threatening event was reported.  The most notable 
AEs were those related to increases in hematologic laboratory measures in the 1.0 mg/kg dose 
group: HCT, Hgb, and RBC count.  The AEs of increased Hgb and/or HCT were reported for 
seven of the eight subjects in this dose group.  These events were reported as mild or moderate 
elevations; all were considered probably related to study drug treatment.  Three of the subjects in 
the 1.0 mg/kg group with elevated Hgb underwent phlebotomies and all Hgb elevations resolved 
by the end of the follow-up period.  No erythroid lineage AEs were reported in the 0.1 or 0.3 
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Sotatercept (ACE-011)
Protocol ACE-011-MDS-001
Celgene Corporation
Confidential and Proprietary
25
ACE-011-MDS-001 Amendment 4 Final: 04 Aug 2015
mg/kg treatment groups.  Hemoglobin for all subjects with elevations returned to within normal 
limits by the end of the study.  
Paresthesia and dizziness were reported more frequently in the sotatercept groups, though the 
events were < Grade 2 and generally not considered drug related.  Other frequently reported 
events (eg, fatigue, upper respiratory infection) did not appear to increase with dose and were 
generally mild.  
Adrenal cortical function was monitored through evaluation of serum electrolytes (sodium and 
potassium) and through cortisol response to ACTH stimulation.  All ACTH stimulation test 
results were normal.  
The PK profile of sotatercept was linear after SC administration.  Both AUC0-28d and maximum 
concentration (Cmax) were dose proportional from 0.1 to 1.0 mg/kg following the first SC 
administration.  The t1/2, z of sotatercept following the last dose in all three dose groups was 
identical, with mean t1/2, z being approximately 23 days.  Based on one-compartmental modeling, 
the mean apparent total clearance (CL/F) ranged from 3.05 to 3.90 mL/d/kg and the mean 
apparent volume of distribution (Vz/F) ranged from 97.47 to 103.03 mL/kg, with no apparent 
dependence on dose.  
Bone mineral density was assessed by dual-energy X-ray absorptiometry (DXA).  A 
dose-dependent increase in the BMD of the total hip from baseline to end of study was observed, 
with a significant and rapid increase of 2.4% in the 1.0 mg/kg dose group, compared to a 0.7% 
decrease in the placebo group.  Bone mineral density results for lumbar spine showed slight 
increases of 0.4% to 1.0% from baseline to study end in all active treatment groups, compared 
with a 0.5% decrease in the placebo group.
1.3.3.
A011-04:  A Phase 2a Study in Patients with Osteolytic Lesions of Multiple 
Myeloma 
Study A011-04 was a Phase 2a, multi-center, randomized, double-blind, placebo-controlled, 
multiple-dose, parallel group, dose-escalation study to evaluate the safety, tolerability, and 
efficacy of sotatercept in subjects with osteolytic lesions of MM.  
In this study, subjects were randomized in a 4:1 ratio to one of three doses of sotatercept (0.1, 
0.3, and 0.5 mg/kg) or placebo, administered every 28 days by SC injection, for up to four doses 
over a 3-month period. Sotatercept was evaluated in combination with the anti-myeloma therapy 
of melphalan (4 mg/m2 on Days 1 to 7), prednisolone (40 mg/m2 on Days 1 to 7), and 
thalidomide (100 mg per day) (MPT). The sites, Sponsor and Sponsor representatives were 
blinded to treatment assignment.  
Thirty subjects were randomized and received at least one dose of study treatment: six subjects 
received placebo, 24 subjects received sotatercept (eight subjects per dosing cohort [0.1, 0.3, and 
0.5 mg/kg sotatercept]).  Twenty-six (86.7%) subjects completed the study.  Two subjects 
discontinued study treatment due to AEs, including one subject in each of the 0.1 and 0.5 mg/kg 
dose groups.  Two subjects discontinued study treatment due to non-AE reasons including one 
subject in the 0.1 mg/kg dose group who withdrew consent and was discontinued, and one 
subject in the 0.3 mg/kg dose group who was discontinued at the request of the investigator.  
In this study, 50.0% of subjects were female and the mean (range) age was 60.9 (41 to 79) years.  
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bje


Sotatercept (ACE-011)
Protocol ACE-011-MDS-001
Celgene Corporation
Confidential and Proprietary
26
ACE-011-MDS-001 Amendment 4 Final: 04 Aug 2015
The mean time since diagnosis of MM was 3.3 years, the majority of subjects had stage III MM 
disease at screening (83.3%) and had received prior chemotherapy (93.3%).  A total of 43.3% of 
subjects were receiving bisphosphonates at screening, which continued during the study.  
Fourteen out of 24 subjects (58%) who received sotatercept received three doses or more (four 
out of eight subjects in the 0.5 mg/kg dose cohort, five out of eight subjects in the 0.3 mg/kg 
dose cohort, and five out of eight subjects in the 0.1 mg/kg dose cohort).  
 
 
 
 
 
 
 
 
 
Table 2 summarizes the most frequent AEs ≥5% in all treatment groups 
 
  
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Sotatercept (ACE-011)
Protocol ACE-011-MDS-001
Celgene Corporation
Confidential and Proprietary
27
ACE-011-MDS-001 Amendment 4 Final: 04 Aug 2015
Table 2:
Adverse Events Reported in ≥ 5 % Percent of Subjects Overall
(Study A011-04)
Sotatercept Treatment Group
Placebo
(N=6)
0.1 mg/kg
(N=8)
0.3 mg/kg
(N=8)
0.5 mg/kg
(N=8)
All Sotatercept
(N=24)
Preferred 
Terma
Any 
Grade
Grade ≥3
Any 
Grade
Grade ≥3
Any 
Grade
Grade ≥3
Any
Grade
Grade ≥3
Any
Grade
Grade ≥3
Subjects with 
≥one AE
1 (16.7%)
5 (62.5%)
3 (37.5%)
7 (87.5%)
15 (62.5%)
Neutropenia
1 (16.7%)
2 (25.0%)
2 (25.0%)
3 (37.5%)
7 (29.2%)
Leukopenia
0 (0.0%)
1 (12.5%)
0 (0.0%)
1 (12.5%)
2 (8.3%)
Granulo-
cytopenia
0 (0.0%)
1 (12.5%)
1 (12.5%)
1 (12.5%)
3 (12.5%)
Anemia
0 (0.0%)
1 (12.5%)
1 (12.5%)
1 (12.5%)
3 (12.5%)
RTI
0 (0.0%)
1 (12.5%)
0 (0.0%)
0 (0.0%)
1 (4.2%)
Thrombo-
cytopenia
0 (0.0%)
0 (0.0%)
0 (0.0%)
1 (12.5%)
1 (4.2%)
Pyrexia
0 (0.0%)
0 (0.0%)
0 (0.0%)
0 (0.0%)
0 (0.0%)
BP increased
0 (0.0%)
1 (12.5%)*
0 (0.0%)
0 (0.0%)
1 (4.2%)
Bronchitis
0 (0.0%)
0 (0.0%)
0 (0.0%)
0 (0.0%)
0 (0.0%)
Compression 
fracture
0 (0.0%)
0 (0.0%)
0 (0.0%)
0 (0.0%)
0 (0.0%)
Pathological 
fracture
0 (0.0%)
0 (0.0%)
0 (0.0%)
1 (12.5%)
1 (4.2%)
BP = blood pressure; RTI = respiratory tract infection.
a Adverse events (AEs) were those that were treatment-emergent, defined as newly acquired or worsened during or after 
administration of first dose of study treatment. A subject with multiple occurrences of an AE counted only once under each 
preferred term. 
* Indicates the adverse event was assessed by the investigator as related (possibly, probably, or definitely) to study drug 
(sotatercept or placebo).  
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Sotatercept (ACE-011)
Protocol ACE-011-MDS-001
Celgene Corporation
Confidential and Proprietary
28
ACE-011-MDS-001 Amendment 4 Final: 04 Aug 2015
Increases in Hgb were observed within 28 days after administration of the first dose of 
sotatercept/placebo and sustained for ≥ 28 days from baseline at any time as presented in 
Table 4.
Table 4:
Number of Subjects with an Increase in Hgb from Baseline at Any Time and 
Sustained for ≥28 Days (Study A011-04)
Increase in 
Hemoglobin
Dose Sotatercept/Placebo
0.1 mg/kg
(N=8)
0.3 mg/kg
(N=8)
0.5 mg/kg
(N=8)
Placebo
(N=6)
Overall
(N=30)
≥1.0 g/dL
5
3
7
4
19
≥1.5 g/dL
3
3
5
2
13
≥2.0 g/dL
2
3
2
0
7
Source: Table 14.3.2.7, Clinical Study Report A011-04.
Improvements in hip bone mineral density were observed in selected sotatercept dose groups. A 
mean percentage increase from baseline in hip BMD was observed in the 0.1 mg/kg and 0.3 
mg/kg sotatercept dose groups at Days 85 and 169/early termination; whereas, the placebo group 
showed a mean percentage decrease at both time points.
As with serum bone biomarkers, the BMD results tended to be more variable in subjects who 
were on bisphosphonates. In subjects who were not taking bisphosphonates, a maximum mean 
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Sotatercept (ACE-011)
Protocol ACE-011-MDS-001
Celgene Corporation
Confidential and Proprietary
29
ACE-011-MDS-001 Amendment 4 Final: 04 Aug 2015
percent increase was observed for most BMD parameters (total, hip, and lumbar spine) in most 
sotatercept dose groups; whereas, there was a maximum mean percent decrease in the placebo 
group.  Further, substantial improvements in BMD were observed in some subjects, and these 
improvements were more likely to occur in subjects who received the full course of sotatercept 
treatment.  Review of individual data showed that 8/24 (33.3%) subjects who received 
sotatercept had a ≥ 5% increase from baseline in spine or femur BMD at one or more time points 
during the study period.  Further, a ≥ 5% increase in BMD was observed in 4/6 subjects who 
received all four sotatercept doses versus 2/8 subjects who received three doses and 2/10 subjects 
who received one or two doses.  One of 6 (16.7%) subjects who received placebo also showed a 
≥ 5% increase in spine or femur BMD during the study period.
Taken together, these data, suggest a beneficial pharmacodynamic effect of sotatercept on 
erythropoiesis in a patient population with cancer CIA.
1.3.4.
A011-08: A Phase 2 Study in Women with Metastatic Breast Cancer with 
Chemotherapy-induced Anemia
Study A011-08 was a Phase 2, double-blind, randomized, placebo-controlled study to evaluate 
the efficacy, safety, and tolerability of sotatercept for the treatment of CIA in women with 
metastatic breast cancer. Subjects were randomized to one of three sotatercept (0.1, 0.3, and 
0.5 mg/kg) treatment groups or to a placebo treatment group. Planned enrollment included 
30 subjects in each of the three sotatercept treatment groups and 15 subjects in the placebo 
treatment group (2:2:2:1 ratio). Study treatment was administered via SC injection every 
28 days for up to 4 treatments (Days 1, 29, 57, and 85). Subjects were administered concurrent 
treatment with a myelosuppressive chemotherapy regimen for metastatic breast cancer per 
standard of care at the study site.
Due to changes in guidance for the treatment of CIA and a slower than expected rate of 
enrollment, the study was terminated after 30 subjects were enrolled. All 30 subjects had been 
administered at least one dose of treatment: five subjects in the placebo treatment group, eight 
subjects in the sotatercept 0.1 mg/kg treatment group, 10 subjects in the sotatercept 0.3 mg/kg 
treatment group, and seven subjects in the sotatercept 0.5 mg/kg treatment group. The majority 
of subjects (29/30 [96.7%]) were white; all of the subjects were female; with a median age of 51 
years; and age ranged from 32 to 74 years. Demographic characteristics were similar across 
treatment groups.
Fourteen of 30 (46.7%) subjects completed study treatment. Fourteen subjects in the three 
sotatercept treatment groups combined and two subjects in the placebo treatment group 
prematurely discontinued study treatment. Of the 16 subjects who withdrew during the treatment 
period, eight subjects (50.0%) discontinued due to PD, four subjects (25.0%) withdrew consent, 
three subjects (18.8%) discontinued due to an AE, and one subject (6.3%) discontinued due to 
administration of an ESA.
Of the 25 subjects in the three sotatercept treatment groups combined, four (16.0%) were 
administered the planned four doses of study treatment. In the 0.1 mg/kg, 0.3 mg/kg, and 
0.5 mg/kg treatment groups, respectively, 1/8 (12.5%), 3/10 (30.0%), and 0/7 (0.0%) subjects 
were administered all four doses of sotatercept. Fourteen of 25 (56.0%) subjects in the three 
sotatercept treatment groups combined skipped and/or had at least one dose modification during 
the treatment period. One of five (20.0%) subjects in the placebo treatment group was 
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administered all four doses, and 3/5 (60.0%) subjects had skipped a dose and/or had a single dose 
modified during the treatment period.
The primary efficacy endpoint was the rate of hematopoietic response, defined as the proportion 
of subjects who demonstrated a Hgb increase ≥ 1 g/dL from baseline for 28 consecutive days up 
to two months after the last dose of study treatment, in the absence of RBC transfusion or 
treatment with an ESA (Table 5).
Table 5:
Primary Efficacy Analysis: Subjects with Hemoglobin Increase from 
Baseline of at Least 1 g/dL for 28 Consecutive Days – Per Protocol Set, 
Central Laboratory Results (Study A011-08)
Sotatercept Treatment Group
Placebo
(N=5)
0.1 mg/kg
(N=5)
0.3 mg/kg
(N=9)
0.5 mg/kg
(N=4)
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Sotatercept
(N=18)
Responder
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0 (0.0%)
3 (33.3%)
2 (50.0%)
5 (27.8%)
Nonresponder
4 (80.0%)
5 (100%)
6 (66.7%)
2 (50.0%)
13 (72.2%)
Five of the 18 (27.8%) subjects in the three sotatercept (0.1, 0.3, and 0.5 mg/kg) treatment 
groups combined demonstrated a response (ie, were responders). One of five (20.0%) subjects in 
the placebo group demonstrated a response. Response rates among subjects in the sotatercept 
0.3 mg/kg (33%) and 0.5 mg/kg (50%) treatment groups were greater than those in the 
sotatercept 0.1 mg/kg (0%) and placebo (20%) treatment groups, and suggest a possible 
sotatercept dose-response relationship.
 
 
 
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Assessments of safety in this study were consistent with the known profile of safety of 
sotatercept. Overall, 20 of 25 (80.0%) subjects in the three sotatercept treatment groups 
combined and all five (100%) subjects in the placebo treatment group reported ≥ 1 AE. Most 
AEs were assessed by the investigator as unrelated to study treatment. There were no 
hypertension or thromboembolic events reported as AEs in subjects administered sotatercept.
 
 
 
 
 
 
The results of this study suggest that sotatercept is safe and demonstrates hematopoietic activity 
when administered as repeated doses of 0.1, 0.3, or 0.5 mg/kg administered every 28 days for the 
treatment of CIA in subjects with metastatic breast cancer. These findings are consistent with a 
robust hematopoietic response following each repeated treatment of sotatercept at doses of 0.3 or 
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Sotatercept (ACE-011)
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ACE-011-MDS-001 Amendment 4 Final: 04 Aug 2015
0.5 mg/kg, but also indicate that responses decline during the intervals between repeated 
treatments. These data suggest that a shorter dosing interval might result in a more sustained 
hematopoietic response and provide a rationale for a dosing interval of less than 28 days.
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Protocol ACE-011-MDS-001
Celgene Corporation
Confidential and Proprietary
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ACE-011-MDS-001 Amendment 4 Final: 04 Aug 2015
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Sotatercept (ACE-011)
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Celgene Corporation
Confidential and Proprietary
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ACE-011-MDS-001 Amendment 4 Final: 04 Aug 2015
 
 
 
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Protocol ACE-011-MDS-001
Celgene Corporation
Confidential and Proprietary
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Sotatercept (ACE-011)
Protocol ACE-011-MDS-001
Celgene Corporation
Confidential and Proprietary
37
ACE-011-MDS-001 Amendment 4 Final: 04 Aug 2015
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Sotatercept (ACE-011)
Protocol ACE-011-MDS-001
Celgene Corporation
Confidential and Proprietary
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ACE-011-MDS-001 Amendment 4 Final: 04 Aug 2015
 
 
 
 
 
1.5.
Rationale for Study
In normal hematopoiesis, TGF-β inhibits proliferation of hematopoietic stem cells (Sitnicka, 
1996), and negatively regulates erythropoiesis (Zermati, 2000a; Zermati, 2000b).  Because TGF-
β signaling generally has a negative effect on cell growth, inactivation of this pathway may 
prevent suppression of primary hematopoietic stem cells and facilitate terminal erythroid 
maturation.  Increased plasma concentrations of TGF-β, and upregulation and overactivation of 
SMAD2, have been reported in bone marrow progenitors in patients with MDS and provide 
evidence of activation of sustained TGF-β signaling in MDS (Zhou, 2011).  Thus, activation of 
SMAD2 by TGF-β signaling may be an important event in ineffective hematopoiesis, and 
inhibition of SMAD2 could stimulate hematopoiesis from primary MDS progenitors.  Evidence 
to support this concept is provided in the observation that in vivo administration of LY-2157299, 
an antagonist of TGF-β receptor I kinase, improved anemia in a transgenic mouse model 
overexpressing TGF-β and stimulated hematopoiesis in bone marrow from patients with MDS 
(Zhou, 2011).  
 
 
 
 
 
 
 
 
 
  
Sotatercept has the potential to provide benefit in a variety of conditions in which ineffective 
erythropoiesis contributes significantly to anemia and overall disease morbidity, including MDS.  
The ability of sotatercept to rapidly increase and sustain Hgb concentrations in anemic patients 
supports the clinical development of sotatercept for the treatment of patients with anemia 
associated with MDS.
1.6.
Summary
Based on the safety data from the two completed Phase 1 studies, single doses of sotatercept up 
to 3.0 mg/kg IV and multiple doses of sotatercept up to 0.3 mg/kg SC were generally well-
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Sotatercept (ACE-011)
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tolerated in healthy postmenopausal women.  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
Additionally, preliminary review of available safety data from ACE-011-MDS-001 in the 
0.1 mg/kg, 0.3 mg/kg, 0.5 mg/kg, and 1.0 mg/kg dose levels shows a benign safety profile 
consistent with the known safety profile of sotatercept, with no new safety signals identified.  
Furthermore, analysis of clinical and PK/PD data from completed studies at single dose levels up 
to 3.0 mg/kg IV (A011-01) and multi-dose levels up to 1.0 mg/kg SC (A011-02) in regards to 
dose required for a sustained hemoglobin increase, support exploration of dose levels up to 
2.0 mg/kg.
ACE-011-MDS-001 includes strict monitoring procedures to ensure that safety is appropriately 
and adequately monitored and would continue at dose levels up to 2.0 mg/kg. They include a 
Steering Committee that will closely monitor safety and efficacy data throughout study conduct, 
weekly hemoglobin and blood pressure monitoring required per protocol, specific dose 
reduction/modification/discontinuation guidelines and clearly-defined dose-limiting toxicity 
definitions to ensure safety is adequately assessed at all dose levels prior to each treatment 
administration.
As with all biologics, there is the potential for anti-drug antibodies that can be associated with 
increased drug clearance and hypersensitivity reaction.  Celgene will monitor the data and 
communicate to Investigators any new findings.  Investigators should monitor subjects for signs 
and symptoms of injection site and hypersensitivity reactions.  Treat injection site and 
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Sotatercept (ACE-011)
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Celgene Corporation
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ACE-011-MDS-001 Amendment 4 Final: 04 Aug 2015
hypersensitivity reactions according to your standard of care.  Sotatercept should not be 
administered to any subject who develops hypersensitivity to sotatercept.
Please refer to the Investigator Brochure for additional detailed information on the 
pharmacology, toxicology, drug metabolism, clinical studies, and AE profile, of sotatercept.
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Sotatercept (ACE-011)
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Celgene Corporation
Confidential and Proprietary
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ACE-011-MDS-001 Amendment 4 Final: 04 Aug 2015
2.
STUDY OBJECTIVES
2.1.
Primary Objective
The primary objective of this study is to determine a safe, tolerable, and effective dose of 
sotatercept that results in the greatest frequency of erythroid hematological improvement (HI-E)
in patients with anemia and low- or int-1 risk MDS or non-proliferative CMML.
2.2.
Secondary Objectives
The secondary objectives of this study are to evaluate the:
1. Safety of sotatercept
2. Rate of RBC transfusion independence in transfusion-dependent subjects
3. Time to HI-E
4. Duration of HI-E
5. Time to progression to acute myeloid leukemia (TPAML)
6. Time to progression to events of higher risk MDS (TTPHR) (ie, int-2 or high risk IPSS)
7. Progression-free survival (PFS)
8. Overall survival (OS)
9. Pharmacokinetics (PK) of sotatercept
 
 
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Sotatercept (ACE-011)
Protocol ACE-011-MDS-001
Celgene Corporation
Confidential and Proprietary
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ACE-011-MDS-001 Amendment 4 Final: 04 Aug 2015
 
 
 
 
 
 
 
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ACE-011-MDS-001 Amendment 4 Final: 04 Aug 2015
3.
STUDY ENDPOINTS
3.1.
Primary Endpoint
The primary endpoint of this study is the rate of HI-E (Appendix C) starting before the 
completion of five cycles of treatment. Subjects who have a sustained Hgb increase or a 
decreased transfusion burden by the end of Cycle 5 but for a period less than or equal to 8 
consecutive weeks (potential late responders) may continue treatment for up to an additional 
three cycles (Cycles 6-8) for the purpose of meeting response criteria.
#
HI-E [(for subjects that require a transfusion of < 4 units of RBCs) in the 8 weeks 
prior to randomization (Part 1) or start of therapy (Part 2)] is an increase ≥1.5 g/dL 
Hgb sustained over a period ≥8 weeks in the absence of RBC transfusion; or
#
HI-E [(for subjects that require a transfusion of ≥4 units of RBCs) in the 8 weeks 
prior to randomization (Part 1) or start of therapy (Part 2)] is a decrease ≥4 units of 
RBCs transfused over a period of 8 weeks, relative to the number of units of RBCs 
transfused in the 8 weeks immediately prior to Day 1.
3.2.
Secondary Endpoints
The secondary endpoints of this study are:
1. Safety of sotatercept ∀based upon assessments listed in Section 10.7.
2. RBC transfusion independence in transfusion-dependent subjects (Appendix C).
3. Time to HI-E (Appendix C).
4. Duration of HI-E (Appendix C).
5. Time to progression to AML; the time between randomization (Part 1) or start of therapy 
(Part 2) and the date of progression to AML (Appendix C).
6. Time to progression to events of higher risk MDS; the time between randomization (Part 
1) or start of therapy (Part 2) and date of progression to events of higher risk MDS (eg,
int-2 or high-risk IPSS, Appendix B).
7. Progression-free survival (PFS) ∀the time between randomization (Part 1) or start of 
therapy (Part 2) and PD (Appendix C) or death.
8. Overall survival (OS) ∀the time between randomization (Part 1) or start of therapy (Part 
2) and death.
9. Concentration of sotatercept in serum.
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Sotatercept (ACE-011)
Protocol ACE-011-MDS-001
Celgene Corporation
Confidential and Proprietary
44
ACE-011-MDS-001 Amendment 4 Final: 04 Aug 2015
 
 
 
 
 
 
 
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Sotatercept (ACE-011)
Protocol ACE-011-MDS-001
Celgene Corporation
Confidential and Proprietary
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ACE-011-MDS-001 Amendment 4 Final: 04 Aug 2015
4.
OVERALL DESIGN OF THE STUDY
4.1.
Design of Study
This is an open-label, randomized, Phase 2, parallel, dose-ranging, multicenter study of 
sotatercept for the treatment of patients with low- and int-1 risk MDS or non-proliferative 
CMML, by IPSS (Appendix B), with anemia (Hgb ≤9.0 g/dL).
The study is comprised of 2 parts:
Part 1
Subjects will be stratified by concentration of serum EPO (< 500 versus ≥500 mIU/mL), by 
number of transfusions within 56 days prior to study enrollment (< 4 units of RBCs versus ≥4 
units of RBCs), and assigned randomly to one of two treatment groups wherein they will be 
administered sotatercept, SC, 0.1 mg/kg or 0.3 mg/kg Q3W.
Enrollment will continue without hiatus beyond randomization of five subjects into each of the 
0.1 mg/kg and 0.3 mg/kg treatment groups.  Following treatment of five subjects in each of the 
0.1 mg/kg and 0.3 mg/kg treatment groups (with the last subject for each group having 
completed at least one cycle of 21 days), all available safety and efficacy data will be assessed by 
a Steering Committee (Section 4.4).  Based upon the occurrence of dose-limiting toxicity (DLT)
(Section 4.1.1) in ≤1/5 subjects in Cycle 1 in the 0.1 mg/kg and 0.3 mg/kg treatment groups, the 
0.5 mg/kg treatment group will begin inclusion in the randomization scheme.  
Following treatment of at least six subjects in the 0.5 mg/kg treatment group (with at least six 
subjects having completed at least three cycles of 21 days each), all available safety and efficacy 
data will again be assessed by a Steering Committee from all dose levels.  Based upon the 
occurrence of DLT in ≤ 1/6 subjects in Cycle 1 in the 0.5 mg/kg treatment group and an 
acceptable safety profile from all dose levels, the 1.0 mg/kg treatment group will begin inclusion 
in the randomization scheme.  
Following treatment of at least six subjects in the 1.0 mg/kg treatment group (with at least six
subjects having completed at least three cycles of 21 days each), all available safety and efficacy 
data will again be assessed by a Steering Committee from all dose levels.  Based upon the 
occurrence of DLT in ≤ 1/6 subjects in Cycle 1 in the 1.0 mg/kg treatment group and an 
acceptable safety profile from all dose levels, the 2.0 mg/kg treatment group will begin inclusion 
in the randomization scheme.  The 2.0 mg/kg sotatercept dose was reduced to 1.5 mg/kg for 
ongoing and newly enrolled subjects (Amendment 4).
Intermediate cohorts (not to exceed 2.0 mg/kg) may be added at the time of dose escalation up to 
1.0 mg/kg and up to 2.0 mg/kg (eg, 0.75 mg/kg or 1.5 mg/kg respectively) based on assessment 
by the Steering Committee of available safety and efficacy data when at least six subjects have at 
least three cycles of treatment in the current dose level.  Enrollment will continue beyond 
randomization in all dose levels (unless dose level(s) is closed due to safety reasons or lack of 
efficacy as recommended by the Steering Committee) until up to a total of 20 subjects in each 
dose level.  Meetings of the Steering Committee are planned periodically throughout the study to 
review all available safety and efficacy data.  For any treatment group, if ≥40% of the subjects 
(minimum four subjects experiencing an event) experience a DLT of related (suspected) AE ≥ 
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Grade 2 (other than hypertension and hemoglobin DLT as defined in Section 4.1.1), the Steering 
Committee may recommend the closure of the treatment group.  
In addition, if > 33% of the subjects (minimum two subjects experiencing an event) experience 
hemoglobin > 12 g/dL (not influenced by transfusions) sustained for ≥7 days, confirmed by two
assessments ≥1 week apart, the Steering Committee may recommend the closure of the 
treatment group.
Moreover, if > 33% of the subjects (minimum two subjects experiencing an event) experience a 
hypertension DLT (Refer to Section 4.1.1) confirmed by the investigator by two readings 
obtained 5 minutes apart, the Steering Committee may recommend the closure of the treatment 
group.  In order to harmonize DLT assessment for hypertension across the study, additional 
guidance must be followed as defined in Section 4.1.1. Additionally, for any treatment group that 
accrues a minimum of 10 subjects or less if recommended by the Steering Committee (with the 
last subject having received at least one complete cycle of 21 days), in the absence of any sign of 
efficacy (defined as an increase of Hgb > 1 g/dL in the absence of transfusion or at least a 50% 
reduction in transfusion requirements if reduction seen is less than 4 units), the Steering 
Committee may recommend the closure of the treatment group.
Figure 4:
Design of Study
a Intermediate cohorts (not to exceed 2.0 mg/kg) may be added at the time of dose escalation up to 1.0 mg/kg and up 
to 2.0 mg/kg (eg, 0.75 mg/kg or 1.5 mg/kg respectively) based on assessment by the Steering Committee of
available safety and efficacy data when at least six subjects have at least three cycles of treatment in the current 
dose level
b Randomization to the sotatercept 0.5 mg/kg SC Q3W treatment group may begin only after treatment of five
subjects in the 0.1 mg/kg SC and five subjects in the 0.3 mg/kg SC treatment groups with the last subject for each 
group having completed at least one cycle of 21 days, and an assessment of all available safety and efficacy data 
for all subjects.
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ACE-011-MDS-001 Amendment 4 Final: 04 Aug 2015
c Randomization to the sotatercept 1.0 mg/kg SC Q3W treatment group may begin only after treatment of at least 
six subjects in the 0.5 mg/kg treatment group (or current dose level if intermediate cohort is added) with at least 
six subjects having completed at least three cycles of 21 days each, and an assessment of all available safety and 
efficacy data for all subjects. 
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six subjects in the 1.0 mg/kg treatment group (or current dose level if intermediate cohort is added) with at least 
six subjects having completed at least three cycles of 21 days each, and an assessment of all available safety and 
efficacy data for all subjects.  Per Steering Committee assessment on 02 Mar 2015, the sotatercept 2.0 mg/kg dose 
was reduced to 1.5 mg/kg.  Subjects already receiving sotatercept 2.0 mg/kg were dose reduced to 1.5 mg/kg
(Amendment 4).
Upon completion of up to 20 evaluable subjects in each of the treatment groups, analyses will be
conducted in order to evaluate the safety profile of sotatercept and identify the dose that results 
in the greatest frequency of HI-E.
Part 2 (Expansion Cohort)
Following the assessment of efficacy and safety parameters in Part 1, 15 additional evaluable 
subjects will be enrolled in Part 2 and complete treatment at the dose level of sotatercept that 
demonstrates the greatest frequency of HI-E.
Steering Committee Recommendation 
Based on the 02 Mar 2015 Steering Committee’s review of safety, efficacy and pharmacokinetic 
data of subjects enrolled in the Part 1 dose levels, including the sotatercept 2.0 mg/kg cohort 
level:
Part 1 - The sotatercept 2.0 mg/kg cohort was closed.  Ongoing and newly enrolled subjects are 
to be dose reduced to sotatercept 1.5 mg/kg.
Part 2 - Subjects enrolled in Part 2 (Expansion Cohort) will receive sotatercept at 1.0 mg/kg.  
This update is reflected in Amendment 4.
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Sotatercept (ACE-011)
Protocol ACE-011-MDS-001
Celgene Corporation
Confidential and Proprietary
48
ACE-011-MDS-001 Amendment 4 Final: 04 Aug 2015
4.1.1.
Dose-limiting Toxicity
The following are DLTs if treatment-related (suspected):
Dose-limiting Toxicity (DLT)
Definition
Hemoglobin
Hgb > 12 g/dL (not influenced by transfusions) 
sustained for ≥ 7 days, confirmed by two
assessments ≥ 1 week apart.
Hypertension*
Subjects within normal limits (WNL) and not 
receiving antihypertensive treatment at baseline
≥ Grade 2 (140 mmHg systolic BP [blood pressure]
or 90 mmHg diastolic) according to the National 
Cancer Institute Common Terminology Criteria for 
Adverse Events (NCI CTCAE) version 4.0 (current 
active minor version) (Appendix F)
Prehypertensive subjects (systolic BP 120 - 139 
mmHg or diastolic 80-89 mmHg) and not receiving 
antihypertensive treatment at baseline
Systolic ≥ 140 or diastolic increase ≥ 90 mmHg 
AND:
Introduction of anti-hypertensive treatment
OR
An increase of > 20 mmHg (systolic or diastolic) 
from baseline
For patients with blood pressure controlled on 
antihypertensive treatment at baseline
Systolic BP increase ≥ 140 or diastolic increase 
≥90 mmHg AND:
More intensive antihypertensive treatment than 
previously used at baseline
OR
Additional antihypertensive treatment than 
previously used at baseline.
Any other treatment-related (suspected) toxicity
≥ Grade 2 per NCI-CTCAE version 4.0 (current 
active minor version)
* Hypertension DLT should be confirmed by study investigator and should be the mean of two readings obtained 
approximately 5 minutes apart with the patient seated for approximately 10 minutes prior to the initial reading.
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Sotatercept (ACE-011)
Protocol ACE-011-MDS-001
Celgene Corporation
Confidential and Proprietary
49
ACE-011-MDS-001 Amendment 4 Final: 04 Aug 2015
4.1.2.
Study Periods
Both Part 1 and Part 2 of the study are comprised of the following periods:
Screening – Assessments to be performed up to 28 days prior to enrollment (Day 1).  If 
screening assessments, with the exception of Hgb and blood pressure, are conducted within 7 
days of enrollment (Day 1), they are not required to be repeated at enrollment (Day 1).  
Hemoglobin and blood pressure must be assessed within 8 hours prior to study drug 
administration (or closest time prior to dosing that is logistically feasible for the study site).
Treatment – Comprised of five complete cycles of 21 days each of treatment on a schedule of 
Q3W.  Subjects requiring ≥4 units of RBC at baseline who fail to demonstrate, after completing 
five cycles of treatment, a decrease ≥4 units of RBC transfused over a period of 8 weeks, 
relative to the units of RBCs transfused in the 8 weeks immediately prior to enrollment (Day 1), 
will discontinue treatment.  Subjects requiring < 4 units of RBC at baseline who have sustained 
Hgb increase by the end of Cycle 5 but for a period less than or equal to 8 consecutive weeks 
(potential late responders) may continue treatment for up to an additional three cycles (Cycles 6-
8) for the purpose of meeting response criteria.  Subjects requiring ≥ 4 units of RBC at baseline 
who have a sustained decrease in transfusion requirements by the end of Cycle 5 but for a period 
of less than or equal to 8 consecutive weeks (potential late responders) may also continue 
treatment for up to an additional three cycles (Cycles 6-8).
End of Treatment – Assessments to be conducted upon:
#
Completion (≥5 cycles) of participation in the Treatment Period of the study, prior
to the first dose of sotatercept in the Extension Period.
#
Early (< 5 cycles) termination of participation in the Treatment Period of the study,
after last dose of sotatercept.
Extension – After completion of 5 cycles of treatment (or up to 8 cycles for potential late 
responders), subjects who meet at least one of the criteria listed below may enter the Extension 
Period, subject to Rules for Delay, Reduction, and Discontinuation of Treatment (Section 8.2.1), 
until PD, treatment failure, or other reason, as appropriate, listed in Section 12, Discontinuations.  
HI-E (Non-transfusion-dependent [NTD] subjects) with an increase ≥ 1.5g/dL Hgb from 
baseline, sustained over a period of ≥ 8 consecutive weeks in the absence of RBC transfusions.
HI-E (Transfusion-dependent [TD] subjects) with a decrease ≥ 4 units of RBCs transfused over a 
period of 8 consecutive weeks, relative to the number of units of RBCs transfused in the 8 weeks 
immediately prior to Day 1.
NTD subjects exhibiting at least a 1.0 g/dL rise in Hgb compared to baseline at the investigator’s 
discretion.
TD subjects exhibiting a 50% reduction in transfusion requirement compared to baseline at the 
investigator’s discretion.
End of Extension – Assessments to be conducted upon completion of participation in the 
Extension Period of the study.
Follow-up – Following the end of treatment (last dose of sotatercept administered) in the 
Treatment Period or the Extension Period, follow-up will include a pregnancy test approximately
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Sotatercept (ACE-011)
Protocol ACE-011-MDS-001
Celgene Corporation
Confidential and Proprietary
50
ACE-011-MDS-001 Amendment 4 Final: 04 Aug 2015
28 days after the last treatment, assessment of efficacy (ie, Hgb levels, transfusions) 
approximately 28 days after the last treatment and repeated once per month until 3 months after 
the last treatment or until the start of the next treatment, whichever is first, assessment of PK at a 
single time point 3 months after the last treatment, assessment of ADA repeated every 3 months 
until 1 year after the last treatment, and assessment of progression to AML and OS every 
6 months up to 2 years following the first administration of sotatercept.
4.2.
Rationale for the Design of the Study
This is an open-label, randomized, Phase 2, parallel, dose-ranging, multicenter study designed to 
assess the effect of sotatercept on hematopoietic endpoints in subjects with low- and 
intermediate-1 risk myelodysplastic syndromes or non-proliferative CMML, by IPSS
(Appendix B).  The randomized, parallel-group, design is typical of Phase 2 studies evaluating a 
range of doses for an investigational drug.  Subjects will be randomized to treatment groups to 
limit scientific bias within the study.  The duration of treatment of 15 weeks (5 cycles) has been
shown to be adequate to assess safety and to demonstrate a pharmacodynamic effect of 
sotatercept on hematopoietic parameters 
 in both healthy volunteers and patients.
 
 
 
 
 
 
 
 
 
  
Dose escalation in 100% increment from 0.5 mg/kg to 2.0 mg/kg Q3W is proposed to achieve 
adequate separation in the systemic sotatercept exposure between doses.  This would facilitate 
the evaluation of the dose-response relationship for effectiveness and toxicity as well as to 
minimize the number of subjects exposed to likely sub-therapeutic doses. Intermediate cohorts 
(not to exceed 2.0 mg/kg) may be added at the time of dose escalation up to 1.0 mg/kg and up to 
2.0 mg/kg (eg, 0.75 mg/kg or 1.5 mg/kg respectively) based on assessment by the Steering 
Committee of available safety and efficacy data when at least six subjects have at least three 
cycles of treatment in the current dose level.  Three cycles of data in six subjects in the current
dose level will ensure that an adequate amount of safety and efficacy data is available prior to 
dose escalation or treatment group closure at dose levels where limited multi-dose clinical data is 
available from previous studies (eg, 1.0 mg/kg and 2.0 mg/kg).  
Note:  Based on the 02 Mar 2015 Steering Committee’s review of safety, efficacy and 
pharmacokinetic data of subjects enrolled in the Part 1 dose levels, including the sotatercept 
2.0 mg/kg cohort level:
Part 1 - The sotatercept 2.0 mg/kg cohort was closed.  Ongoing and newly enrolled subjects are 
to be dose reduced to sotatercept 1.5 mg/kg.
Part 2 - Subjects enrolled in Part 2 (Expansion Cohort) will receive sotatercept at 1.0 mg/kg.  
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Sotatercept (ACE-011)
Protocol ACE-011-MDS-001
Celgene Corporation
Confidential and Proprietary
51
ACE-011-MDS-001 Amendment 4 Final: 04 Aug 2015
4.3.
Duration of the Study
Both Part 1 and Part 2 of the study are comprised of the following periods:
Screening – Assessments to be performed up to 28 days prior to enrollment (Day 1).
Treatment – Comprised of five complete cycles of 21 days each of treatment.  Subjects who 
have a sustained Hgb increase or a decreased transfusion burden by the end of Cycle 5 but for a 
period less than or equal to 8 consecutive weeks (potential late responders) may continue 
treatment for up to an additional three cycles (Cycles 6-8) for the purpose of meeting response 
criteria.
Extension – After completing 5 cycles of treatment (or up to 8 cycles for potential late 
responders), subjects who qualify for the Extension Period (refer to Section 4.1.2), may enter the 
Extension Period and continue treatment, subject to Rules for Delay, Reduction, and 
Discontinuation of Treatment (Section 8.2.1), until PD, treatment failure, or other reason, as 
appropriate, listed in Section 12, Discontinuations.
Follow-up – Following the End of Treatment (last dose of sotatercept administered) in the 
Treatment Period or the Extension Period, follow-up will include a pregnancy test approximately
28 days after the last treatment, assessment of efficacy (ie, Hgb levels, transfusions) 
approximately 28 days after the last treatment and repeated once per month until 3 months after 
the last treatment or until the start of the next treatment, whichever is first, assessment of
pharmacokinetics at a single time point 3 months after the last treatment, assessment of ADA 
repeated every 3 months until 1 year after the last treatment, and assessment of progression to 
AML and OS every 6 months up to 2 years following the first administration of sotatercept.
The End of Trial is defined as either the date of the last visit of the last subject to complete the
study, or the date of receipt of the last data point from the last subject that is required for
primary, secondary 
 analysis, as pre-specified in the protocol and/or the
Statistical Analysis Plan, whichever is the later date.
The sponsor may decide to 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 any subjects who
remain on study may be consented and continue to receive treatment with IP.  It must be the 
opinion of the investigator that the remaining subject(s) continue to receive benefit from 
treatment with IP.  
4.4.
Steering Committee
A Steering Committee will be established by charter.  The Steering Committee will be comprised
of Study Investigators, an Independent Cardiologist, representatives of Celgene, and may include 
additional ad hoc members.  The Steering Committee will advise and recommend to the sponsor:
#
Inclusion of the 0.5 mg/kg treatment group in the randomization scheme, based upon 
the occurrence of DLT (Section 4.1.1) in ≤1/5 subjects in Cycle 1 in the 0.1 mg/kg 
and 0.3 mg/kg treatment groups and a review of all available safety and efficacy data 
following treatment of five subjects in each of those treatment groups (with the last 
subject for each group having completed at least one cycle of 21 days).
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Sotatercept (ACE-011)
Protocol ACE-011-MDS-001
Celgene Corporation
Confidential and Proprietary
52
ACE-011-MDS-001 Amendment 4 Final: 04 Aug 2015
#
Inclusion of the 1.0 mg/kg treatment group in the randomization scheme, based upon 
the occurrence of DLT (Section 4.1.1) in ≤ 1/6 subjects in Cycle 1 in the 0.5 mg/kg 
treatment group and a review of all available safety and efficacy data (with at least six 
subjects in the 0.5 mg/kg treatment group having completed at least three cycles of 21 
days each).
#
Inclusion of the 2.0 mg/kg treatment group in the randomization scheme, based upon 
the occurrence of DLT (Section 4.1.1) in ≤ 1/6 subjects in Cycle 1 in the 0.5 mg/kg 
treatment group and a review of all available safety and efficacy data (with at least six 
subjects in the 1.0 mg/kg treatment group having completed at least three cycles of 21 
days each).  The 2.0 mg/kg sotatercept dose was reduced to 1.5 mg/kg for ongoing 
and newly enrolled subjects per Amendment 4.
#
Inclusion of additional intermediate dose levels (not to exceed 2.0 mg/kg) based on 
assessment of all available safety and efficacy data at time of dose escalation to up to 
1.0 mg/kg and up to 2.0 mg/kg (eg, 0.75 mg/kg or 1.5 mg/kg respectively).  
#
Discontinuation of enrollment and/or treatment in treatment groups without signal of 
efficacy or with unacceptable risk to the safety of the subject.  For any treatment 
group that accrues a minimum of 10 subjects or less if recommended by the Steering 
Committee (with the last subject having received at least one complete cycle of 21 
days), in the absence of any sign of efficacy (defined as an increase of Hgb > 1 g/dL 
in the absence of transfusion or at least a 50% reduction in transfusion requirements if 
the reduction observed is less than 4 units).  
#
Closure of a study treatment group:
∀
if ≥40% of the subjects (minimum four subjects experiencing an event) 
experience a DLT of related (suspected) adverse event ≥ Grade 2 (other than a 
hemoglobin or hypertension DLT as defined in Section 4.1.1).
∀
if > 33% of the subjects (minimum two subjects experiencing an event) 
experience hemoglobin > 12 g/dL (not influenced by transfusions) sustained for
≥7 days, confirmed by two assessments ≥1 week apart.
∀
if > 33% of the subjects (minimum two subjects experiencing an event) 
experience a hypertension DLT (refer to Section 4.1.1) confirmed by the 
investigator as two readings obtained approximately 5 minutes apart with the 
subject seated for approximately 10 minutes prior to initial reading, the Steering 
Committee may recommend the closure of the treatment group.  In order to 
harmonize DLT assessment for hypertension across the study, additional guidance 
must be followed as defined in Section 4.1.1. 
#
Changes to the protocol or conduct of the study based upon emerging clinical or 
scientific data from this and/or other studies.
#
Procedures to ensure the safety of subjects and integrity of study data.
#
Procedures to meet the overall goals and objectives of the study.
Meetings of the Steering Committee will occur:
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Sotatercept (ACE-011)
Protocol ACE-011-MDS-001
Celgene Corporation
Confidential and Proprietary
53
ACE-011-MDS-001 Amendment 4 Final: 04 Aug 2015
#
Following treatment of at least five subjects in each of the 0.1 mg/kg and 0.3 mg/kg 
treatment groups (with the last subject for each group having completed at least one 
cycle of 21 days).
#
Following treatment of at least six subjects in the 0.5 mg/kg treatment group (with at 
least six subjects having completed at least three cycles of 21 days each).
#
Following treatment of at least six subjects in the 1.0 mg/kg treatment group (with at 
least six subjects having completed at least three cycles of 21 days each).
#
Following treatment of at least six subjects in the 2.0 mg/kg treatment group (with at 
least six subjects having completed at least three cycles of 21 days each).
#
Following treatment of at least six subjects in any additional interim treatment group 
(eg, 0.75 mg/kg or 1.5 mg/kg) if previously recommended to be opened by the 
Steering Committee (with at least six subjects having completed at least three cycles
of 21 days each).
#
Following treatment of each block of approximately five to six subjects in each 
ongoing treatment group (with all subjects in each block having completed at least 
three cycles of 21 days each).
#
Ad hoc
Additional details of the function and schedule of meetings of the Steering Committee will 
be specified in the Charter of the Steering Committee.
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Sotatercept (ACE-011)
Protocol ACE-011-MDS-001
Celgene Corporation
Confidential and Proprietary
54
ACE-011-MDS-001 Amendment 4 Final: 4 AUG 2015
5.
TABLE OF EVENTS
Table 7:
Schedule of Assessments
Period
Screening
Treatment
End of 
Treatment
Periodr or 
Early 
Termination Extensions
End of 
Extension
Periodt
Follow
-up
Cycle
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Cycle 5 (up 
to 6-8 for 
potential 
late 
responderss)
After 
Completion 
of 
Treatment 
Period
For 
extension 
subjects-
upon 
discontin-
uation of 
study 
treatment
Daya
-28 to 0
1
8
15
1
8
15
1
8
15
1
8
15
1
8
15
Randomize subject to sotatercept in 
IVRS system
-
•
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Administer sotatercept
-
•
-
- •
-
-
•
-
-
•
-
-
•
-
-
-
•
-
-
Medical history, Height
•
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Record prior meds and treatments
•
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
MDS disease history and baseline 
assessment and prior therapyb
•
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Transfusion logb
•
•
-
- •
-
-
•
-
-
•
-
-
•
-
-
•
•
•
• v
Record current therapies (including 
concomitant medications)/procedures
•
•
-
- •
-
-
•
-
-
•
-
-
•
-
-
•
•
•
• v
Record adverse eventsc
Record on an ongoing basis.
Physical exam, including weight + 
vitalsd
•
•
-
- •
-
-
•
-
-
•
-
-
•
-
-
•
•
•
-
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Early
Early
Terminatio
Terminat
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Cycle
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4
Cycle
Cycle 5 (
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up 
to 
t 6-8 for
for
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5< 1)
1
8
15
1
8
15
$5
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7$5
-
-
-
7$
7$
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•
-
-
5,
5,
5,(
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-
-
-
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-
-
-
23
23
23
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-
-
-
-
-
-
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•
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Sotatercept (ACE-011)
Protocol ACE-011-MDS-001
Celgene Corporation
Confidential and Proprietary
55
ACE-011-MDS-001 Amendment 4 Final: 4 AUG 2015
Table 7:
Schedule of Assessments (Continued)
Period
Screening
Treatment
End of 
Treatment 
Periodr or 
Early 
Termination Extensions
End of 
Extension 
Periodt
Follow
-up
Cycle
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Cycle 5 (up 
to 6-8 for 
potential 
late 
responderss)
After 
Completion 
of 
Treatment 
Period
For 
extension 
subjects-
upon 
discontinu
ation of 
study 
treatment 
Daya
-28 to 0
1
8
15
1
8
15
1
8
15
1
8
15
1
8
15
Blood Pressured
•
• • • • •
•
• •
•
• •
•
• •
•
•
•
•
-
ECGd
•
-
-
-
-
-
-
•
-
-
-
-
-
•
-
-
•
-
-
-
ECOG performance statusd
•
•
-
- •
-
-
•
-
-
•
-
-
•
-
-
•
•
•
-
Hematologye assessed prior to each 
treatment
Include CBC with diff and retic count
•
• • • • •
•
• •
•
• •
•
• •
•
•
•
•
•e
Serum chemistryf
•
• • • •
-
-
•
-
-
•
-
-
•
-
-
•
•
•
-
Urinalysish
•
•
-
- •
-
-
•
-
-
•
-
-
•
-
-
•
•
•
-
Serum Erythropoietin
•
• • • •
-
-
•
-
-
•
-
-
•
-
-
•
-
-
-
Pregnancy testingi
•
•
-
- •
-
-
•
-
-
•
-
-
•
-
-
•
•
•
•
Pharmacokineticsj
-
• • • • •
•
•
-
-
•
-
-
•
-
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352


Sotatercept (ACE-011)
Protocol ACE-011-MDS-001
Celgene Corporation
Confidential and Proprietary
56
ACE-011-MDS-001 Amendment 4 Final: 4 AUG 2015
Table 7:
Schedule of Assessments (Continued)
Period
Screening
Treatment
End of 
Treatment 
Periodr or 
Early 
Termination Extensions
End of 
Extension 
Periodt
Follow
-up
Cycle
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Cycle 5 (up 
to 6-8 for 
potential 
late 
responderss)
After 
Completion 
of 
Treatment 
Period
For 
extension 
subjects-
upon 
discontinu
ation of 
study 
treatment 
Daya
-28 to 0
1
8
15
1
8
15
1
8
15
1
8
15
1
8
15
Antidrug antibody (ADA)k
-
•
-
- •
-
-
•
-
-
•
-
-
•
-
-
•
•
•
•k
MDS response assessmentl
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
•
-
•
•u
Bone marrow aspirate, standardm
(with iron staining);Peripheral blood 
smearn
•
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
•
-
•
-
a Variations of ± 5 business days of the scheduled visit are permitted.  An unscheduled visit can occur at any time during the study.  Source documents for unscheduled visits must 
be maintained. The date of the visit and data generated must be recorded on the appropriate CRF.  In the Follow-Up Period (for those visits not requiring sample collection 
only), a variation of ± 15 business days of the schedule visit are permitted.
b MDS disease history and baseline assessment and prior therapy - to include date of diagnosis, WHO subtype, IPSS (Appendix B), and blast percentage, cytopenia and karyotype; 
cytogenetics and historic molecular mutational analyses -(ie, SF3B1, and other MDS related molecular mutations), at original diagnosis (including all historical data) and at 
study baseline (assessed during the screening period prior to Day 1 dosing); and record of prior therapy for MDS including history of administration of erythropoiesis stimulating 
agents.  For baseline MDS disease assessment, if bone marrow biopsy and/or aspirate results within 90 days prior to screening period are available, they may be used contingent 
that subject had no additional treatment (including ESAs and steroids) since sample obtainment.  Supportive care (ie, transfusions) since sample obtainment is acceptable.  
All transfusions (ie, RBC, platelets, whole blood, etc) are to be recorded at baseline from at least 12 weeks prior to enrollment; up through 3 months post last dose of sotatercept
and associated pre-transufsion hemoglobin levels at closest time prior to RBC transfusions, if available. .
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Sotatercept (ACE-011)
Protocol ACE-011-MDS-001
Celgene Corporation
Confidential and Proprietary
57
ACE-011-MDS-001 Amendment 4 Final: 4 AUG 2015
c Record on an ongoing basis from the time of provision of written informed consent to participate in this study to 42 days after the last treatment.  Beyond 42 after the last 
treatment, any SAE related to treatment should be reported.
d If physical examination, vital signs (except blood pressure), weight, or ECOG performance status were done within 7 days of Day 1, they do not need to be repeated at Study 
Day 1.  Blood pressure should be monitored during screening, prior to each study drug administration, and on a weekly basis during the first five cycles.  In addition, blood 
pressure should be assessed approximately 24 hours after the initial study drug administration during Cycle 1. On study drug dosing days, blood pressure must be assessed 
within 8 hours prior to study drug administration (or closest time prior to dosing that is logistically feasible for the study site).  Monitoring of blood pressure may be performed at 
home on nondosing days.  For home monitoring, a plan with instructions and thresholds regarding when to contact the investigator in the event significant increases are observed 
should be established with the subject.  In the absence of clinically significant changes in blood pressure after five cycles of treatment, monitoring frequency may decrease to 
once per cycle at the investigator’s discretion.  ECG should be performed during screening, Cycle 3 Day 1, Cycle 5 Day 1, and at the End of Treatment Period.  In the absence of 
clinically significant changes in ECG readings after completion of five cycles of treatment, ECGs will no longer be required until the End of Treatment Period unless deemed 
necessary by the investigator.  
e Hematology, including CBC with differential and reticulocyte count are done at baseline and weekly during the treatment period.  In the Follow-Up Period, Hematology values
(ie, Hgb levels) will be collected approximately 28 days after the last treatment and repeated once per month until 3 months after the last treatment or until the start of the next 
treatment, whichever occurs first, to assess potential late response to sotatercept after discontinuation.  
f Serum chemistry includes sodium, potassium, chloride, CO2 (bicarbonate), calcium, magnesium, phosphorus, BUN, creatinine, glucose, amylase, lipase, albumin, total protein, 
alkaline phosphatase, bilirubin (total and direct), AST/SGOT, ALT/SGPT, LDH, creatinine clearance (per Cockcroft-Gault formula).
h Urinalysis includes albumin (quantitative), bilirubin, creatinine (quantitative), glucose, Hgb, total protein (quantitative), ketones, pH, albumin/creatinine ratio, protein/creatinine 
ratio, 
.
i Pregnancy tests for females of childbearing potential.  A female of childbearing potential is a sexually mature female who: 1) has not undergone hysterectomy or bilateral 
oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (ie, has had menses at any time in the preceding 24 consecutive months). Urine or 
serum pregnancy tests must occur within 3 days prior to sotatercept for Cycle 1.  Urine or serum pregnancy tests must occur immediately prior to each treatment; approximately 
every 28 days during delays in treatment; at discontinuation of treatment; and approximately 28 days after the last treatment.
Note:  Local laboratory assessments are allowed in cases when timely results are needed (eg, randomization, study treatment dosing decisions, hematology assessments between 
clinic visits).  Whenever possible a “split” sample should also be forwarded to the central laboratory for analysis.  Local laboratory data should be collected in the eCRF. 
j Pharmacokinetics - Blood samples will be collected for assessment of pharmacokinetics in all subjects as per the schedule in Table 7.  On days of treatment administration the 
sample must be collected prior to administration of sotatercept.  During the Extension Period the sample must be collected prior to every other administration of sotatercept on 
days of treatment administration as per the schedule for assessment of ADA.  A blood sample will be collected for the assessment of pharmacokinetics at the end of the 
Extension Period.  During the Follow-up Period a blood sample will be collected for assessment of pharmacokinetics at a single time point 3 months after the last treatment. At 
each pharmacokinetics time point, approximately 3 mL blood will be collected and serum prepared 
k Antidrug antibody (ADA) - Blood samples will be collected for assessment of ADA in all subjects.  During the Treatment Period the sample must be collected prior to each 
administration of sotatercept on days of treatment administration.  During the Extension Period the sample must be collected prior to every other administration of sotatercept on 
days of treatment administration as per the schedule of assessment of pharmacokinetics.  A blood sample will be collected for the assessment of ADA at the end of the Extension 
Period.  At the end of the treatment, assessment of ADA will be repeated every 3 months until 1 year after the last treatment.  If a serum sample is provided for assessment of 
pharmacokinetics, the assay for ADA will be performed on that serum sample and an additional sample need not be provided.  If a serum sample is not provided for assessment 
of pharmacokinetics (ie, during the Follow-up Period) a serum sample (
 must be 
provided for the assay of ADA.
l MDS response assessment - per International Working Group (IWG) Response Criteria in Myelodysplasia (Appendix C), to include best response at end of treatment.
m Bone marrow aspirate, standard (with iron staining) - for: local assessment of cytogenetics employing standard banding overall and FISH for del (5q) only; preparation of smears
with Wright and Giemsa stain for local and central assessment of cell differential, morphology, and cellularity; standard assessment by flow cytometry.  For central assessment, 
refer to central lab manual for staining requirements.  During screening, if cytogenetic results from within 90 days of Screening Period are available, they may be used contingent
subject did not receive treatment (including ESAs and steroids) since sample obtainment.  Supportive care (ie, transfusions) since sample obtainment is acceptable.
n Peripheral blood smear - <0.1 ml of peripheral blood for preparation of smear with Wright and Giemsa stain for local and central assessment of cell morphology.
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Sotatercept (ACE-011)
Protocol ACE-011-MDS-001
Celgene Corporation
Confidential and Proprietary
58
ACE-011-MDS-001 Amendment 4 Final: 4 AUG 2015
 
 
 
 
r For Extension Subjects – assessments should be completed prior to the first dose of sotatercept in the Extension Period.  For Early Termination Subjects – assessments to be 
completed after last dose of sotatercept.
s After completing 5 cycles of treatment (or up to 8 cycles for late responders), subjects who qualify for the Extension Period (refer to Section 4.1.2) may continue therapy until 
PD or treatment failure in the Extension Phase following a Q3W visit schedule.  Subjects who have a sustained Hgb increase or a decreased transfusion burden by the end of 
Cycle 5 but for a period less than or equal to eight consecutive weeks (potential late responders) may continue treatment for up to an additional three cycles (Cycles 6-8) for the 
purpose of meeting response criteria.
t End of Extension Period – Assessments to be conducted upon completion of participation in the Extension Period (discontinuation of sotatercept).
u MDS Response Assessment during Follow-up Period to include only progression to AML and OS assessed every 6 months up to 2 years following the first administration of 
sotatercept. 
v Assessment of efficacy (ie, Hgb levels, transfusions) to continue approximately 28 days after the last treatment and repeated once per month until 3 months after the last 
treatment or until the start of the next treatment, whichever occurs first, to assess potential late response to sotatercept after discontinuation.
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Sotatercept (ACE-011)
Protocol ACE-011-MDS-001
Celgene Corporation
Confidential and Proprietary
59
ACE-011-MDS-001 Amendment 4 Final: 4 Aug 2015
6.
PROCEDURES
Procedures conducted on the day of treatment should be conducted prior to administration of 
treatment.  Deviation of ± 5 business days from the day of the scheduled assessment is permitted
during the Treatment Period, Extension Period, and Follow-Up Period (for visits that require 
sample collection).  Other Follow-up Period visits will have a ± 15 business day window.  If the 
deviation is due to missed or delayed visit, the subject should return to the original schedule as 
soon as possible.  If the deviation is due to delayed dose, the subject should adhere to a schedule 
revised to ensure complete cycles of treatment.
An unscheduled visit can occur at any time.  Source documentation must be maintained for 
unscheduled visits.  The date and data from the unscheduled visit must be recorded on the 
appropriate CRF.
If physical examination, vital signs (except blood pressure), weight, or ECOG performance 
status were done within 7 days of Day 1, they do not need to be repeated at Day 1.
Procedures are to be performed according to the schedule in the Table of Events, Table 7, 
Section 5.
1. Randomize subject to sotatercept in the interactive voice response system (IVRS) system
- Subjects who meet all eligibility criteria (Sections 7.2 and 7.3) will be stratified and 
randomized utilizing a validated IVRS.  A subject will be randomized to a Treatment 
Group once a unique multi-digit subject identification number has been assigned by 
IVRS. Subjects should be randomized prior to preparation
) of the first 
treatment (ie, on the same day, if logistically possible).  Randomization is not applicable 
in Part 2.  However, the subject should still be registered in the IVRS system prior to 
preparation of the first study treatment (ie, on the same day, if logistically possible).
2. Administer sotatercept – See Sections
and 8.2.
3. Medical history
4. Height – without shoes
5. Record prior meds (medications) - within the 8-week period prior to enrollment (Day 1)
6. Record prior treatments - within the 8-week period prior to enrollment (Day 1)
7. Myelodysplastic Syndrome or non-proliferative CMML disease history and baseline
assessment and prior therapy - to include date of diagnosis, WHO subtype, IPSS 
(Appendix B), and blast percentage, cytopenia, karyotype and historic molecular 
mutational analysis data - (ie, SF3B1, and other MDS-related molecular mutations) at 
original diagnosis and at study baseline (assessed during the screening period prior to 
Day 1 dosing); and record of prior therapy for MDS including history of administration 
of erythropoiesis stimulating agents and transfusions.  For baseline MDS disease 
assessment, if the results of a bone marrow biopsy and/or aspirate performed within 90 
days prior to screening period are available, they can be used contingent that the subject 
did not receive additional treatment (including ESAs and steroids) since the sample 
obtainment).  Supportive care (ie, transfusions) since sample obtainment is acceptable.  
ule
d for 
d for 
on the
on the
G performa
G perform
at Day
at Day 1.1
y
of f Events
Events
ce response
ce respo
7.2
7.2 and 
and 7.3
7.3
ct will be ra
will be 
ficatio
fication nu
n nu
or to prepar
r to prepar
cally possib
ally poss
ld st
d stillill be re
be re
ment
ent (i(ie,e on
on
ection
ections
s
s (m
s (medicati
edi
reatm
reatments
ent
splast
splasticic Sy
Sy
ment
ment and p
and p
ppendix
pendix B)
mutational
mutationa
ori
original
ginal
Day
Day 1
y
of
of
35


Sotatercept (ACE-011)
Protocol ACE-011-MDS-001
Celgene Corporation
Confidential and Proprietary
60
ACE-011-MDS-001 Amendment 4 Final: 4 Aug 2015
8.
Transfusion log – include all transfusions from at least 12 weeks prior to enrollment 
(Day 1) up through 3 months post last dose of sotatercept and associated pre-transfusion 
Hgb levels at closest time prior to RBC transfusions, if available.  
9. Record of current therapies (including concomitant medications)/procedures
10. Record of AEs – include AEs beginning from the time of provision of written informed 
consent to participate in this study to 42 days after the last treatment.  
11. Physical examination – by body system
12. Vital signs – Pulse rate, weight (without shoes)
13. Blood pressure (systolic and diastolic, after approximately 10 minutes seated, mean of 
two measurements, approximately 5 minutes apart) should be assessed during screening 
and on a weekly basis during the first five cycles.  In addition, blood pressure should be 
recorded (at home by the subject or caretaker) approximately 24 hours after initial study 
drug administration during Cycle 1.  On study drug dosing days, blood pressure must be 
assessed within 8 hours of study drug administration (or closest time prior to dosing that 
is logistically feasible for the study site).  Monitoring of blood pressure may be done at 
home on non-dosing days.  For home monitoring, a plan with instructions and thresholds 
on when to contact the investigator in the event significant increases are observed should 
be established with the subject.  In the absence of clinically significant changes in blood 
pressure after five cycles of treatment, monitoring frequency may decrease to once per 
cycle at the investigator’s discretion.  
14. ECG – 12-lead with rhythm strip - ECG should be performed during screening, Cycle 3 
Day 1, Cycle 5 Day 1, and at the End of Treatment Period.  In the absence of clinically 
significant findings in ECG readings after completing five cycles of treatment, ECGs will 
not be required until the end of Treatment Period unless deemed necessary by the 
investigator.
15. ECOG performance status (Appendix D)
16. Hematology
#
Hemoglobin (Hgb) - must be assessed prior to each treatment administration
#
Hematocrit (Hct)
#
RBC count
#
Absolute reticulocyte count
#
Platelet count
#
WBC count and differential
#
Absolute neutrophil count (ANC)
#
Mean corpuscular volume (MCV)
17. Serum chemistry
#
Sodium
mean of 
ean of 
g screening
g screenin
sure should
sure should
after init
fter initiai
ood pressur
ood pressur
ime prior t
me pri
d pressure m
pressure m
th
th instruct
nstruc
ant increase
nt increase
nically sign
nically sig
frequency 
frequency
ould be
ould be per
per
Treatment 
Treatmen
after comp
after comp
eatment Pe
atment Pe
(Appendix
Appendix
Hgb) 
b) - mu
m stst
t (Hct)
t (Hct)
ount
unt
bsolute reti
bsolute reti
Pl
Platel
telet c
et
#
WBC
WB
#


Sotatercept (ACE-011)
Protocol ACE-011-MDS-001
Celgene Corporation
Confidential and Proprietary
61
ACE-011-MDS-001 Amendment 4 Final: 4 Aug 2015
#
Potassium
#
Chloride
#
CO2 (bicarbonate)
#
Calcium
#
Magnesium
#
Phosphorus
#
BUN
#
Creatinine
#
Glucose
#
Amylase
#
Lipase
#
Albumin
#
Total protein
#
Alkaline phosphatase
#
Bilirubin (total and direct)
#
AST/SGOT
#
ALT/SGPT
#
LDH
#
Creatinine clearance [(per Cockcroft-Gault formula) Appendix H]
19. Serum erythropoietin
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Sotatercept (ACE-011)
Protocol ACE-011-MDS-001
Celgene Corporation
Confidential and Proprietary
62
ACE-011-MDS-001 Amendment 4 Final: 4 Aug 2015
20. Urinalysis
#
Albumin (quantitative)
#
Bilirubin
#
Creatinine (quantitative)
#
Glucose
#
Hemoglobin
#
Total protein (quantitative)
#
Ketones
#
pH
#
Albumin / creatinine ratio
#
Protein / creatinine ratio
Note:  Clinical laboratory evaluations (serum chemistry, hematology, absolute reticulocyte 
count, 
, serum erythropoietin, urinalysis) will be performed by a central 
laboratory.  
Local laboratory assessments are allowed in cases when timely results are needed (eg, 
randomization, study treatment and chemotherapy dosing decisions, hematology assessments 
between clinic visits).  Whenever possible a “split” sample should also be forwarded to the 
central laboratory for analysis.  Local laboratory data should be collected in the eCRF.
21. Pregnancy testing ∀Pregnancy tests, with a minimum sensitivity of 25 mIU/ml, for
females of childbearing potential.  A female of childbearing potential is a sexually mature 
female who: 1) has not undergone hysterectomy or bilateral oophorectomy; or 2) has not 
been naturally postmenopausal for at least 24 consecutive months (ie, has had menses at 
any time in the preceding 24 consecutive months). Urine or serum pregnancy tests must 
occur within 3 days prior to sotatercept for Cycle 1.  Urine or serum pregnancy tests must 
occur immediately prior to each treatment; approximately every 28 days during delays in 
treatment; at discontinuation of treatment; and approximately 28 days after the last 
treatment.
22. Pharmacokinetics ∀Blood samples will be collected for assessment of pharmacokinetics 
in all subjects as per the schedule in Table 7.  On days of treatment administration the 
sample must be collected prior to administration of sotatercept.  During the Extension 
Period the sample must be collected prior to every other administration of sotatercept on 
days of treatment administration as per the schedule for assessment of ADA.  A blood 
sample will be collected for assessment of pharmacokinetics at the end of the Extension 
Period.  During the Follow-up Period a blood sample will be collected for assessment of 
PK at a single time point 3 months after the last treatment. At each PK time point, 
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mmediately 
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sam


Sotatercept (ACE-011)
Protocol ACE-011-MDS-001
Celgene Corporation
Confidential and Proprietary
63
ACE-011-MDS-001 Amendment 4 Final: 4 Aug 2015
approximately 3 mL blood will be collected and serum prepared
.  
23. Antidrug antibody (ADA) ∀Blood samples will be collected for assessment of ADA in 
all subjects.  During the Treatment Period the sample must be collected prior to each 
administration of sotatercept on days of treatment administration.  During the Extension 
Period the sample must be collected prior to every other administration of sotatercept on 
days of treatment administration as per the schedule of assessment of PK.  A blood 
sample will be collected for assessment of ADA at the end of the Extension Period.  At
the end of the treatment, assessment of ADA will be repeated every 3 months until 1 year 
after the last treatment.  If a serum sample is provided for assessment of PK, the assay for 
ADA will be performed on that serum sample and an additional sample need not be 
provided.  If a serum sample is not provided for assessment of PK (ie, during the Follow-
up Period) a serum sample
 
 must be provided for the assay of ADA.  
24. MDS response assessment ∀per the International Working Group (IWG) Response 
Criteria in Myelodysplasia (Cheson, 2006; Appendix C), to include best response at end 
of treatment
25. Bone marrow aspirate, standard:
#
For local assessment of cytogenetics and central review of cytogenetics reports.  
Methods should employ:
∀
Standard banding methods overall, and
∀
Fluorescence in-situ hybridization (FISH) for d5q only.
#
For preparation of smears with Wright and Giemsa stain for local and central
assessment of cell differential, morphology, and cellularity.  For central assessment, 
refer to central laboratory manual for staining requirements.
#
For standard assessment by flow cytometry.
∀
During the screening period, if cytogenetic results from within 90 days prior to
start of screening period are available, they can be used contingent that the subject 
did not receive additional treatment (including ESAs and steroids) since sample 
obtainment.  Supportive care (ie, transfusions) since sample obtainment is 
acceptable.  
26. Peripheral blood smear ∀< 0.1 mL of peripheral blood for preparation of smear with 
Wright and Giemsa stain for local and central assessment of cell morphology.  Refer to 
central lab manual for staining requirements.
 
 
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Sotatercept (ACE-011)
Protocol ACE-011-MDS-001
Celgene Corporation
Confidential and Proprietary
64
ACE-011-MDS-001 Amendment 4 Final: 4 Aug 2015
 
 
 
 
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Sotatercept (ACE-011)
Protocol ACE-011-MDS-001
Celgene Corporation
Confidential and Proprietary
65
ACE-011-MDS-001 Amendment 4 Final: 4 Aug 2015
7.
STUDY POPULATION
7.1.
Number of Subjects and Sites
It is anticipated that up to approximately 140 subjects will be randomized to achieve 75-115
evaluable subjects (Section 10.3): up to 20 subjects in each of the sotatercept 0.1 mg/kg, 0.3 
mg/kg, 0.5 mg/kg, 1.0 mg/kg and 2.0 mg/kg treatment groups, and following the assessment 
of efficacy and safety parameters in Part 1, an additional 15 subjects will be enrolled in Part 
2 and complete treatment at the dose level of sotatercept that demonstrates the greatest 
frequency of HI-E.
Intermediate cohorts (not to exceed 2.0 mg/kg) may be added at the time of dose escalation 
up to 1.0 mg/kg and up to 2.0 mg/kg (eg, 0.75 mg/kg or 1.5 mg/kg respectively) based on 
assessment by the Steering Committee of available safety and efficacy data when at least six 
subjects have at least three cycles of treatment in the current dose level (refer to Section
4.1.).  Up to 20 subjects may also be enrolled at these interim treatment groups.  
Note:  Amendment 4:  Based on the 02 Mar 2015 Steering Committee’s review of safety, 
efficacy and pharmacokinetic data of subjects enrolled in the Part 1 dose levels, including 
the sotatercept 2.0 mg/kg cohort level:
Part 1 - The sotatercept 2.0 mg/kg cohort was closed.  Ongoing and newly enrolled subjects are 
to be dose reduced to sotatercept 1.5 mg/kg.
Part 2 - Subjects enrolled into Part 2 (Expansion Cohort) will receive sotatercept at 1.0 mg/kg.  
This is a multicenter study that will be conducted at up to approximately 25 sites in the 
United States and Europe.
7.2.
Inclusion Criteria
Subjects must satisfy the following criteria to be enrolled in the study:
1. Provide written informed consent prior to the conduct of any study-specific assessment or 
procedure.
2. Age ! 18 years at the time of signing the informed consent form.
3. Able to adhere to the study visit schedule and other requirements of the protocol.
4. Documented diagnosis of MDS or non-proliferative CMML (WBC ≤13,000 /mm3,
WHO, Vardiman, 2009) that meets IPSS (Appendix B) criteria for low- or int-1 risk 
disease.
5. Anemia defined as requiring transfusion ≥2 units of RBCs within 84 days of enrollment 
for Hgb ≤9.0 g/dL.
6. No response or loss of response to prior treatment with rHu EPO (≥40,000 U/wk x 8 or 
equivalent), or darbepoetin alpha (≥500 mcg Q3W x 4 or equivalent), or low chance of 
response to ESAs reflected by endogenous serum EPO concentration > 500 mU/mL.
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6.6.


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7. Subjects must have had no response or loss of response to no greater than 2 prior lines of 
treatment for MDS or non-proliferative CMML (not including treatment with ESAs or 
lines discontinued due to intolerance). Prior treatment with multiple agents given in 
combination will be considered one line.  
8. All previous therapy, including ESAs, granulocyte colony-stimulating factor (G-CSF), 
granulocyte-macrophage colony-stimulating factor (GM-CSF), must have been 
discontinued ≥28 days before enrollment
9. Eastern Cooperative Group (ECOG) performance status (Appendix D) ∃2.
10. Adequate renal function reflected by creatinine < 1.5 X ULN and creatinine clearance >
50 mL/min according to Cockcroft-Gault formula (Appendix H).
11. Total bilirubin ∃3.0 mg/dL, except if associated with primary shunt hyperbilirubinemia
(idiopathic dyserythropoietic jaundice).
12. AST (SGOT) and ALT (SGPT) ∃3.0 x ULN.
13. Females of childbearing potential participating in the study are to use highly effective 
methods of birth control during study participation and for 112 days (approximately five 
times the mean terminal half-life of sotatercept [23 days] based on multiple-dose PK 
data) following the last dose of sotatercept. Females of childbearing potential must have 
a negative serum beta-human chorionic gonadotropin (β-HCG) or urine pregnancy test 
within three days of sotatercept dosing (Day 1). Subjects must be counseled concerning 
measures to be used to prevent pregnancy and potential toxicities prior to the first dose of 
sotatercept. A female of childbearing potential is a sexually mature woman who has not 
undergone a hysterectomy or bilateral oophorectomy or who has not been 
postmenopausal for at least 24 consecutive months (ie, who has had menses at some time 
in the preceding 24 months).
14. Males must agree to use a latex condom during any sexual contact with females of 
childbearing potential while participating in the study and for 7 months (210 days)
following the last dose of sotatercept, even if he has undergone a successful vasectomy.  
Subjects must be counseled concerning measures to be used to prevent pregnancy and 
potential toxicities prior to the first dose of sotatercept.
15. Free of metastatic malignancy (other than MDS) for ! 2 years.
7.3.
Exclusion Criteria
The presence of any of the following will exclude a subject from enrollment:
Patients with MDS with chromosome 5q deletion without documented treatment failure to 
lenalidomide (ie, loss of response or no response after 4 months of treatment, intolerable to 
treatment, or having other cytopenia precluding use of treatment).
1. Women who are pregnant or breast feeding (women who are lactating must agree not to 
breast feed) or planning to become pregnant or breast feed during the period of treatment 
and for 112 days following the last dose of sotatercept.
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1.1. W


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2. Males who do not agree to use a latex condom or non-latex condom NOT made of natural 
(animal) membrane during sexual contact with females of childbearing potential or a 
pregnant female while participating in the study and for at least 7 months (210 days)
following the last dose of sotatercept, even if he has undergone successful vasectomy.
3. Major surgery within 30 days prior to Day 1
4. Incomplete recovery or incomplete healing of wounds from previous surgery.
5. Subjects with classification of 3 or higher heart failure as classified by the New York 
Heart Association (NYHA) (Appendix E).
6. History of deep vein thrombosis, pulmonary emboli, embolic stroke, or myocardial 
infarction occurring within the past 6 months.  Local central line thrombosis is allowed.
7. Subjects requiring ongoing anticoagulant treatment (eg, Coumadin, warfarin, heparin) 
during the course of the study.  Aspirin is allowed.  
8. History of severe allergic or anaphylactic reaction or hypersensitivity to recombinant 
proteins or excipients in the investigational product (refer to the Investigator’s Brochure 
for further information).
9. A condition, including laboratory abnormality, that, as determined by the investigator, 
places the subject at unacceptable risk if he/she was to participate in the study or that 
potentially confounds interpretation of data from the study.
10. Concurrent use of anticancer cytotoxic chemotherapeutic agent or treatment.
11. Known positive for human immunodeficiency virus (HIV) or infectious hepatitis type C
or active infectious hepatitis type B.
12. Clinically significant anemia unrelated to myelodysplastic disease (eg, iron, B12 or folate 
deficiencies, autoimmune or hereditary hemolysis, active gastrointestinal bleeding, and 
chronic renal insufficiency).
13. Thrombocytopenia (platelet count < 30,000/%L).
14. Uncontrolled hypertension (systolic blood pressure [SBP] ≥140 or diastolic blood 
pressure [DBP] ≥90).  
15. Treatment with another investigational drug or device within 28 days prior to Day 1, or if 
the half-life of the previous product is known, within 5 times the half-life prior to dosing, 
whichever is longer.
16. Prior exposure to sotatercept (ACE-011).
17. Any significant medical condition, laboratory abnormality, or psychiatric illness that, as 
determined by the investigator, would prevent the subject from participating in the study
or providing written informed consent.
18. Any condition including the presence of laboratory abnormality that, as determined by 
the investigator, places the subject at unacceptable risk if he/she were to participate in the 
study.
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18.8. A


Sotatercept (ACE-011)
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Celgene Corporation
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19. Any condition that, as determined by the investigator, confounds the interpretation of
data from the study.
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Confidential and Proprietary
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ACE-011-MDS-001 Amendment 4 Final: 4 Aug 2015
8.
DESCRIPTION OF STUDY TREATMENTS
 
 
 
 
 
 
 
 
 
 
 
8.2.
Treatment Administration and Schedule
Sotatercept will be administered after reconstitution as an SC (subcutaneous) injection to 
subjects by the study staff at the clinical site and administration will be documented in the study 
source record.  Subcutaneous injections will be given in the upper arm, abdomen, or thigh.  
Calculated doses requiring reconstituted volume greater than 2 mL should be divided equally 
into two syringes and injected into two separate sites. Rotate sites for each injection.
Subjects will be assigned to be administered treatment as per one of the following regimens:
#
Sotatercept 0.1 mg/kg SC Q3W
#
Sotatercept 0.3 mg/kg SC Q3W
#
Sotatercept 0.5 mg/kg SC Q3W
#
Sotatercept 1.0 mg/kg SC Q3W
#
Sotatercept 1.5 mg/kg SC Q3W (Amendment 4)
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Sotatercept (ACE-011)
Protocol ACE-011-MDS-001
Celgene Corporation
Confidential and Proprietary
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ACE-011-MDS-001 Amendment 4 Final: 4 Aug 2015
#
Sotatercept 2.0 mg/kg SC Q3W (cohort closed – Amendment 4)
Additional intermediate dose levels may be added (eg, 0.75 mg/kg SC Q3W or 1.5 mg/kg 
SC Q3W, not to exceed 2.0 mg/kg SC Q3W) if recommended by the upon review of safety 
and efficacy data (Refer to Section 4.1) at time of dose escalation to 1.0 mg/kg and 2.0 
mg/kg respectively).  
Note:  Amendment 4:  Based on the 02 Mar 2015 Steering Committee’s review of safety, 
efficacy and pharmacokinetic data of subjects enrolled in the Part 1 dose levels, including 
the sotatercept 2.0 mg/kg cohort level:
Part 1 - The sotatercept 2.0 mg/kg cohort was closed.  Ongoing and newly enrolled subjects are 
to be dose reduced to sotatercept 1.5 mg/kg.
Part 2 - Subjects enrolled into Part 2 (Expansion Cohort) will receive sotatercept at 1.0 mg/kg.  
Subjects who have a sustained Hgb increase or a decreased transfusion burden by the end of 
Cycle 5 but for a period less than or equal to 8 consecutive weeks (potential late responders) 
may continue treatment for up to an additional three cycles (Cycles 6-8) for the purpose of 
meeting response criteria.  After completing the Treatment Period, subjects who qualify for 
the Extension Period (refer to Section 4.1.2) may continue treatment in the Extension Period 
until PD or therapeutic failure.  
8.2.1.
Rules for Delay, Reduction, and Discontinuation of Treatment
Subjects must have Hgb assessed and results available within 8 hours (or closest time prior 
to dosing that is logistically feasible for the study site) prior to each study drug 
administration.
For subjects who are transfusion independent (ie, transfusion burden of < 4 units of RBCs in 
the eight weeks prior to randomization or enrollment), baseline (ie, Cycle 1 only) pre-dose 
Hgb should be < 9.0 g/dL prior to dosing administration.
Subjects must have blood pressure assessed within 8 hours (or closest time prior to dosing 
that is logistically feasible for the study site) prior to each study drug administration.  Blood 
pressure values should be confirmed by mean of two readings obtained approximately 5 
minutes apart with the patient seated for approximately 10 minutes prior to initial reading.
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Table 8:
Rules for Delay, Reduction, and Discontinuation of Treatment
Observation
Action
#
Hypertension DLT as defined in 
Section 4.1.1. 
#
Discontinue treatment
#
Treatment-related (suspected) toxicity ≥ 
Grade 3 (other than Hgb or Hypertension)
#
Discontinue treatment
#
Treatment-related (suspected) toxicity ≤ 
Grade 2 that delays treatment by more than 
3 months
#
Discontinue treatment
For Hemoglobin ≤ 11 g/dL (prior to dosing)
#
Hgb < 2 g/dL increase (not influenced by 
transfusions) at Day 21 from last dose
#
Continue current dose
#
Hgb > 2 g/dL increase (not influenced by 
transfusions) at Day 21 from last dose
#
Continue dosing - one level dose reduction 
(see Table 9).
For Hemoglobin > 11 g/dL and ≤ 12 g/dL (prior to dosing)
#
Hgb < 2 g/dL increase (not influenced by 
transfusions) at Day 21 from last dose
#
Dose delay until Hgb ≤11 g/dL and 
hypertension < SBP 140 mmHg and < DBP 
90 mmHg
#
Dosing can commence ! 7 days after the 
originally planned ACE-011 dose that was 
delayed. Hgb must be < 11 g/dL.
#
Subsequent ACE-011 dosing will resume 
21 days following this revised treatment 
dose date
#
Hgb > 2 g/dL (not influenced by 
transfusions) increase at Day 21 from last 
dose
#
Dose delay
#
Hold dose for one treatment visit
#
Re-evaluate Hgb & BP prior to resuming 
treatment
#
If Hgb < 11 g/dL and hypertension < SBP 
140 mmHg and < DBP 90 mmHg at the 
next scheduled visit, resume dosing - one 
level dose reduction (See Table 9)
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Protocol ACE-011-MDS-001
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Table 8:
Rules for Delay, Reduction, and Discontinuation of Treatment (Continued)
Observation
Action
For Hemoglobin > 12 g/dL and ≤ 14 g/dL
#
Hgb > 12 g/dL and ≤ 14 g/dL (not 
influenced by transfusions) sustained for 
≥7 days, confirmed by two assessments ≥
1 week apart
#
Dose delay
#
Hold dose for one treatment visit
#
Re-evaluate Hgb & BP prior to resuming 
treatment
#
If Hgb < 11 g/dL and hypertension < SBP 
140 mmHg and < DBP 90 mmHg at the 
next scheduled visit, resume dosing - two 
level dose reduction (see Table 9)
For Hemoglobin > 14 g/dL
#
Hgb >14 g/dL(not influenced by 
transfusions), sustained for ≥7 days, 
confirmed by two assessments ≥1 week 
apart
#
Discontinue treatment (see Section 12)
Note:  Local laboratory assessments are allowed in cases when timely results are needed (eg, 
randomization, study treatment dosing decisions, hematology assessments between clinic visits).  
Whenever possible a “split” sample should also be forwarded to the central laboratory for 
analysis.  Local laboratory data should be collected in the eCRF.  When indicated, per dose 
modification rules (Table 8) the dose of sotatercept should be reduced as per the schedule in
Table 9, Sotatercept dose reduction levels.
Table 9:
Sotatercept Dose Reduction Levels
Sotatercept 
Treatment Group
0.1 mg/kg
0.3 mg/kg
0.5 mg/kg
1.0 mg/kg
1.5 mg/kgb
2.0 mg/kgb
Dose Reduction #1
0.075 mg/kg
0.1 mg/kg
0.3 mg/kg
a 0.75 mg/kg
1.0 mg/kg
a 1.5 mg/kg 
Dose Reduction #2
Discontinue 
treatment
0.075 mg/kg
0.1 mg/kg
0.5 mg/kg
0.75 mg/kg
1.0 mg/kg
Dose Reduction #3
Discontinue 
treatment
0.075 mg/kg
0.3 mg/kg
0.5 mg/kg
0.75 mg/kg
Dose Reduction #4
Discontinue 
treatment
0.1 mg/kg
0.3 mg/kg
0.5 mg/kg
Dose Reduction #5
(if applicable)
0.075 mg/kg
0.1 mg/kg
0.3 mg/kg 
Dose Reduction #6
(if applicable)
Discontinue 
treatment
0.075 mg/kg
0.1 mg/kg
Dose Reduction #7
(if applicable)
Discontinue 
treatment
0.075 mg/kg
Dose Reduction #8
Discontinue 
treatment
a Dose reduction #1 for 1.0 mg/kg and 2.0 mg/kg treatment groups may be to 0.5 mg/kg and 1.0 mg/kg respectively, at the 
investigator’s discretion.  Subsequent dose reductions should then continue to follow Table 9 (eg, dose reduction #2 for 1.0 
mg/kg treatment group would be 0.3 mg/kg).
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b Sotatercept dose level 2.0 mg/kg has been discontinued, ongoing and newly enrolled subjects dose reduced to sotatercept 1.5 
mg/kg (Amendment 4).
A dose reduction will be maintained unless subsequent dose reductions are indicated.  Doses
may not be increased.
If applicable, for additional intermediate treatment groups opened per recommendation by the 
Steering Committee (eg, 0.75 mg/kg, 1.5 mg/kg, Refer to Section 4.1), dose level reduction 
should still follow Table 9 (eg, if starting dose level is 0.75 mg/kg, dose reduction #1 would be 
0.5 gm/kg, dose reduction #2 would be 0.3 mg/kg, and so on).  If intermediate treatment group 
dose level is not found on Table 9, dose should be decreased by 25% for each required dose 
reduction step.
8.3.
Method of Treatment Assignment
8.3.1.
Part 1
Subjects will be stratified by concentration of serum erythropoietin (< 500 versus ≥500 
mIU/mL) and by number of transfusions within 56 days prior to study enrollment (< 4 RBC units 
versus ≥4 RBC units), and then assigned randomly to one of two treatment groups wherein they 
will be administered sotatercept, SC, 0.1 mg/kg or 0.3 mg/kg Q3W.  An IVRS will be utilized to 
ensure an equal weight central randomization based on a permuted-block randomization method 
according to stratification factors defined in Section 4.1, Design of Study.  Following treatment 
of five subjects in each of the 0.1 mg/kg and 0.3 mg/kg treatment groups (with the last subject 
for each group having completed at least one cycle of 21 days), all available safety and efficacy 
data will be assessed by a Steering Committee (Section 4.4).  Based upon the occurrence of DLT
(Section 4.1.1) in ≤1/5 subjects in Cycle 1 in the 0.1 mg/kg and 0.3 mg/kg treatment groups, the 
0.5 mg/kg treatment group will begin inclusion in the randomization scheme.  
Following treatment of at least six subjects in the 0.5 mg/kg treatment group (with at least six
subjects having completed at least three cycles of 21 days each), all available safety and efficacy 
data will be assessed by a Steering Committee from all dose levels.  Based upon the occurrence 
of DLT in ≤ 1/6 subjects in Cycle 1 in the 0.5 mg/kg treatment group and an acceptable safety 
profile from all dose levels, the 1.0 mg/kg treatment group will begin inclusion in the 
randomization scheme.  
Following treatment of at least six subjects in the 1.0 mg/kg treatment group (with at least six
subjects having completed at least three cycles of 21 days each), all available safety and efficacy 
data will be assessed by a Steering Committee from all dose levels.  Based upon the occurrence 
of DLT in ≤ 1/6 subjects in Cycle 1 in the 1.0 mg/kg treatment group and an acceptable safety 
profile from all dose levels, the 2.0 mg/kg treatment group will begin inclusion in the 
randomization scheme.  The 2.0 mg/kg sotatercept dose was reduced to 1.5 mg/kg for ongoing 
and newly enrolled subjects (Amendment 4).
Intermediate cohorts (not to exceed 2.0 mg/kg) may be added at the time of dose escalation up to 
1.0 mg/kg and up to 2.0 mg/kg (eg, 0.75 mg/kg or 1.5 mg/kg respectively) based on assessment 
by the Steering Committee of available safety and efficacy data when at least six subjects have at 
least three cycles of treatment in the current dose level.  Enrollment will continue beyond
randomization in all dose levels (unless dose level[s] is closed due to safety reasons or lack of 
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efficacy as recommended by the Steering Committee) until up to a total of 20 subjects in each 
dose level.  
Meetings of the Steering Committee are planned periodically throughout the study to review all 
available safety and efficacy data.  For any treatment group, if ≥40% of the subjects (minimum 
four subjects experiencing an event) experience a DLT of related (suspected) adverse event ≥ 
Grade 2 (other than hemoglobin or hypertension DLT as defined in Section 4.1.1), the Steering 
Committee may recommend the closure of the treatment group.
In addition, if > 33% of the subjects (minimum two subjects experiencing an event) experience 
hemoglobin > 12 g/dL (not influenced by transfusions),sustained for ≥7 days, confirmed by two
assessments ≥1 week apart, the Steering Committee may recommend the closure of the 
treatment group.
Moreover, if > 33% of the subjects (minimum two subjects experiencing an event) experience a 
hypertension DLT (refer to Section 4.1.1), the Steering Committee may recommend the closure 
of the treatment group.  In order to harmonize DLT assessment for hypertension across the study, 
additional guidance must be followed as defined in Section 4.1.1. Additionally, for any treatment 
group that accrues a minimum of 10 subjects or less if recommended by the Steering Committee 
(with the last subject having received at least one complete cycle of 21 days), in the absence of 
any sign of efficacy (defined as an increase of Hgb > 1 g/dL in the absence of transfusion or at 
least a 50% reduction in transfusion requirements if the reduction is less than 4 units), the 
Steering Committee may recommend the closure of the treatment group.
8.3.2.
Part 2
Following the assessment of efficacy and safety parameters in Part 1, 15 additional evaluable 
subjects will be enrolled in Part 2 and complete treatment at the dose level of sotatercept that 
demonstrates the greatest frequency of HI-E.
Steering Committee Recommendation 
Based on the 02 Mar 2015 Steering Committee’s review of safety, efficacy and pharmacokinetic 
data of subjects enrolled in the Part 1 dose levels, including the sotatercept 2.0 mg/kg cohort 
level:
Part 1 - The sotatercept 2.0 mg/kg cohort was closed.  Ongoing and newly enrolled subjects are 
to be dose reduced to sotatercept 1.5 mg/kg.
Part 2 - Subjects enrolled into Part 2 (Expansion Cohort) will receive sotatercept at 1.0 mg/kg.  
8.4.
Packaging and Labeling
The IP will be labeled per local regulatory requirements. Additional information may be 
included on the label as applicable per local regulations.
8.5.
Investigational Product Accountability and Disposal
Accountability for sotatercept is the responsibility of the investigator.  Investigational clinical 
supplies must be received by a designated person at the clinical site and kept in a secured 
location.  The investigational site must maintain accurate records indicating dates and amounts of 
sotatercept received, to whom it was administered (subject-by-subject accounting), and accounts 
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8.5


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Protocol ACE-011-MDS-001
Celgene Corporation
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of sotatercept accidentally or deliberately destroyed or returned.  Unless otherwise notified, all 
vials of sotatercept, both used and unused, should be saved for drug accountability.  The used 
vials may be discarded, per the institution’s standard practice, after drug accountability has been 
completed.  The investigator must return all unused vials of sotatercept to Celgene at the end of 
the study, or the sotatercept may be destroyed at the clinical site with the permission of Celgene.  
For either scenario, the outcome must be documented on the drug accountability log.  Celgene 
will instruct the investigator on the return, disposal and/or destruction of IP.
8.6.
Investigational Product Compliance
Accurate recording of all IP administration will be made.  The investigator or designee is 
responsible for accounting for all IP that is administered during the course of the study.
8.7.
Overdose
Overdose, as defined for this protocol, refers to sotatercept dosing only.  On a per dose basis, an 
overdose is defined as the following amount over the protocol-specified dose of sotatercept 
assigned to a given patient, regardless of any associated adverse events or sequelae.  
SC 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 case report form.  See Section 11.1 for the reporting of adverse events associated 
with overdose.  
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Sotatercept (ACE-011)
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Celgene Corporation
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9.
CONCOMITANT MEDICATIONS AND PROCEDURES
9.1.
Permitted Concomitant Medications and Procedures
9.1.1.
Medications
During screening, and during the study, subjects should take only stable doses of medications for 
chronic conditions that are not specifically excluded by the protocol.  Concomitant medications 
will be recorded throughout the course of the study at each visit.
9.1.2.
RBC Transfusions
Concurrent treatment for anemia with blood transfusions is recommended when Hgb is < 8 g/dL 
or at the discretion of the investigator if Hgb is ≥8 g/dL and associated with symptom(s) of 
anemia (eg, hemodynamic or pulmonary compromise requiring treatment) or comorbidity
justifying a threshold ≥8 g/dL Hgb.
9.2.
Prohibited Concomitant Medications and Procedures
Concomitant growth factors (G-CSF or GM-CSF) are not allowed except in case of febrile 
neutropenia.
Iron supplementation within 7 days of Day 1 (besides an oral multivitamin with iron) will not be 
allowed.  If a subject becomes iron deficient during study treatment (ferritin < 100 ng/mL 
[< 224.7 pmol/L] or transferrin saturation < 20%), treatment with iron supplementation is at the 
discretion of the investigator.
No ESA is allowed.
No concurrent treatment with another investigational agent is allowed.
Concomitant anticoagulant treatment (eg, Coumadin, warfarin, heparin) is not allowed during 
study treatment.  Aspirin is allowed.
9.3.
Required Concomitant Medications and Procedures
None.
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Sotatercept (ACE-011)
Protocol ACE-011-MDS-001
Celgene Corporation
Confidential and Proprietary
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ACE-011-MDS-001 Amendment 4 Final: 4 Aug 2015
10.
STATISTICAL ANALYSES
10.1.
Overview
This is an open-label, randomized, Phase 2, parallel, dose-ranging, multicenter study of 
sotatercept for the treatment of patients with low- and int-1 risk MDS or non-proliferative 
CMML, with anemia, defined as requiring ≥2 units of RBCs within 84 days of study enrollment.  
The study is comprised of 2 parts.  In Part 1, subjects will be assigned randomly to one of two 
treatment groups wherein they will be administered sotatercept, SC, 0.1 mg/kg or 0.3 mg/kg 
Q3W.  Randomization will be stratified by concentration of serum EPO (< 500 versus ≥500 
mIU/mL) and by number of transfusions within 56 days prior to study enrollment (< 4 RBC units 
versus ≥4 RBC units).  Enrollment will continue without hiatus beyond randomization of five
subjects into each of the 0.1 mg/kg and 0.3 mg/kg treatment groups.  Following treatment of five
subjects in each of the 0.1 mg/kg and 0.3 mg/kg treatment groups (with the last subject for each 
group having completed at least one cycle of 21 days), all available safety and efficacy data will 
be assessed by a Steering Committee (Section 4.4).  Based upon the occurrences of DLTs in 
Cycle 1, as described in Section 4.1.1, the 0.5 mg/kg treatment group may be included into the 
randomization scheme. Initiation of randomization into the 1.0 mg/kg and 2.0 mg/kg treatment 
groups will have the same requirements as initiation of randomization into the 0.5 mg/kg 
treatment group with the exception of requiring at least six subjects completing at least three 
cycles of 21 days each and all available safety and efficacy data will be assessed by a Steering 
Committee. Meetings of the Steering Committee are planned periodically throughout the study 
to review available safety and efficacy data.  Also, the Steering Committee may meet to review 
efficacy and safety due to occurrences of DLTs or for lack of efficacy as described in 
Section 4.1.1.
Intermediate cohorts (not to exceed 2.0 mg/kg) may be added at the time of dose escalation up to 
1.0 mg/kg and up to 2.0 mg/kg (eg, 0.75 mg/kg or 1.5 mg/kg respectively) based on assessment 
by the Steering Committee of available safety and efficacy data when at least six subjects have at 
least three cycles of treatment in the current dose level.  Upon completion of up to 20 evaluable 
subjects in each of the treatment groups, analyses will be conducted in order to evaluate the 
safety profile of sotatercept and identify the dose that results in the greatest frequency of HI-E.  
Following the assessment of efficacy and safety parameters in Part 1, 15 additional evaluable 
subjects will be enrolled in Part 2 and complete treatment at the dose level of sotatercept that 
demonstrates the greatest frequency of HI-E.
Note:  Amendment 4:  Based on the 02 Mar 2015 Steering Committee’s review of safety, 
efficacy and pharmacokinetic data of subjects enrolled in the Part 1 dose levels, including the 
sotatercept 2.0 mg/kg cohort level:
Part 1 - The sotatercept 2.0 mg/kg cohort was closed.  Ongoing and newly enrolled subjects are 
to be dose reduced to sotatercept 1.5 mg/kg.
Part 2 - Subjects enrolled in Part 2 (Expansion Cohort) will receive sotatercept at 1.0 mg/kg.  
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Sotatercept (ACE-011)
Protocol ACE-011-MDS-001
Celgene Corporation
Confidential and Proprietary
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ACE-011-MDS-001 Amendment 4 Final: 4 Aug 2015
10.2.
Definitions of Study Populations
Five study populations will be used for analyses.
#
The Intent-to-Treat (ITT) Population ∀All subjects randomized
#
Safety Population ∀All subjects who take at least one dose of study medication
#
Efficacy Evaluable (EE) Population ∀All ITT subjects who take at least one dose of 
study medication and have baseline and at least one post-baseline assessment of 
efficacy without major deviation from protocol
#
Transfusion-dependent Efficacy Population (TDE) ∀All subjects in the EE 
population who require a transfusion of > 4 units of RBCs in the 8 weeks prior to 
randomization (Part 1) or start of therapy (Part 2) are transfusion dependent at 
randomization.
#
Transfusion-independent Efficacy Population (TIE) – All subjects in the EE 
population who require a transfusion of < 4 units of RBCs in the 8 weeks prior to 
randomization (Part 1) or start of therapy (Part 2) are not transfusion-dependent at 
randomization.
10.3.
Sample Size and Power Considerations
Subjects will be enrolled to provide up to 115 evaluable subjects in this study (Parts 1 and 2, 
combined).  An evaluable subject is one who meets criteria for HI-E (Section 3.1), or one who 
completes five cycles of 21 days each of treatment without meeting criteria for HI-E, and without 
major deviation from protocol.  Subjects who have a sustained Hgb increase or a decreased 
transfusion burden by the end of Cycle 5 but for a period less than or equal to 8 consecutive 
weeks (potential late responders) may continue treatment for up to an additional three cycles
(Cycles 6-8) for the purpose of meeting response criteria.
Confidence intervals for response rates based on various sample sizes are presented in Table 10.
Table 10:
95% Confidence Intervals for Selected Sample Sizes and Response Rates
N
Responses
Response Rate
Lower 95% CI
Upper 95% CI
20
4
0.20
0.057
0.437
20
6
0.30
0.119
0.543
20
10
0.50
0.272
0.728
20
14
0.70
0.457
0.881
20
16
0.80
0.563
0.943
15
3
0.20
0.043
0.481
15
6
0.40
0.163
0.677
15
9
0.60
0.323
0.836
15
12
0.80
0.519
0.957
10
2
0.20
0.025
0.556
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Sotatercept (ACE-011)
Protocol ACE-011-MDS-001
Celgene Corporation
Confidential and Proprietary
79
ACE-011-MDS-001 Amendment 4 Final: 4 Aug 2015
Table 10:
95% Confidence Intervals for Selected Sample Sizes and Response Rates
(Continued)
N
Responses
Response Rate
Lower 95% CI
Upper 95% CI
10
5
0.50
0.187
0.813
10
8
0.80
0.444
0.975
5
1
0.20
0.005
0.716
5
2
0.40
0.053
0.853
5
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0.80
0.284
0.995
10.4.
Background and Demographic Characteristics
Subjects’ baseline transfusion dependency and baseline concentration of serum EPO (< 500 
versus ≥500 mIU/mL) will be summarized using frequency tabulations.  Subjects’ age, height, 
weight, and baseline characteristics will be summarized overall and by treatment group using 
descriptive statistics, while gender, race and other categorical variables will be summarized using 
frequency tabulations.  Data on medical history will be summarized using frequency tabulations 
by system organ class and preferred term.
10.5.
Subject Disposition
Subject disposition (analysis population allocation, entered, discontinued, along with primary 
reason for discontinuation) will be summarized overall and by treatment group using frequency 
and percent for both treatment and follow-up periods.  A summary of subjects enrolled by site 
will be provided. Deviations from protocol will be summarized by frequency tabulations.
10.6.
Analysis of Efficacy
The primary objective of this study is to determine a safe, tolerable, and effective dose of 
sotatercept that results in the greatest frequency of HI-E in patients with anemia and low- or int-1
risk MDS or non-proliferative CMML.  The primary endpoint of this study is the rate of HI-E
(Appendix C) starting before the completion of five cycles of treatment.  Subjects who have 
sustained Hgb increase or decreased transfusion burden by end of Cycle 5 but for a period less 
than or equal to 8 consecutive weeks (potential late responders) may continue treatment for up to 
an additional three cycles (Cycles 6-8) for the purpose of meeting response criteria.
#
HI-E (TIE) is an increase ≥1.5g/dL Hgb from baseline, sustained over a period of ≥8 
consecutive weeks in the absence of RBC transfusion; 
or
#
HI-E (TDE) is a decrease ≥4 units of RBCs transfused over a period of 8 consecutive 
weeks, relative to the number of units of RBCs transfused in the 8 weeks immediately 
prior to Day 1.
Erythroid hematological improvement (HI-E) response rates will be presented separately for TIE 
and TDE subjects. The HI-E response rate and other binary endpoints will be summarized using 
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H


Sotatercept (ACE-011)
Protocol ACE-011-MDS-001
Celgene Corporation
Confidential and Proprietary
80
ACE-011-MDS-001 Amendment 4 Final: 4 Aug 2015
a point estimate and 95% CI. 
 
The secondary endpoints of efficacy of this study are:
1. Achievement of transfusion-independence in transfusion-dependent subjects 
(Appendix C).
2. Time to HI-E (Appendix C); the time between randomization (Part 1) and the start of 
therapy (Part 2) and the date the start of HI-E.
3. Duration of HI-E (Appendix C); the length of time between the first assessment and the 
last assessment the subject was in HI-E response for subjects who had an HI-E response. 
If the subject had an HI-E response that continued at the subject’s last assessment, the 
duration will be censored at the last assessment.
4. Time to progression to AML (TPAML); the time between randomization (Part 1) and 
start of therapy (Part 2) and the date of progression to AML (Appendix C).  If a subject 
dies prior to progression, the subject will be censored at the date of death.  If a subject 
does not have a progression to AML, the subject will be censored at the last assessment.
5. Time to progression to events of higher risk MDS (TTPHR); the time between 
randomization (Part 1) and start of therapy (Part 2) and date of progression to events of 
higher risk MDS (eg, int-2 or high risk IPSS, Appendix B).  If a subject dies due to 
reasons other than progression to events of higher risk MDS, the subject will be censored 
at the death date.  If a subject does not have progression to events of higher risk MDS, 
then the subject will be censored at the last assessment.
6. Progression-free survival (PFS) - the time between randomization (Part 1) and start of 
therapy (Part 2) and PD (Appendix C) or death.  Subjects who progress or die will be 
considered to have had an event, except if this event occurs after the start of subsequent 
therapy for MDS, in which case the subject is censored at the time of last assessment of 
MDS prior to or on the first day of the first subsequent therapy for MDS.  The date of 
progression is taken as the earliest date of:  date of PD as evaluation of response, death 
date, if death is caused by PD, treatment termination date if reason is PD, progression 
date as documented on treatment termination page, progression date as documented on 
the follow-up visit page.  Subjects who do not progress or die (lost to follow-up or still 
being treated without documented PD or started subsequent antitumor therapy) will be 
censored at the date of the last assessment of MDS.
7. Overall survival (OS) - the time between randomization (Part 1) and start of therapy (Part 
2) and death.  A subject, who dies regardless of the cause of death, will be considered to 
have had an event.  All subjects who are lost to the follow-up prior to the end of the study 
or who are withdrawn from the study will be censored at the time of last contact.  
Subjects who are still being treated will be censored at the last available date when the 
subject was known to be alive.
8. Concentration of sotatercept in serum (Section 10.9).
For duration and time-to-event data, the Kaplan-Meier method will be used to estimate the 
distribution function.  For continuous data, descriptive statistics will be provided.  Data listings 
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8


Sotatercept (ACE-011)
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will be provided for all relevant data collected during the studies.  Further details will be 
included in the Statistical Analysis Plan. 
10.7.
Analysis of Safety
All subjects who take at least one dose of study medication will be included in analyses of safety.  
Exposure to sotatercept will be summarized.  Adverse events, DLTs, vital signs, clinical 
laboratory information, ECG interpretations, and concomitant medications will be tabulated and 
summarized overall and by treatment group.  The incidence of AEs will be summarized by 
severity based on the NCI CTCAE version 4.0 (current active minor version).  The incidence of 
deaths, SAEs, and AEs leading to dose modifications and discontinuations of study treatment 
will be summarized overall and by treatment group.  Safety information obtained during 
treatment, post-treatment (42 days after the last dose), and during follow-up will be provided for 
these analyses.  Laboratory results will be summarized by NCI CTCAE grade overall and by 
treatment group.
10.8.
Interim Analysis
In Part 1, following treatment of five subjects in each of the 0.1 mg/kg and 0.3 mg/kg treatment 
groups (with the last subject for each group having completed at least one cycle of 21 days), all 
available safety and efficacy data will be assessed by a Steering Committee (Section 4.4).  
Enrollment will continue without hiatus beyond randomization of five subjects into each of the 
0.1 mg/kg and 0.3 mg/kg treatment groups.  Based upon the occurrences of DLTs in Cycle 1 as 
described in Section 4.1.1, the 0.5 mg/kg treatment group may be included into the 
randomization scheme.  Initiation of randomization into the 1.0 mg/kg treatment group will have 
the same requirements as initiation of randomization into the 0.5 mg/kg treatment group with the 
exception of requiring at least six subjects enrolled in the 0.5 mg/kg treatment group completing 
at least three cycles of 21 days each.  Initiation of randomization into the 2.0 mg/kg treatment
group will have the same requirements as initiation of randomization into the 1.0 mg/kg 
treatment group.  Meetings of the Steering Committee are planned periodically throughout the 
study to review available safety and efficacy data.  Also, the Steering Committee may meet to 
review efficacy and safety due to occurrences of DLTs or for lack of efficacy as described in 
Section 4.1.1.
Intermediate cohorts (not to exceed 2.0 mg/kg) may be added at the time of dose escalation up to 
1.0 mg/kg and up to 2.0 mg/kg (eg, 0.75 mg/kg or 1.5 mg/kg respectively) based on assessment 
by the Steering Committee of available safety and efficacy data when at least six subjects have at 
least three cycles of treatment in the current dose level.  Upon completion of up to 20 evaluable 
subjects in each of the treatment groups (Part 1), analyses will be conducted in order to evaluate 
the safety profile of sotatercept and identify the dose that results in the greatest frequency of 
HI-E.
Note:  Amendment 4:  Based on the 02 Mar 2015 Steering Committee’s review of safety, 
efficacy and pharmacokinetic data of subjects enrolled in the Part 1 dose levels, including the 
sotatercept 2.0 mg/kg cohort level:
Part 1 - The sotatercept 2.0 mg/kg cohort was closed.  Ongoing and newly enrolled subjects are 
to be dose reduced to sotatercept 1.5 mg/kg.
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Protocol ACE-011-MDS-001
Celgene Corporation
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ACE-011-MDS-001 Amendment 4 Final: 4 Aug 2015
Part 2 - Subjects enrolled in Part 2 (Expansion Cohort) will receive sotatercept at 1.0 mg/kg.  
10.9.
Pharmacokinetics
Pharmacokinetic parameters for sotatercept, such as Cmax, time to maximum serum concentration 
(Tmax), and AUC, will be estimated.  Dose proportionality may be assessed using exposure data 
after the first dose.  Descriptive statistics will be provided for serum concentrations and PK 
parameters.  The relationship between exposure to sotatercept and response (ie, safety, efficacy, 
) may be explored, if appropriate.  
 
 
 
 
 
 
 
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Sotatercept (ACE-011)
Protocol ACE-011-MDS-001
Celgene Corporation
Confidential and Proprietary
83
ACE-011-MDS-001 Amendment 4 Final: 4 Aug 2015
11.
ADVERSE EVENTS
11.1.
Monitoring, Recording and Reporting of Adverse Events
An adverse event (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 below), 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 CRF rather than the individual signs or symptoms of the diagnosis or 
syndrome. 
An overdose, accidental or intentional, whether or not it is associated with an AE, or abuse, 
withdrawal, sensitivity or toxicity to an investigational product should be reported as an AE.  If 
an overdose is associated with an AE, the overdose and adverse event should be reported as 
separate terms.
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 other 
appropriate tests and procedures.
All AEs will be recorded by the investigator from the time the subject signs informed consent to 
42 days after the last dose of IP.  AEs and SAEs will be recorded on the AE page of the CRF and 
in the subject’s source documents.  All SAEs must be reported to Celgene Drug Safety within 24 
hours of the investigator’s knowledge of the event by facsimile, or other appropriate method, 
using the SAE Report Form, or approved equivalent form.
11.2.
Evaluation of Adverse Events
A qualified investigator will evaluate all adverse events as to:
11.2.1.
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);
#
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.
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Sotatercept (ACE-011)
Protocol ACE-011-MDS-001
Celgene Corporation
Confidential and Proprietary
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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 starting of treatment on study); must 
be documented in the source document and the CRF.  Hospitalization or prolonged 
hospitalization for a complication remains a reportable SAE.
#
An elective treatment of a pre-existing condition unrelated to the studied indication. 
#
Emergency outpatient treatment or observation that does not result in admission, 
unless fulfilling other seriousness criteria above.
If an AE is considered serious, both the AE page/screen of the CRF and the SAE Report Form 
must be completed.
For each SAE, the investigator will provide information on severity, start and stop dates, 
relationship to IP, action taken regarding IP, and outcome.
11.2.2.
Severity / Intensity
For both AEs and SAEs, the investigator must assess the severity /intensity of the event.
The severity of AEs will be graded based upon the subject’s symptoms according to the current 
active minor version of NCI CTCAE Version 4.0; 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40
AEs that are not defined in the NCI CTCAE should be evaluated for severity according to the 
following scale:
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Sotatercept (ACE-011)
Protocol ACE-011-MDS-001
Celgene Corporation
Confidential and Proprietary
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#
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.
11.2.3.
Causality 
The investigator must determine the relationship between the administration of IP and the 
occurrence of an AE/SAE as Not Suspected or Suspected as defined below:
Not suspected:
Means 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:
Means 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 
drug and the adverse event.
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.
11.2.4.
Duration
For both AEs and SAEs, the investigator will provide a record of the start and stop dates of the 
event.
11.2.5.
Action Taken
The investigator will report the action taken with IP as a result of an AE or SAE, as applicable 
(eg, discontinuation or reduction of IP, as appropriate) and report if concomitant and/or 
additional treatments were given for the event. 
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Sotatercept (ACE-011)
Protocol ACE-011-MDS-001
Celgene Corporation
Confidential and Proprietary
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11.2.6.
Outcome
All SAEs that have not resolved upon discontinuation of the subject’s participation in the study 
must be followed until recovered, recovered with sequelae, not recovered (death due to another 
cause) or death (due to the SAE). 
11.3.
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.
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 on the AE page/screen of the CRF.  If the abnormality was not a 
part of a diagnosis or syndrome, then the laboratory abnormality should be recorded as the AE.
11.4.
Pregnancy
11.4.1.
Females of Childbearing Potential
Pregnancies and suspected pregnancies (including a positive pregnancy test regardless of age or 
disease state) of a female subject occurring while the subject is on IP, or within 112 days of the 
subject’s last dose of IP, are considered immediately reportable events.  IP is to be discontinued 
immediately.  The pregnancy, suspected pregnancy, or positive pregnancy test must be reported 
to Celgene Drug Safety immediately by 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 (not necessarily one with 
reproductive toxicity experience) 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 (either 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 or therapeutic 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 by facsimile, or 
other appropriate method, within 24 hours of the investigator’s knowledge of the event using the 
SAE Report Form, or approved equivalent form.
All neonatal deaths that occur within 28 days of birth should be reported, without regard to 
causality, as SAEs.  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 to Celgene Drug Safety by 
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Sotatercept (ACE-011)
Protocol ACE-011-MDS-001
Celgene Corporation
Confidential and Proprietary
87
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facsimile, or other appropriate method, within 24 hours of the investigator’s knowledge of the 
event using the SAE Report Form, or approved equivalent form.
11.4.2.
Male Subjects
If a female partner of a male subject taking investigational product 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.
11.5.
Reporting of Serious Adverse Events
Any AE that meets a criterion for an SAE requires the completion of an SAE Report Form in 
addition to being recorded on the AE page/screen of the CRF.  All SAEs must be reported to 
Celgene Drug Safety within 24 hours of the investigator’s knowledge of the event by facsimile, 
or other appropriate method, using the SAE Report Form, or approved equivalent form.  This 
instruction pertains to initial SAE reports as well as any follow-up reports.
The investigator is required to ensure that the data on these forms is accurate and consistent.  
This requirement applies to all SAEs (regardless of relationship to IP) that occur during the study 
(from the time the subject signs informed consent up to and including 42 days following the last 
study treatment), and those made known to the investigator at anytime thereafter that are 
suspected of being related to IP.  SAEs occurring prior to treatment will be captured.
The SAE report should provide a detailed description of the SAE and include summaries of 
hospital records and other relevant documents.  If a subject died and an autopsy has been 
performed, copies of the autopsy report and death certificate are to be sent to Celgene Drug 
Safety as soon as these become available.  Any follow-up data will be detailed in a subsequent 
SAE Report Form, or approved equivalent form, and sent to Celgene Drug Safety.  
Where required by local legislation, the investigator is responsible for informing the 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.
11.5.1.
Safety Queries
Queries pertaining to SAEs will be communicated from Celgene Drug Safety to the site via 
facsimile or electronic mail.  The response time is expected to be no more than five (5) business 
days.  Urgent queries (eg, missing causality assessment) may be handled by phone.
11.6.
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 sotatercept based on the Investigator Brochure.
In the United States, all suspected unexpected serious adverse reactions will be reported in an 
expedited manner in accordance with 21 CFR 312.32.
For countries within the European Economic Area (EEA), Celgene or its authorized 
representative will report in an expedited manner to Regulatory Authorities and Ethics 
Committees concerned, suspected unexpected serious adverse reactions (SUSARs) in accordance 
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Sotatercept (ACE-011)
Protocol ACE-011-MDS-001
Celgene Corporation
Confidential and Proprietary
88
ACE-011-MDS-001 Amendment 4 Final: 4 Aug 2015
with Directive 2001/20/EC and the Detailed Guidance on collection, verification and 
presentation of adverse reaction reports arising from clinical studies of investigational products 
for human use (ENTR/CT3) and also in accordance with country-specific requirements.  
Celgene or its authorized representative shall notify the investigator 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, SUSAR);
#
Any finding from tests in laboratory animals that suggests a significant risk for 
human subjects including reports of mutagenicity, teratogenicity, or carcinogenicity.
Where required by local legislation, the investigator shall notify his/her IRB/EC promptly of new 
serious and unexpected AE(s) or significant risks to subjects.
The investigator must keep on file a copy of pertinent safety information including 
correspondence with Celgene and the IRB/EC.  (See Section 15.3 for record retention 
information.)
Celgene Drug Safety Contact Information:
For Local Drug Safety Affiliate Office contact information, please refer to the Serious Adverse 
Event Report Form / Completion Guidelines or to the Pregnancy Report Form / Completion 
Guidelines.
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Sotatercept (ACE-011)
Protocol ACE-011-MDS-001
Celgene Corporation
Confidential and Proprietary
89
ACE-011-MDS-001 Amendment 4 Final: 4 Aug 2015
12.
DISCONTINUATIONS
The following events are considered sufficient reasons for discontinuing a subject from the 
investigational product and/or from the study:
#
Hgb > 14 g/dL (not influenced by transfusions), sustained for ≥7 days, confirmed by 
two assessments ≥1 week apart.
#
Hypertension DLT as defined in Section 4.1.1.
#
Any other (ie, excluding Hgb and hypertension) treatment-related (suspected) toxicity 
≥Grade 3.
#
Treatment-related (suspected) toxicity ≤Grade 2 that delays treatment by more than 3 
months.
#
Adverse event that, in the judgment of the investigator, may cause severe or 
permanent harm or that rules out continuation of treatment.
#
Lack of therapeutic effect, defined by lack of HI-E (Appendix C) after five cycles (or 
up to eight cycles for potential late responders) of treatment.
#
Requirement for reduction of dose to < 0.075 mg/kg Q3W.
#
Hypersensitivity reaction to sotatercept.
#
Disease progression.
#
Withdrawal of consent.
#
Death.
#
Lost to follow-up.
#
Pattern of significant noncompliance.
#
Completed study, per protocol (5 complete cycles of 21 days each).  Subjects who 
have a sustained Hgb increase or a decreased transfusion burden by end of Cycle 5
but for a period less than or equal to 8 consecutive weeks (potential late responders) 
may continue treatment for up to an additional three cycles (Cycles 6-8) for the 
purpose of meeting response criteria.  Survival data and AML progression will 
continue to be collected for up to 24 months from first dose of study treatment.
The reason for treatment discontinuation should be recorded in the CRF and in the source 
documents.
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ts.


Sotatercept (ACE-011)
Protocol ACE-011-MDS-001
Celgene Corporation
Confidential and Proprietary
90
ACE-011-MDS-001 Amendment 4 Final: 4 Aug 2015
13.
EMERGENCY PROCEDURES
13.1.
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/Clinical 
Research Organization (CRO) 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. 
13.2.
Emergency Identification of Investigational Products
This is an open-label study.  The identity of the investigational product is clearly indicated on the 
packaging and labeling.
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Sotatercept (ACE-011)
Protocol ACE-011-MDS-001
Celgene Corporation
Confidential and Proprietary
91
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14.
REGULATORY CONSIDERATIONS
14.1.
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 Conference 
on Harmonization (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/Ethics 
Committee (EC) prior to commencement. The investigator will conduct all aspects of this study 
in accordance with applicable national, state, and local laws of the pertinent regulatory 
authorities.
14.2.
Investigator Responsibilities
Investigator responsibilities are set out in the ICH Guideline for GCP 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. 
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.
The investigator is responsible for keeping a record of all subjects who sign an informed consent 
document 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 CRFs and queries.
14.3.
Subject Information and Informed Consent
The investigator must obtain informed consent of a 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 informed consent document 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 
informed consent document 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 informed 
consent document.  The revised informed consent document signed and dated by the study
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Sotatercept (ACE-011)
Protocol ACE-011-MDS-001
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subject and by the person informing the study subject must be maintained in the investigator’s 
study files and a copy given to the study subject.
14.4.
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.
Should direct access to medical records require a waiver or authorization separate from the 
subject’s signed informed consent document, it is the responsibility of the investigator to obtain 
such permission in writing from the appropriate individual.
14.5.
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.
14.6.
Institutional Review Board/Independent Ethics Committee Review 
and Approval
Before the start of the study, the study protocol, informed consent document, 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 
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Protocol ACE-011-MDS-001
Celgene Corporation
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determine whether formal approval must be sought and whether the informed consent document 
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.
14.7.
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 AEs 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.
14.8.
Closure of the Study
Celgene reserves the right to terminate this study 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.).
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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15.
DATA HANDLING AND RECORDKEEPING 
15.1.
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 CRFs or CD-ROM.
15.2.
Data Management
Data will be collected via CRF and entered into the clinical database per Celgene 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.
15.3.
Record Retention
Essential documents must be retained by the investigator for a minimum of 2 years after the last 
approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region, or at least 2 years have elapsed since the 
formal discontinuation of clinical development of the IP. 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 informed consent documents 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
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Sotatercept (ACE-011)
Protocol ACE-011-MDS-001
Celgene Corporation
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#
All other source documents (subject records, hospital records, laboratory records, 
etc.)
#
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/Institution should take measures to prevent accidental or premature destruction of 
these documents.
ne
ities.
ties.
destruction
destruction


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16.
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 standard 
operating procedures.
16.1.
Study Monitoring and Source Data Verification
Celgene ensures that appropriate monitoring procedures are performed before, during and after 
the study.  Before the study is initiated at a site visit or at an investigator meeting, all aspects of 
the study are reviewed with the investigator and the staff.  Prior to enrolling subjects into the 
study, a Celgene representative will review the protocol, CRFs, procedures for obtaining 
informed consent, record keeping, and reporting of AEs/SAEs with the investigator.  Monitoring 
will include on-site visits with the investigator and his/her staff as well as any appropriate 
communications by mail, email, fax, or telephone.  At each monitoring visit, the facilities, 
investigational product storage area, CRFs, subject’s source documents, and all other study 
documentation will be inspected/reviewed by the Celgene representative for accuracy, adherence 
to the protocol and GCP.
Accuracy will be checked by performing source data verification that is a direct comparison of 
the entries made onto the CRFs 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 CRFs 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.
16.2.
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 GCP guidelines and 
regulations.
The investigator is required to permit direct access to the facilities where the study took place, 
source documents, CRFs and applicable supporting records of study subject participation for 
audits and inspections by IRB/IECs, regulatory authorities (eg, FDA, 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.
fter 
ter 
ects of 
cts of 
nto the
to the
ining
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tor
tor.  Moni
.  Moniti
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it, the facili
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and all oth
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tive f
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i
or ac
or ac
f
on that i
n that s a
rce docume
ce docum
d/or his/her 
/or his/he
queries by t
queries by t
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d consents, 
roper recor
oper reco
udy
udy-specifi
specifi
s
ng procedu
ng procedu
presentative
resentative
Celgene
Celgene S
quired to p
quired to 
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CRFs and
ect
ectioions by 
ns by I
thorized rep
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dits and/or 
ts and/or 
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ng an inspe


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17.
PUBLICATIONS
The results of this study may be published in a medical publication, journal, or may be used for 
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.  Selection of first authorship 
will be based on several considerations, including, but not limited to study participation, 
contribution to the protocol development, and analysis and input into the manuscript, related 
abstracts, and presentations in a study.
&(/*(1(35235,(7$5<,1)250$7,21


Sotatercept (ACE-011)
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18.
REFERENCES
Acceleron Report Number A011-01:  A single-center, randomized, double-blind, placebo-
controlled, single-dose, dose-escalation study to evaluate the safety, tolerability, 
pharmacokinetics, and effects on bone biomarkers of ACE-011 (ActRIIA-IgG1) administered to 
healthy, postmenopausal volunteers. Report included in Original IND submitted on 27 March 
2009 (Serial No. 0000).
Acceleron Report Number A011-02:  A randomized, double-blind, placebo-controlled, multiple-
dose, dose-escalation study to evaluate the safety, tolerability, and pharmacodynamics of ACE-
011 (ActRIIA-IgG1) in healthy postmenopausal women. Report included in Original IND 
submitted on 27 March 2009 (Serial No. 0000).
 
 
Chen YG, Lui HM, Lin SL, Lee JM, Ying S-Y.  Regulation of cell proliferation, apoptosis, and 
carcinogenesis by activin.  Exp Biol Med. 2002;227:75-87. 
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;108:419-25.
Cockcroft DW, Gault MH.  Prediction of creatinine clearance from serum creatinine.  Nephron 
1976; 16: 31-41.
 
 
Greenberg P, Cox C, Lebeau MM, Fenaux P, Morel P, Sanz G, et al. International scoring 
system for evaluating prognosis in myelodysplastic syndromes. Blood. 1997;89:2079-88.
Heaney ML, Golde DW. Myelodysplasia. N Engl J Med. 1999;340:1649-60.
 
 
 
 
 
Komrokji RS, Sekeres MA, List AF. Management of lower-risk myelodysplastic syndromes: the 
art and evidence. Curr Hematol Malig Rep. 2011;6:145-53.
 
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M, Fenaux 
M, Fenaux 
sisis in myel
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okji R
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Sotatercept (ACE-011)
Protocol ACE-011-MDS-001
Celgene Corporation
Confidential and Proprietary
99
ACE-011-MDS-001 Amendment 4 Final: 4 Aug 2015
Mathews LS.  Activin receptors and cellular signaling by the receptor serine kinase family.  
Endocr Rev. 1994;15: 310-25.
Murata M, Onomichi K, Eto Y, Shibai H, Muramatsu M.  Expression of erythroid differentiation 
factor (EDF) in Chinese hamster ovary cells.  Biochem Biophys Res Commun. 1988;151:230-5.
Nakao K, Kosaka M, Saito S.  Effects of erythroid differentiation factor (EDF) on proliferation 
and differentiation of human hematopoietic progenitors.  Exp Hematol. 1991;19: 1090-5.
National Heart, Lung, and Blood Institute, National Institutes of Health.  New York Heart 
Association Classification. 2008.
 
 
 
Perrien DS, Akel NS, Edwards PK, Carver AA, Bendre MS, Swain FL, et. al.  Inhibin A is an 
endocrine stimulator of bone mass and strength.  Endocrinology. 2007;148:1654-65.
Raza A., Reeves JA, Feldman EJ, Dewald GW, Bennett JM, Deeg HJ, et al. Phase 2 study of 
lenalidomide in transfusion-dependent, low-risk, and intermediate-1 risk myelodysplastic 
syndromes with karyotypes other than deletion 5q. Blood. 2008;111:86-93.
Rivier J, Spiess J, McClintock R, Vaughan J, Vale W.  Purification and partial characterization 
of inhibin from porcine follicular fluid.  Biochem Biophys Res Commun. 1985; 133:120-7.
Ruckle J, Jacobs M, Kramer W, Pearsall AE, Kumar R, Underwood KW, et. al.  Single-dose, 
randomized, double-blind, placebo-controlled study of ACE-011 (ActRIIA-IgG1) in 
postmenopausal women.  J Bone Miner Res. 2009;24:744-52.
  
 
 
 
Shiozaki M, Sakai R, Tabuchi M, Nakamura T, Sugino K, Sugino H, et al.  Evidence for the 
participation of endogenous activin A/erythroid differentiation factor in the regulation of 
erythropoiesis.  Proc Natl Acad Sci USA. 1992;89:1553-6. 
Shiozaki M, Sakai R, Tabuchi M, Eto Y, Kosaka M, Shibai H.  In vivo treatment with erythroid 
differentiation factor (EDF/activin A) increases erythroid precursors (CFU-E and BFU-E) in 
mice.  Biochem Biophys Res Commun. 1989;165:1155-61.
Sitnicka E, Ruscetti FW, Priestley GV, Wolf NS, Bartelmez SH. Transforming growth factor 
beta 1 directly and reversibly inhibits the initial cell divisions of long-term repopulating 
hematopoietic stem cells. Blood. 1996;88:82-8.
&(/*(1(
R, Tabuchi 
Tabuchi 
endogenous
ndogenous
  Proc Nat
Proc Na
M, Sakai R
, Sakai R
ntiat
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ochem
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Sitnicka E,
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2008;111:
2008;111
 Purificat
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ophys Re
Kumar R, U
umar R, U
ed study o
ed study of
Res
Res. 2009;2
2009;2
23
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Sotatercept (ACE-011)
Protocol ACE-011-MDS-001
Celgene Corporation
Confidential and Proprietary
100
ACE-011-MDS-001 Amendment 4 Final: 4 Aug 2015
Vardiman JW, Thiele J, Arber DA, Brunning RD, Borowitz MJ, Porwit A, et al. The 2008 
revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute 
leukemia: rationale and important changes. Blood. 2009;114:937-51.
Woodruff TK.  Regulation of cellular and system function by activin.  Biochem Pharmacol.
1998;55:953-63. 
Ying SY.  Inhibins, activins, and follistatins:  gonadal proteins modulating the secretion of 
follicle-stimulating hormone.  Endocrine Rev. 1988;9:267-93.
Zermati Y, Fichelson S, Valensi F, Freyssinier JM, Rouyer-Fessard P, Cramer E, et al.
Transforming growth factor inhibits erythropoiesis by blocking proliferation and accelerating 
differentiation of erythroid progenitors. Exp Hematol. 2000a;28:885-94
Zermati Y, Varet B, Hermine O. TGF-beta1 drives and accelerates erythroid differentiation in 
the epo-dependent UT-7 cell line even in the absence of erythropoietin. Exp Hematol.
2000b;28:256-66.
Zhou L, McMahon C, Bhagat T, Alencar C, Yu Y, Fazzari M, et al. Reduced SMAD7 leads to 
overactivation of TGF-beta signaling in MDS that can be reversed by a specific inhibitor of 
TGF-beta receptor I kinase. Cancer Res. 2011;71:955-63.
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19.
APPENDICES
Appendix A: The World Health Organization (WHO) Classification of the 
Myeloid Neoplasms and Leukemia (Vardiman, 2009)
* For this study only non-proliferative CMML will be included.
Category
Peripheral Blood
Bone Marrow
Refractory anemia (RA)
Anemia
< 1% blasts
< 1x109 monocytes
Erythroid dysplasia
< 10 % myeloid or megakaryocytic dysplasia
< 5% blasts
< 15% sideroblasts 
Refractory anemia with ring 
sideroblasts (RARS)
Anemia
< 1% blasts 
< 1x109 monocytes
Erythroid dysplasia
< 10 % myeloid or megakaryocytic dysplasia
< 5% blasts
> 15% sideroblasts
Refractory cytopenia with 
multilineage dysplasia 
(RCMD)
Bi-or pancytopenia
< 1% blasts
< 1x109 monocytes
Dysplasia in > 10% of the cells in 2 or more cell lines
< 5% blasts
< 15% sideroblasts
Refractory anemia with 
multilineage dysplasia and 
ring sideroblasts (RCMD-RS)
Bi-or pancytopenia
< 1% blasts
< 1x109 monocytes
Dysplasia in > 10% of the cells in 2 or more cell lines
< 5% blasts 
> 15% sideroblasts
Refractory anemia with excess 
blasts type I & II (RAEB-1 & 
RAEB II)
Cytopenia
Type I: 1-5% blasts
Type II: 5-19% blasts 
Uni or multilineage dysplasia
Type I 5-9% blasts
Type II 10-19% blasts
5q- syndrome
Anemia
Normal or elevated 
platelets
< 5% blasts
Normal or increased megakaryocytes
<5% blasts
MDS unclassified (MDS-U)
Cytopenia
< 1% blasts
unilineage dysplasia of myeloid or megakaryocytic line
< 5% blasts
MDS/MPN
Myelodysplastic 
syndromes/myeloproliferative 
neoplasms
-CMML*
--MDS/MPN-U
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Appendix B: International Prognostic Scoring System for MDS
(Greenberg, 1997)
Survival and AML Evolution Score Value
Prognostic Variable
0
0.5
1.0
1.5
2.0
Marrow Blasts (%)
< 5
5 to 10
n/a
11 to 20
21 to 30
Karyotype
Good
Normal or any 1 
of:
-Y
del(5q)
del(20q)
Intermediate
Any other 
chromosome 
anomaly
Poor
chromosome 7 
anomalies;
Complex:
! 3 chromosome 
anomalies
n/a
n/a
Cytopenias:
Neutrophil count < 1800/%L
Platelets < 100,000/%L
Hb < 10 g/dL
0 or 1
2 or 3
n/a
n/a
n/a
The total IPSS score and IPSS risk category are calculated as the sum of three individual scores 
based on the marrow blast percentage, the karyotype, and the number of cytopenias.
Risk Category
Combined Score = Sum of Marrow blast + Karyotype + Cytopenia Score
Low
0
Intermediate-1
0.5 to 1.0
Intermediate-2
1.5 to 2.0
High
! 2.5
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Appendix C: International Working Group (IWG) Response Criteria in 
Myelodysplasia (Cheson, 2006)
Altering Disease Natural History
Complete remission (CR)
Bone marrow: ≤5% myeloblasts with normal maturation of all cell lines
Persistent dysplasia will be noted
Peripheral blood:
Hemoglobin ≥11 g/dL
Platelets ≥100 x 109/L
Neutrophils ≥1.0 x 109/L
Blasts 0%
Partial remission (PR)
All CR criteria if abnormal before treatment, except:
Bone marrow blasts decreased by ≥50% over pretreatment but still > 5%
Cellularity and morphology not relevant
Marrow CR
Bone marrow:  ≤5% myeloblasts and decrease by ≥50% over 
pretreatment
Peripheral blood:  if HI responses, they will be noted in addition to marrow 
CR
Stable disease (SD)
Failure to achieve at least PR, but no evidence of progression for
> 8 weeks
Failure
Death during treatment
Disease progression characterized by worsening of cytopenias, increase in 
% of bone marrow blasts, or progression to a more advanced MDS FAB 
subtype than pretreatment
Disease Progression (PD)
For patients with:
# Less than 5% blasts:  ≥50% increase in blasts to > 5% blasts
# 5%-10% blasts:  ≥ 50% increase in blasts to > 10% blasts
# 10%-20% blasts:  ≥50% increase in blasts to > 20% blasts
# 20%-30% blasts:  ≥50% increase in blasts to > 30% blasts
Any of the following:
# At least 50% decrement from maximum remission/response levels in 
granulocytes or platelets
# Reduction in Hgb concentration by ≥2 g/dL 
# Transfusion dependence
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Appendix C: International Working Group (IWG) Response Criteria in 
Myelodysplasia (Cheson, 2006) (Continued)
Altering Disease Natural History
Disease transformation
Transformation to AML (30% or more blasts)
Relapse after CR or PR
At least one of the following:
# Return to pretreatment bone marrow blast %
# Decrement of ≥50% from maximum remission/response levels in 
granulocytes or platelets
# Reduction in Hgb concentration by ≥1.5 g/dL or transfusion 
dependence
Cytogenetic Response
Complete
Disappearance of the chromosomal abnormality without appearance of 
new ones
Partial
At least 50% reduction of the chromosomal abnormality
Hematological Improvement (HI)
Erythroid response (HI-E)
(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 weeks compared with the pretreatment 
transfusion number in the previous 8 weeks.  Only RBC transfusions 
given for a Hgb of ≤9.0 g/dL pretreatment will count in the RBC 
transfusion evaluation
Platelet response (HI-P)
(Pretreatment < 100 x 109/L)
Absolute increase of ≥30 x 109/L for patients starting with > 20 x 109/L
Increase from < 20 x 109/L to > 20 x 109/L and by at least 100%
Neutrophil response (HI-N)
(Pretreatment < 1.0 x 109/L)
At least 100% increase and an absolute increase of > 0.5 x 109/L
Progression/relapse after HI 
At least one 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
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Appendix D: ECOG Performance Status Scale
The ECOG Performance Status Scale is used to score a subject’s quality of life through
evaluation, by a health professional, of daily activities and how those activities are affected by 
the disease of the subject.
Score
Description
0
Fully active, able to carry on all pre-disease performance without restriction.
1
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2
Ambulatory and capable of all self-care but unable to carry out any work activities.  Up and 
about more than 50% of waking hours.
3
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours.
4
Completely disabled.  Cannot carry on any self-care.  Totally confined to bed or chair.
5
Dead
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Sotatercept (ACE-011)
Protocol ACE-011-MDS-001
Celgene Corporation
Confidential and Proprietary
106
ACE-011-MDS-001 Amendment 4 Final: 4 Aug 2015
Appendix E: New York Heart Association ∀Classification of Heart Failure
Classification of Heart Failure
Class
Symptoms
Class 1
No limitation of activities.  No symptoms from ordinary activities
Class 2
Mild limitation of activity.  Comfortable with rest or mild exertion
Class 3
Marked limitation of activity and be comfortable only at rest
Class 4
Complete rest, confined to bed or chair; any physical activity brings on discomfort and 
symptoms occur at rest
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Sotatercept (ACE-011)
Protocol ACE-011-MDS-001
Celgene Corporation
Confidential and Proprietary
107
ACE-011-MDS-001 Amendment 4 Final: 4 Aug 2015
Appendix F: National Cancer Institute (NCI) Common Terminology Criteria 
for Adverse Events (CTCAE) Version 4.0
Currently active minor version of NCI CTCAE, Version 4.0:
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40
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Sotatercept (ACE-011)
Protocol ACE-011-MDS-001
Celgene Corporation
Confidential and Proprietary
109
ACE-011-MDS-001 Amendment 4 Final: 4 Aug 2015
Appendix H: Cockcroft-Gault Estimation Of Creatinine Clearance (Crcl)
Cockcroft-Gault estimation of creatinine clearance (CRcl): CRcl (mL/min) = (140 – age) (weight 
[kg]) / 72 (serum creatinine [mg/dl]); for females, the formula is multiplied by 0.85 (Cockcroft, 
1976; Luke, 1990).
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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.
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Sotatercept (ACE-011)
Summary of Changes ACE-011-MDS-001
Celgene Corporation
Confidential and Proprietary
3
ACE-011-MDS-001 Amendment 4 Final: 04 Aug 2015
1.
JUSTIFICATION FOR AMENDMENT
Significant changes included in this amendment are summarized below:
!
Subjects in the sotatercept 2.0 mg/kg dosing group were dose reduced to sotatercept 1.5 
mg/kg.
!
Subsequent enrollment into this dosing group is at sotatercept 1.5 mg/kg.
!
Enrollment into Part 2 (expansion) to commence without delay at a sotatercept dose 
level of 1.0 mg/kg. 
Revised Sections: Summary of Protocol, Section 4.1, 4.2, 7.1, 8.2, 8.2.1, 8.3.2, 10.1 and 10.8
The ACE-011-MDS-001 Steering Committee met on 02 Mar 2015 to review available safety, 
efficacy and pharmacokinetic data up to and including the sotatercept 2.0 mg/kg dose level (five 
subjects at 2.0 mg/kg). The following recommendations were made:
!
Closure of the 2.0 mg/kg cohort to further enrollment and sotatercept dose reduction to 
1.5 mg/kg, at the next planned dose administration, for active patients and subsequent 
patients enrolled to this cohort. 
!
Begin enrollment into Part 2 (expansion) of the study immediately at 1.0 mg/kg 
sotatercept.
A letter was sent to the investigative sites on 04 Mar 2015 directing immediate implementation
of the Steering Committee recommendations listed above. 
The Steering Committee recommendations have been incorporated in Amendment 4.
!
Language was added to include the availability of a roll-over protocol for subjects that 
remain on study following the analysis of all key endpoints and objectives of the study.
Revised Sections: Summary of Protocol and Section 4.3
Subjects who are still deriving benefit from sotatercept therapy will have the opportunity to 
continue therapy when enrolled into the planned rollover protocol, per investigator discretion.
!
A request for historic MDS molecular mutational analysis data, if available, has been
added.
Revised Sections: Summary of Protocol, Sections 5 (Table of Events) and 6.
Historic MDS molecular mutational analysis data is requested to assess any correlation of a 
specific mutation(s) and safety and efficacy parameters.   
!
Recently published preclinical data has been added.
Revised Section:  Sections 1.1 and 1.2.1
 
!
Addition of references related to recently published preclinical data.
Revised Section:  References
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&


Sotatercept (ACE-011)
Summary of Changes ACE-011-MDS-001
Celgene Corporation
Confidential and Proprietary
4
ACE-011-MDS-001 Amendment 4 Final: 04 Aug 2015
The amendment also includes several other minor clarifications and corrections:
!
Addition of the name of the Therapeutic Area Head.
Revised Section:  Celgene Therapeutic Area Head Signature Page
!
Clarifying language has been added to describe the completion of treatment in the 
Treatment Period versus the completion of treatment in the Extension Period to facilitate 
more accurate data capture and assessment implementation. 
Revised Sections: Summary of Protocol, Sections 4.1.2, 4.3 and 5 (Table of Events)
!
Clarification on when transfusions should be recorded and recording of pre-transfusion
hemoglobin levels.
Revised Sections: Summary of Protocol, Section 5 (Table of Events), and 6
!
Clarification of subject eligibility for the Extension Period of the study has been added. 
Revised Section: Section 4.1.2
!
Clarification of bone marrow aspirate slide staining has been added to facilitate correct 
preparation.
Revised Sections: Section 5 (Table of Events) and 6
!
Other administrative changes (e.g., correction of typographical errors, editorial changes, 
etc.) were also incorporated.
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Sotatercept (ACE-011)
Protocol ACE-011-MDS-001
Celgene Corporation
Confidential and Proprietary
3
ACE-011-MDS-001 Amendment 3 Final: 05 Aug 2013
1.
JUSTIFICATION FOR AMENDMENT
Significant changes included in this amendment are summarized in this section.
The main objective of this amendment is to include additional dose levels beyond 0.5 mg/kg, as 
described below:
!
Additional dose levels added beyond 0.5 mg/kg cohort (ie, 1.0 mg/kg SC Q3W and 2.0 
mg/kg SQ Q3W), as 0.5 mg/kg may be sub-therapeutic in study population.  
!
Additional safety measure added to ensure adequate data are available and reviewed by 
the Steering Committee prior to all future dose escalation.
!
Additional safety measure added to allow potential exploration of intermediate dose 
levels (eg, 0.75 mg/kg and 1.5 mg/kg) at time of dose escalation to 1.0 mg/kg and 2.0 
mg/kg respectively upon Steering Committee review of safety and efficacy data.
!
Additional dose reduction levels added to account for additional dose levels added 
beyond 0.5 mg/kg.
!
New text added to provide guidance to sites when total volume of calculated dose 
exceeds what is typically administered in one SC injection.  
!
 
!
New text added related to timing of Steering Committee meetings to account for 
additional dose levels beyond 0.5 mg/kg.
The following changes are based on feedback from the Steering Committee, site investigators, or 
site staff after commencement of enrollment and additional experience obtained during conduct 
of the trial.
!
Additional guidance related to pre-dose Hgb level prior to Cycle 1 Day 1 treatment 
administration for subjects who are deemed TIE per protocol.  
!
New text added related to Steering Committee guidance on closure of treatment group to 
further enrollment due to lack of efficacy to minimize number of patients enrolled at sub-
therapeutic doses after their review of safety and efficacy data.
!
New text added to account for varying operational logistics at study sites related to timing 
of availability of pre-dose Hgb result.  
!
Clarification on HI-E definition for subjects who are classified as TIE per protocol.
!
Clarification added that hypertension DLT should be confirmed by study 
investigator/clinical site at the clinical site and not based solely on a measurement taken 
at home by the subject or caretaker.
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Sotatercept (ACE-011)
Protocol ACE-011-MDS-001
Celgene Corporation
Confidential and Proprietary
4
ACE-011-MDS-001 Amendment 3 Final: 05 Aug 2013
!
Clarification added related to protocol-required prior ESA treatment, accepting either 
alpha or beta (applicable in EU) rHu EPO and to account that subjects may receive 
optimal dose regimen at varying frequencies.
 
Additional inclusion criteria added to limit number of lines of prior MDS treatment (not 
including ESAs) to balance heavily pre-treated and non-heavily pre-treatment patient population.
 
 
New text added to account for varying operational logistics at study sites related to timing of 
availability of pre-dose Hgb result.  
New text added to clarify that weekly blood pressure monitoring at home (if applicable to 
subject) may be measured by subject or caretaker.
New text added related to “End of Trial” and “Overdose” definition from updated Celgene 
protocol template.
Other changes (eg, update of protocol template sections, correction of typographical errors, 
editorial changes, changes to ensure consistency of text throughout document, modifications 
related to Celgene Style Guide, etc.) were also incorporated and are detailed in Section 2, 
Itemized Changes.
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Sotatercept (ACE-011)
Summary of Changes ACE-011-MDS-001
Celgene Corporation
Confidential and Proprietary
3
ACE-011-MDS-001 Amendment 2 Final: 13 Feb 2013
1.
JUSTIFICATION FOR AMENDMENT
Significant changes included in this amendment are summarized below.
The following changes are based on feedback received from the Steering Committee, study 
investigators, and site staff upon review of Amendment 1 of protocol ACE-011-MDS-001 in 
forums such as the Steering Committee Kick-Off Meeting, Investigator Meeting, Site Initiation 
Visits, or site ad hoc review of the protocol:
!
Add clarification related to the hypertension dose-limiting toxicity (DLT) definition to 
ensure harmonization of DLT assessment for hypertension across all study sites due to 
unique attributes of the study population.  
!
Provide clear parameters for Extension Period eligibility to offer flexibility for those 
subjects who do not meet protocol-defined erythroid hematological improvement (HI-E) 
to enter the Extension Period, at the investigator’s discretion, if clinical benefit is seen at 
the conclusion of the Treatment Period.  
!
Remove the Cycle 3 Day 1 mandatory MDS response assessment as it is deemed too 
soon after initiation of treatment of study drug.
!
Continue to follow efficacy parameters (ie Hgb and transfusions) for up to 3 months after 
the last dose of study drug or start of next treatment to assess potential late response after 
study drug discontinuation as is sometimes observed with erythroid stimulating agents 
(ESAs).
!
Modify the adverse event reporting period to 42 days after the last dose is administered
(regardless of causality) to account for the likelihood that the subject will begin 
additional cytotoxic treatment after treatment discontinuation.  Beyond 42 days, all SAEs 
deemed suspected related to study drug will still be reported.
!
Include chromosome del5q MDS patients who have failed on lenolidomide, intolerable to 
lenalidomide, or have other cytopenia precluding use of lenalidomide, as these patients 
could potentially benefit from treatment with sotatercept.
The following changes are based on 
 
 review of Amendment 1 of protocol ACE-011-MDS-001:
!
Increase the frequency of blood pressure monitoring from once per cycle to weekly 
during the first 5 cycles of treatment, with the added flexibility of home monitoring.  
!
Addition of an Independent Cardiologist to the Steering Committee to focus on potential 
cardiovascular effects of the study drug.
!
Increase the contraception use requirement for males after the last administration of study 
drug from 112 days to 7 months/210 days to account for the limited data on the study 
drug’s effect on spermatogenesis.  
The following changes are based on 
review 
of Amendment 1 of protocol ACE-011-MDS-001:
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Sotatercept (ACE-011)
Summary of Changes ACE-011-MDS-001
Celgene Corporation
Confidential and Proprietary
4
ACE-011-MDS-001 Amendment 2 Final: 13 Feb 2013
!
Agreement on additional language related to clarification of the hypertension DLT 
definition.
!
Exclusion of subjects at high risk for cardiovascular events, including those requiring 
chronic anticoagulant therapy during the course of the study and those with myocardial 
infarction within 6 months of study start.  
!
Addition of ECG assessments during the Treatment Period to further explore potential 
cardiovascular effects of the study drug.
Other administrative changes (eg, update of protocol template sections, correction of 
typographical errors, editorial changes) were also incorporated and are detailed in Section 2, 
Itemized Changes.
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Sotatercept (ACE-011)
Summary of Changes ACE-011-MDS-001
Celgene Corporation
Confidential and Proprietary
3
ACE-011-MDS-001 AMENDMENT 1 FINAL: 13SEP2012
1.
JUSTIFICATION FOR AMENDMENT
Significant changes included in this amendment are summarized below.  
The following changes are based on feedback received following
 
review of the final protocol ACE-011-MDS-001:
1. Revision of protocol title and Inclusion Criteria to reflect the inclusion of CMML as a 
sub-classification of the MDS/MPN sub-group as outlined in protocol Appendix A ‘The 
World Health Organization (WHO) Classification of the Myeloid Neoplasms and 
Leukemia’.
2. Revision of the dose-limiting toxicity (DLT) criteria, Rules for Delay, Reduction and 
Discontinuation of Treatment (Table 7) and Reasons for Discontinuation for:
a.
Hemoglobin > 12 g/dL, sustained for ≥7 days, confirmed by 2 assessments ≥1 
week apart.
b. Hypertension ≥Grade 2 according to National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0 (current 
active minor version), blood pressure values must be confirmed by two readings 
obtained 5 minutes apart.
c.
Treatment-related (suspected) toxicity ≥Grade 3.
3. Clarification of definition of favorable safety profile as a safe, tolerable and effective 
dose of sotatercept that results in the greatest frequency of erythroid hematological 
improvement in patients with anemia and low- or intermediate-1 risk myelodysplastic 
syndromes.   
4. Addition of specific early stopping criteria for an excess number of DLTs or the absence 
of efficacy within a dose cohort.
5. Revision of inclusion criteria to:
a.
Only allow subjects requiring red blood cell transfusions to be eligible for the 
study. 
b. Add language that females of child bearing potential must agree to use effective 
contraception while participating in this study. 
c.
Add pregnancy prevention language for males participating in this study.
6. Revision of exclusion criteria to exclude subjects with uncontrolled hypertension 
(systolic blood pressure (SBP) > 140 mm Hg or diastolic blood pressure (DBP) ≥90).  
a.
Controlled hypertension for this protocol is considered ≤ Grade 1 according to 
NCI CTCAE version 4.0 (current active minor version).
7. Revision of Rules for Delay, Reduction and Discontinuation of Treatment Section,
including Table 7, to:
a.
Clarify discontinuation due to treatment-related (suspected) toxicity ≥Grade 3.
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7.7


Sotatercept (ACE-011)
Summary of Changes ACE-011-MDS-001
Celgene Corporation
Confidential and Proprietary
4
ACE-011-MDS-001 AMENDMENT 1 FINAL: 13SEP2012
b. Clarify discontinuation due to treatment-related (suspected) toxicity ≤Grade 2 
that delays treatment by more than 3 months.
c.
Provide dose reduction guidance for subjects who experience a rapid rise in 
hemoglobin.
8. Revision of Causality Section to define that a temporal relationship is not necessary to 
make causality possible. 
9. Clarification of the Treatment Plan for Part 1 and Part 2 of the study. 
10. Clarification of reporting of all Suspected Unexpected Serious Adverse Reactions in 
accordance with 21 Code of Federal Regulations (CFR) 312.32.
Additional changes include:
11. Addition of serum erythropoietin assessment during screening period to determine 
stratification
12. Modification of Introduction to include information about variation of anemia associated 
with myelodysplastic syndromes and revise description of sotatercept.  
13. Clarification of the scope of activity and meeting schedule of the steering committee.
14. Clarification of the start of enrollment into Part 2 of the study.
15. Clarification of the study start timeframe as the date of randomization in Part 1 and the 
date of start of therapy in Part 2 of the study.
16. Revision of the approximate number of study sites to participate in the study.
17. Clarify use of central laboratory for clinical laboratory assessments and when a local 
laboratory is allowed to be utilized.
18. Clarify version of NCI CTCAE to be utilized in the study.
19. Addition of a reference.
Other administrative changes (eg, protocol template section updates, correction of 
typographical errors, editorial changes, etc.) were also incorporated and are outlined in 
Section 2, Itemized Changes.
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Sotatercept (ACE-011)
Statistical Analysis Plan: ACE-011-MDS-001
Celgene Corporation
Confidential and Proprietary
1
STATISTICAL ANALYSIS PLAN
AN OPEN-LABEL, RANDOMIZED, PHASE 2, PARALLEL, 
DOSE-RANGING, MULTICENTER STUDY OF SOTATERCEPT
FOR THE TREATMENT OF PATIENTS WITH ANEMIA AND 
LOW- OR INTERMEDIATE-1 RISK MYELODYSPLASTIC 
SYNDROMES OR NON-PROLIFERATIVE CHRONIC 
MYELOMONOCYTIC LEUKEMIA (CMML)
Prepared by:
Celgene Corporation
86 Morris Avenue
Summit, NJ 07901
STUDY DRUG:
Sotatercept (ACE-011)
PROTOCOL NUMBER:
ACE-011-MDS-001
DATE FINAL:
May 1, 2018
CONFIDENTIAL
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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Sotatercept (ACE-011)
Statistical Analysis Plan: ACE-011-MDS-001
Celgene Corporation
Confidential and Proprietary
2
TABLE OF CONTENTS
1.
LIST OF ABBREVIATIONS...................................................................................6
2.
INTRODUCTION..................................................................................................10
3.
OBJECTIVES ........................................................................................................11
4.
INVESTIGATIONAL PLAN .................................................................................13
4.1.
Design of Study......................................................................................................13
5.
STUDY ENDPOINTS............................................................................................17
5.1.
Primary Endpoint....................................................................................................17
5.2.
Secondary Endpoints ..............................................................................................17
5.4.
Sample Size............................................................................................................18
6.
GENERAL STATISTICAL CONSIDERATIONS .................................................19
6.1.
Reporting Conventions ...........................................................................................19
6.1.1.
Dates Handling.......................................................................................................19
6.1.2.
Calculation using dates...........................................................................................20
6.2.
Data Included in Planned Analyses.........................................................................21
6.2.1.
Data Included in the Analysis for the Clinical Study Report (CSR).........................21
6.3.
Analysis Populations ..............................................................................................21
6.3.1.
Intent-to-Treat Population.......................................................................................21
6.3.2.
Safety Population....................................................................................................21
6.3.3.
Efficacy Evaluable (EE) Population........................................................................21
6.3.4.
Transfusion-Dependent Efficacy (TDE) Population................................................21
6.3.5.
Non Transfusion-Dependent Efficacy (NTDE) Population......................................21
6.3.6.
Pharmacokinetic (PK) Population...........................................................................21
6.4.
Definitions..............................................................................................................22
6.4.1.
Study Treatment Start Date.....................................................................................22
6.4.2.
Study Treatment End Date......................................................................................22
6.4.3.
End Date of each Cycle ..........................................................................................22
6.4.4.
Calculation of Cycles..............................................................................................22
6.4.5.
Baseline..................................................................................................................22
6.4.6.
Treatment emergent assessment/event ....................................................................22
7.
STUDY DISPOSITION..........................................................................................23
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Sotatercept (ACE-011)
Statistical Analysis Plan: ACE-011-MDS-001
Celgene Corporation
Confidential and Proprietary
3
7.1.
Subject Disposition.................................................................................................23
7.2.
Protocol Violations / Deviations .............................................................................23
8.
DEMOGRAPHICS AND BASELINE CHARACTERISTICS................................25
8.1.
Demographics.........................................................................................................25
8.2.
Baseline Disease Characteristics.............................................................................25
8.3.
Baseline Laboratories .............................................................................................25
8.4.
Medical History......................................................................................................26
8.5.
Prior MDS Therapy ................................................................................................26
8.6.
Prior and Concomitant Medications........................................................................26
9.
STUDY TREATMENTS AND EXTENT OF EXPOSURE....................................27
9.1.
Treatment Duration.................................................................................................27
9.2.
Dose Modification..................................................................................................27
10.
EFFICACY ANALYSIS ........................................................................................28
10.1.
RBC-Transfusion Analysis .....................................................................................28
10.2.
Hemoglobin Analysis .............................................................................................29
10.3.
Time to Progression to AML and Time to Progression of higher risk MDS.............29
10.4.
Progression Free Survival (PFS) .............................................................................30
10.5.
Overall Survival .....................................................................................................30
11.
PHARMACOKINETIC ANALYSIS......................................................................31
11.1.
Pharmacokinetic Analysis.......................................................................................31
11.1.1.
Data Handling ........................................................................................................31
11.1.2.
Pharmacokinetic Parameters...................................................................................31
11.2.
PK Analysis............................................................................................................32
12.
SAFETY ANALYSIS ............................................................................................33
12.1.
Dose-limiting Toxicity............................................................................................33
12.2.
Adverse Events.......................................................................................................34
12.3.
Clinical Laboratory Evaluations..............................................................................34
12.4.
Vital Sign Measurements........................................................................................34
12.5.
Electrocardiogram ..................................................................................................34
13.
REFERENCES.......................................................................................................35
14.
APPENDICES........................................................................................................36
14.1.
Date Imputation Guideline......................................................................................36
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Sotatercept (ACE-011)
Statistical Analysis Plan: ACE-011-MDS-001
Celgene Corporation
Confidential and Proprietary
4
14.1.1.
Impute Missing AE/ Prior or Concomitant Medications Start Dates........................36
14.1.2.
Impute Missing AE/ Prior or Concomitant Medications Stop Dates ........................36
14.2.
Schedule of Assessments........................................................................................38
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Sotatercept (ACE-011)
Statistical Analysis Plan: ACE-011-MDS-001
Celgene Corporation
Confidential and Proprietary
5
SIGNATURE PAGE
Study Statistician
Signature
Printed 
Name
Date
Therapeutic Head of Statistics
Signature
Printed Name
Date
Clinical Research Physician
Signature
Printed 
Name
Date
Safety Physician 
Signature
Printed 
Name
Date
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Sotatercept (ACE-011)
Statistical Analysis Plan: ACE-011-MDS-001
Celgene Corporation
Confidential and Proprietary
6
1.
LIST OF ABBREVIATIONS 
Table 1:
Abbreviations and Special Terms
Abbreviation or special term
Explanation
ADA
Antidrug Antibody
AE
Adverse Event
AML
Acute Myeloid Leukemia
ANC
Absolute Neutrophil Count
ATC
Anatomical Therapeutical Chemical
AUC
Area Under the Curve
CMML
Chronic Myelomonocytic Leukemia
CR
Complete Response
CRF
Case Report Form
CTC
Common Toxicity Criteria
CTCAE
Common Terminology Criteria for Adverse Events
 
DLT
Dose-Limiting Toxicity
EBMT
European Group for Blood and Marrow 
Transplantation
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
EE
Efficacy Evaluable Population
EPO
Erythropoietin
ESA
Erythropoietin Stimulating Agent 
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Sotatercept (ACE-011)
Statistical Analysis Plan: ACE-011-MDS-001
Celgene Corporation
Confidential and Proprietary
7
Abbreviation or special term
Explanation
ADA
Antidrug Antibody
AE
Adverse Event
AML
Acute Myeloid Leukemia
ANC
Absolute Neutrophil Count
ATC
Anatomical Therapeutical Chemical
AUC
Area Under the Curve
CMML
Chronic Myelomonocytic Leukemia
CR
Complete Response
CRF
Case Report Form
CTC
Common Toxicity Criteria
CTCAE
Common Terminology Criteria for Adverse Events
 
DLT
Dose-Limiting Toxicity
EBMT
European Group for Blood and Marrow 
Transplantation
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
EE
Efficacy Evaluable Population
EPO
Erythropoietin
ESA
Erythropoietin Stimulating Agent 
Abbreviation or special term
Explanation
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Sotatercept (ACE-011)
Statistical Analysis Plan: ACE-011-MDS-001
Celgene Corporation
Confidential and Proprietary
8
Hgb
Hemoglobin
HI-E
Erythroid Hematological Improvement
IWG
International Working Group
IPSS
International Prognostic Scoring System
IVRS/IWRS
Interactive Voice/Web Response System
MedDRA
Medical Dictionary for Regulatory Activities
MR
Minimal Response
MDS
Myelodysplastic Syndromes
MTD
Maximum Tolerated Dose
NCI 
National Cancer Institute 
NTDE
Non Transfusion-Dependent Efficacy Population
ORR
Overall Response Rate
OS
Overall Survival
PD
Progressive Disease
PK
Pharmacokinetics
PFS
Progression-free Survival
PR
Partial Response
RBC
Red Blood Cell
SAP
Statistical Analysis Plan
Abbreviation or special term
Explanation
SAS®
Statistical Analysis System (software package)
SD
Stable Disease
TDE
Transfusion-Dependent Efficacy Population
TEAE
Treatment-emergent Adverse Event
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Sotatercept (ACE-011)
Statistical Analysis Plan: ACE-011-MDS-001
Celgene Corporation
Confidential and Proprietary
9
WHO
World Health Organization
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Sotatercept (ACE-011)
Statistical Analysis Plan: ACE-011-MDS-001
Celgene Corporation
Confidential and Proprietary
10
2.
INTRODUCTION
This statistical analysis plan (SAP) describes the analyses and data presentations to be performed
for Celgene’s protocol ACE-011-MDS-001, “An open-label, randomized, Phase 2, parallel, 
dose-ranging, multicenter study of sotatercept for the treatment of patients with anemia and low-
or intermediate-1 risk myelodysplastic syndromes or non-proliferative chronic myelomonocytic 
leukemia (CMML).” It contains definitions of analysis populations, derived variables and 
statistical methods for the analysis of efficacy and safety.
This SAP will be finalized and signed off prior to final clinical database lock and analysis. All 
statistical analyses detailed in this SAP will be conducted using SAS® Version 9.2 or higher. 
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Sotatercept (ACE-011)
Statistical Analysis Plan: ACE-011-MDS-001
Celgene Corporation
Confidential and Proprietary
11
3.
OBJECTIVES
The primary objective is:
!
To determine a safe, tolerable and effective dose of sotatercept that results in the 
greatest frequency of erythroid hematological improvement (HI-E) in patients with 
anemia and low- or intermediate-1 risk Myelodysplastic syndromes (MDS) or non-
proliferative chronic myelomonocytic leukemia (CMML). 
The secondary objectives are:
1. Safety of sotatercept
2. Rate of red blood cell (RBC) transfusion independence in transfusion-dependent subjects
3. Time to HI-E
4. Duration of HI-E
5. Time to progression to acute myeloid leukemia (AML)
6. Time to progression to events of higher risk MDS (ie, int-2 or high-risk IPSS)
7. Progression-free survival (PFS)
8. Overall survival (OS)
9. Pharmacokinetics (PK) of sotatercept
 
 
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Sotatercept (ACE-011)
Statistical Analysis Plan: ACE-011-MDS-001
Celgene Corporation
Confidential and Proprietary
12
 
 
 
 
 
 
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Sotatercept (ACE-011)
Statistical Analysis Plan: ACE-011-MDS-001
Celgene Corporation
Confidential and Proprietary
13
4.
INVESTIGATIONAL PLAN
4.1.
Design of Study
This is an open-label, randomized, Phase 2, parallel, dose-ranging, multicenter study of 
sotatercept for the treatment of patients with low- and int-1 risk MDS or non-proliferative 
CMML (IPSS), with anemia requiring a transfusion (subjects should have received at least 2 
units of RBCs within 84 days prior to study enrollment).
The study is comprised of 2 parts:
Part 1
Subjects will be stratified by concentration of serum erythropoietin (EPO, < 500 versus ≥ 
500 mIU/mL) and by number of transfusions within 56 days prior to study enrollment (< 4 units 
of RBCs versus ≥ 4 units of RBCs), and assigned randomly to one of two treatment groups, 
wherein they will be administered sotatercept subcutaneously (SC) 0.1 mg/kg or 0.3 mg/kg once 
every 3 weeks (Q3W).
Enrollment will continue without hiatus beyond randomization of 5 subjects into each of the 
0.1 mg/kg and 0.3 mg/kg treatment groups.  Following treatment of 5 subjects in each of the 0.1 
mg/kg and 0.3 mg/kg treatment groups (with the last subject for each group having completed at 
least 1 cycle of 21 days), all available safety and efficacy data will be assessed by a Steering 
Committee.  Based upon the occurrence of dose-limiting toxicity (DLT) in ≤ 1/5 subjects in 
Cycle 1 in the 0.1 mg/kg and 0.3 mg/kg treatment groups, the 0.5 mg/kg treatment group will 
begin inclusion in the randomization scheme.
Following treatment of at least 6 subjects in the 0.5 mg/kg treatment group (with at least 6 
subjects having completed at least 3 cycles of 21 days each), all available safety and efficacy 
data from all dose levels will be assessed by a Steering Committee.  Based upon the occurrence 
of dose-limiting toxicity (DLT) in ≤ 1/6 subjects in Cycle 1 in the 0.5 mg/kg treatment group and 
an acceptable safety profile from all dose levels, the 1.0 mg/kg treatment group will begin 
inclusion in the randomization scheme.  
Following treatment of at least 6 subjects in the 1.0 mg/kg treatment group (with at least 6  
subjects having completed at least 3 cycles of 21 days each), all available safety and efficacy 
data from all dose levels will be assessed by a Steering Committee.  Based upon the occurrence 
of dose-limiting toxicity (DLT) in ≤ 1/6 subjects in Cycle 1 in the 1.0 mg/kg treatment group and 
an acceptable safety profile from all dose levels, the 2.0 mg/kg treatment group will begin 
inclusion in the randomization scheme.  
Meetings of the Steering Committee are planned periodically throughout the study to review all 
available safety and efficacy data.  For any treatment group, if ≥ 40% of the subjects (minimum 
4 subjects experiencing an event) experience a DLT of related (suspected) adverse event (AE) 
≥Grade 2 (other than Hgb or hypertension), the Steering Committee may recommend the closure 
of the treatment group.
In addition, if >= 33% of the subjects (minimum 2 subjects experiencing an event) experience 
Hgb > 12 g/dL (not influenced by transfusions) sustained for ≥ 7 days, confirmed by 2 
assessments ≥ 1 week apart, the Steering Committee may recommend the closure of the 
treatment group.
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Sotatercept (ACE-011)
Statistical Analysis Plan: ACE-011-MDS-001
Celgene Corporation
Confidential and Proprietary
14
Moreover, if ≥33% of the subjects (minimum 2 subjects experiencing an event) experience a 
hypertension DLT, the Steering Committee may recommend the closure of the treatment group.
Additionally, for any treatment group that accrues a minimum of 10 subjects or less if 
recommending by the Steering Committee (with the last subject having received at least one 
complete cycle of 21 days), in the absence of any sign of efficacy (defined as an increase of Hgb 
> 1 g/dL in the absence of transfusion or at least a 50% reduction in the transfusion requirements 
if the reduction observed is less than 4 units).
Figure 1:
Design of Study
a
Intermediate cohorts (not to exceed 2.0 mg/kg) may be added at the time of dose escalation up to 1.0 mg/kg and up to 2.0 
mg/kg (eg 0.75 mg/kg or 1.5 mg/kg respectively) based on assessment by the Steering Committee of available safety and 
efficacy data when at least 6 subjects have at least 3 cycles of treatment in the current dose level. 
b
Randomization to the sotatercept 0.5 mg/kg SC Q3W treatment group may begin only after treatment of 5 subjects in the 0.1 
mg/kg SC and 5 subjects in the 0.3 mg/kg SC treatment groups with the last subject for each group having completed at least 
1 cycle of 21 days, and an assessment of all available safety and efficacy data for all subjects. 
c
Randomization to the sotatercept 1.0 mg/kg SC Q3W treatment group may begin only after treatment of at least 6 subjects in 
the 0.5 mg/kg treatment group (or current dose level if intermediate cohort is added) with at least 6 subjects having 
completed at least 3 cycles of 21 days each, and an assessment of all available safety and efficacy data for all subjects. 
d
Randomization to the sotatercept 2.0 mg/kg SC Q3W treatment group may begin only after treatment of at least 6 subjects in 
the 1.0 mg/kg treatment group (or current dose level if intermediate cohort is added) with at least 6 subjects having 
completed at least 3 cycles of 21 days each, and an assessment of all available safety and efficacy data for all subjects. 
Upon completion of up to 20 evaluable subjects in each of the treatment groups, analyses will be 
conducted in order to evaluate the safety profile of sotatercept and identify the dose that results 
in the greatest frequency of HI-E.
Subjects 
who meet 
eligibility 
criteria 
and 
provide 
written 
informed 
consent
After  
5 -8
cycles of
treatment, 
assess 
erythroid 
hematologic 
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No Response
Discontinue 
treatment 
Response
Continue 
treatment Q3W
Sotatercept 0.1 mg/kg SC Q3W
Sotatercept 0.3 mg/kg SC Q3W
bSotatercept 0.5 mg/kg SC Q3W
Up to 20 
subjects in each 
dose level
Randomize
Assess 
MDS and 
OS q6 
months, up to
24 months following first
treatment 
Part 1
Progression or 
Therapeutic failure
Discontinue treatment
a,cSotatercept 1.0 mg/kg SC 
Q3W
a, d Sotatercept 2.0
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Sotatercept (ACE-011)
Statistical Analysis Plan: ACE-011-MDS-001
Celgene Corporation
Confidential and Proprietary
15
Part 2
Following the assessment of efficacy and safety parameters in Part 1, 15 additional subjects will 
be enrolled in Part 2 at the dose level of sotatercept that demonstrates the greatest frequency of 
HI-E.
DLT
DLT’s are described in Section 12.1.


Sotatercept (ACE-011)
Statistical Analysis Plan: ACE-011-MDS-001
Celgene Corporation
Confidential and Proprietary
16
Study Periods
Both Part 1 and Part 2 of the study are comprised of the following periods:
Screening – Assessments to be performed up to 28 days prior to enrollment (Day 1).  If screening 
assessments, with the exception of Hgb and blood pressure, are conducted within 7 days of enrollment 
(Day 1), they are not required to be repeated at enrollment (Day 1).  Hemoglobin and blood pressure must 
be assessed within 8 hours prior to study drug administration.
Treatment – Comprised of 5 complete cycles of 21 days each of treatment on a schedule of Q3W.  
Subjects requiring ≥ 4 units of RBC at baseline who fail to demonstrate, after completing 5 cycles of 
treatment, a decrease ≥ 4 units of RBC transfused over a period of 8 weeks, relative to the units of RBCs 
transfused in the 8 weeks immediately prior to enrollment (Day 1), will discontinue treatment.  Subjects 
requiring < 4 units of RBC at baseline who have sustained Hgb increase by the end of Cycle 5 but for a 
period less than or equal to 8 consecutive weeks (potential late responders) may continue treatment for up 
to an additional 3 cycles (Cycles 6-8) for the purpose of meeting response criteria.  Subjects requiring ≥ 4 
units of RBC at baseline who have a sustained decrease in transfusion requirements by the end of Cycle 5 
but for a period of less than or equal to 8 consecutive weeks (potential late responders) may also continue 
treatment for up to an additional 3 cycles (Cycles 6-8).
Extension – After completion of the Treatment Period, subjects who qualify may enter the Extension 
Period until PD, treatment failure, or other reason, as appropriate.  Subjects who exhibit at least a 1.0 g/dL 
rise in Hgb or a 50% reduction in transfusion requirement compared to baseline if the reduction observed 
is less than 4 units at the end of the Treatment Period may also enter the Extension Period at the 
investigator’s discretion.  Visits will be Q3W to coincide with the schedule of treatment administration.  
Follow-up – Following the End of Treatment in the Treatment Period or the Extension Period, Follow-up 
will include pregnancy test approximately 28 days after the last treatment, assessment of efficacy (ie, Hgb 
levels, transfusions) approximately 28 days after the last treatment and repeated once per month until 3 
months after the last treatment or until the start of the next treatment, whichever is first, assessment of PK 
at a single timepoint 3 months after the last treatment, assessment of Antidrug Antibody (ADA) repeated 
every 3 months until 1 year after the last treatment, and assessment of progression to AML and OS every 
6 months up to 2 years following the first administration of sotatercept.
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Sotatercept (ACE-011)
Statistical Analysis Plan: ACE-011-MDS-001
Celgene Corporation
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17
5.
STUDY ENDPOINTS
5.1.
Primary Endpoint
The primary endpoint of this study is the rate of HI-E starting before the completion of 5 cycles of 
treatment.  Subjects who have a sustained Hgb increase or a decreased transfusion burden by the end of 
Cycle 5 but for a period less than or equal to 8 consecutive weeks (potential late responders) may 
continue treatment for up to an additional 3 cycles (Cycles 6-8) for the purpose of meeting response 
criteria.
!
HI-E [(for subjects that require a transfusion of < 4 units of RBCs) in the 8 weeks prior to 
randomization (Part 1) or start of therapy (Part 2)] is an increase ≥ 1.5 g/dL Hgb sustained over a 
period ≥8 weeks in the absence of RBC transfusion; or
!
HI-E [(for subjects that require a transfusion of ≥ 4 units of RBCs) in the 8 weeks prior to 
randomization (Part 1) or start of therapy (Part 2)] is a decrease ≥4 units of RBCs transfused over 
a period of 8 weeks, relative to the number of units of RBCs transfused in the 8 weeks 
immediately prior to Day 1.
5.2.
Secondary Endpoints
The secondary endpoints of this study are:
1. Safety of sotatercept.
2.
RBC transfusion independence in transfusion-dependent subjects.
3.
Time to HI-E.
4.
Duration of HI-E.
5.
Time to progression to AML; the time between randomization (Part 1) or start of therapy (Part 2)
and the date of progression to AML.
6.
Time to progression to events of higher risk MDS; the time between randomization (Part 1) or 
start of therapy (Part 2) and date of progression to events of higher risk MDS (e.g., int-2 or high-
risk IPSS).
7.
Progression-free survival (PFS) ∀the time between randomization (Part 1) or start of therapy 
(Part 2) and PD or death.
8.
Overall survival (OS) ∀the time between randomization (Part 1) or start of therapy (Part 2) and 
death.
9.
Concentration of sotatercept in serum.
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Sotatercept (ACE-011)
Statistical Analysis Plan: ACE-011-MDS-001
Celgene Corporation
Confidential and Proprietary
18
 
 
 
 
 
.
5.4.
Sample Size
Subjects will be enrolled to provide up to 115 evaluable subjects in this study (Parts 1 and 2, 
combined).  An evaluable subject (for sample size determination only) is one who meets criteria 
for HI-E, or one who completes 5 cycles of 21 days each of treatment without meeting criteria 
for HI-E, and without deviation from protocol.  Subjects who have a sustained Hgb increase or a 
decreased transfusion burden by the end of Cycle 5 but for a period less than or equal to 8 
consecutive weeks (potential late responders) may continue treatment for up to an additional 3 
cycles (Cycles 6-8) for the purpose of meeting response criteria.
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Sotatercept (ACE-011)
Statistical Analysis Plan: ACE-011-MDS-001
Celgene Corporation
Confidential and Proprietary
19
6.
GENERAL STATISTICAL CONSIDERATIONS
Subjects will be classified according to the sotatercept dose level assigned if the dose level was 
received at least once. If the assigned dose level was never received, then the subject will be 
assigned the initial dose level received.
Individual subject listings will be provided to support the corresponding tables.
6.1.
Reporting Conventions
Summary tables, listings, and any supportive SAS output will include a “footer” of explanatory 
notes that will indicate, at a minimum, the following: 
!
Program source (e.g., SAS program name, including the path, that generates the output) 
and
!
Data extraction date (e.g., the database lock date, run date)
The purpose of the data extraction date is to link the output to a final database, either active or 
archived, that is write-protected for replication and future reference.  An output date will also 
appear on each output page and will indicate the date the output was generated by the analysis 
program. Individual source listings will display all the relative values supporting corresponding 
table and figure.
6.1.1.
Dates Handling
Dates will be stored as numeric variables in the SAS analysis files and reported in 
DDMMMYYYY format (i.e., the Date9. datetime format in SAS).  Dates in the clinical database 
are classified into the categories of procedure dates, log dates, milestone dates, outcome dates, 
and special dates.
!
Procedure Dates are the dates on which given protocol-specified procedure are performed.  
They include the dates of blood draws for laboratory testing, physical examinations, tumor 
scans, etc.  They should be present whenever data for a protocol-specified procedure is 
present and should only be missing when a procedure is marked as NOT DONE in the 
database.  Procedure dates will not be imputed.
!
Log Dates are dates recorded in CRF data logs.  Specifically, they are the start and end dates 
for adverse events and concomitant medications/procedures.  They should not be missing 
unless an event or medication is marked as ongoing in the database.  Otherwise, incomplete 
log dates will be imputed according to the rules in Appendix 15.1 (e.g., for duration or cycle 
assignment etc). However, in listings, log dates will be shown as recorded without 
imputation.
!
Milestone Dates are dates of protocol milestones such as randomization, study drug start 
date, study termination, etc.  They should not be missing if the milestone occurs for a subject.  
They will not be imputed.
!
Outcome Dates are dates corresponding to study endpoints such as survival, progression, etc.  
In most cases they are derived either from a milestone (e.g., the survival date is derived from 
the death date), or a procedure date (e.g., the progression date is derived from the date of the 
tumor scan that was used to determine progression).  They may be subject to endpoint-
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Statistical Analysis Plan: ACE-011-MDS-001
Celgene Corporation
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20
specific censoring rules if the outcome did not occur, but are not otherwise subject to 
imputation.
!
Special Dates cannot be classified in any of the above categories and they include the date of 
birth.  They may be subject to variable-specific censoring and imputation rules (see section 
5.1.2 below). 
Dates recorded in comment fields will not be imputed or reported in any specific format. 
6.1.2.
Calculation using dates
Calculations using dates (e.g., subject’s age or relative day after the first dose of study 
medication) will adhere to the following conventions: 
!
Study days after the start day of study drug will be calculated as the difference 
between the date of interest and the first date of dosing of study medication (e.g., 
sotatercept) plus 1 day. The generalized calculation algorithm for relative day: 
STUDY DAY = [(TARGET DATE – DSTART) + 1 where DSTART = the start day 
of study drug].  Note that Study Day 1 is the first day of treatment of study drug. For 
Study days before the start of study drug will be calculated as the difference between 
the date of interest and the first date of dosing of study medication. The generalized 
calculation algorithm for relative day: STUDY DAY = [(TARGET DATE –
DSTART). Negative study days are reflective of observations obtained during the 
baseline/screening period.  Note: Partial date for the first study drug is not imputed in 
general. All effort should be made to avoid incomplete study drug start date. 
!
Age (expressed in days) is calculated: AGE = DATE of RANDOMIZATION –
DATE of BIRTH + 1.  In practice, age will be transformed to years by dividing the 
difference by 365.25 days, then truncating.
o
Using calculated age from the clinical database is preferred. When not 
available, the calculated age from the case report forms (CRF) or interactive 
voice response system (IVRS) may be used
o
Partial birth date: impute missing day as 15th of the month; impute missing 
month as July; set age as missing if missing year
!
Intervals that are presented in weeks will be transformed from days to weeks by using 
(without truncation) the following conversion formula:
WEEKS = DAYS /7.
!
Intervals that are presented in months will be transformed from days to months by 
using (without truncation) the following conversion formula:
MONTHS = DAYS /30.4167.
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Sotatercept (ACE-011)
Statistical Analysis Plan: ACE-011-MDS-001
Celgene Corporation
Confidential and Proprietary
21
6.2.
Data Included in Planned Analyses
6.2.1.
Data Included in the Analysis for the Clinical Study Report (CSR)
The analysis for the CSR will be completed after all subjects have completed six cycles of 
sotatercept or have discontinued the study.
After the analysis for the CSR, any additional data collected will be included in a supplementary 
analysis. The CSR will be amended to include the additional analysis when it becomes available.
6.3.
Analysis Populations
6.3.1.
Intent-to-Treat Population
The Intent-to-Treat population is defined as all subjects who are enrolled in the study.
6.3.2.
Safety Population
The Safety Population analysis set is defined as all subjects who receive at least one dose of
study medication. Drug exposure and all safety analyses (including AEs, labs and deaths) will be 
based on the safety population.
6.3.3.
Efficacy Evaluable (EE) Population
The Efficacy Evaluable Population analysis set is defined as all subjects who take at least one 
dose of study medication and have baseline and at least one post-baseline assessment of efficacy 
without major deviation from protocol.
6.3.4.
Transfusion-Dependent Efficacy (TDE) Population
All subjects in the EE population who require a transfusion of > 4 units of RBCs in the 8 weeks 
prior to randomization (Part 1) or start of therapy (Part 2) are transfusion dependent at 
randomization.
6.3.5.
Non Transfusion-Dependent Efficacy (NTDE) Population
All subjects in the EE population who require a transfusion of < 4 units of RBCs in the 8 weeks 
prior to randomization (Part 1) or start of therapy (Part 2) are not transfusion-dependent at 
randomization.
6.3.6.
Pharmacokinetic (PK) Population
All subjects who take at least one dose of study medication followed by collection of a sufficient 
amount of post-dose quantifiable pharmacokinetic (PK) samples will be included in the PK 
analysis set.
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Sotatercept (ACE-011)
Statistical Analysis Plan: ACE-011-MDS-001
Celgene Corporation
Confidential and Proprietary
22
6.4.
Definitions
6.4.1.
Study Treatment Start Date
The start date of study treatment is defined as the first date when a dose of sotatercept was administered.
The start date of subsequent cycles will be the dose dates of sotatercept, as this drug is given only once at 
the beginning of each cycle.
6.4.2.
Study Treatment End Date
The treatment end date is the date the subject’s treatment was discontinued as recorded on the 
treatment discontinuation page.
6.4.3.
End Date of each Cycle
The end date of each cycle is one day prior to day 1 of the subsequent cycle. The end date of the 
last cycle is the study treatment end date. If for an analysis for a steering committee a subject is 
still on treatment, then the End Date of the Last Cycle is defined as the start date of last treatment 
cycle plus 21 days.
6.4.4.
Calculation of Cycles
The cycle number for each date of interest, e.g., AE or lab, will be calculated based on the cycle window 
set by their start and end dates of each cycle. The number of the cycle is the number of doses of 
sotatercept that the subject has received. The total number of cycles is the number of sotatercept doses 
taken.
6.4.5.
Baseline
The last available assessment, before the date of start of study treatment, is the baseline assessment. The 
average will be used if there are multiple records on the baseline day. 
For transfusion dependent patients, baseline burden = transfusions received in 8 week window prior to 
first administration of investigational product.  For transfusions on day -56, they should be included in 
baseline burden.  For transfusions occurring on day of first drug administration, they should be counted as 
on study transfusion.  
6.4.6.
Treatment emergent assessment/event
Safety summaries for adverse events and deaths will be summarized based on treatment-emergent 
assessments/events. Treatment-emergent assessment/event is defined as any assessment/event reported as 
starting or worsening on or after the start date of study treatment and up to 42 days (inclusive) after the last 
date of study administration.
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Sotatercept (ACE-011)
Statistical Analysis Plan: ACE-011-MDS-001
Celgene Corporation
Confidential and Proprietary
23
7.
STUDY DISPOSITION
7.1.
Subject Disposition
The subject disposition will be summarized using frequency and percentages for the end of treatment, end 
of extended treatment, and status of follow-up. The subject disposition will include the number of 
subjects enrolled and treated, and the number of subjects in each analysis populations. The subject 
disposition will also include a tabulation of the reasons for discontinuing treatment. The summary of 
subject disposition will be by assigned dosing level of sotatercept:
Reasons for ending study treatment will be collected on the CRF and will be summarized for all 
enrolled subjects with the following categories:
!
Completed (per protocol)
!
Disease Relapse
!
Adverse events
!
Withdrew consent
!
Physician decision (Become eligible for allogeneic bone marrow or stem cell 
transplantation during treatment period)
!
Death
!
Lost to follow-up
!
Protocol violation, specify
!
Lack of Therapeutic Effect
!
Other, specify
Status of Follow-up phase will be collected on the CRF and will be summarized for all treated subjects 
with the following categories.
!
Alive
!
Withdrew Consent from the survival follow-up
!
Lost to Follow-up
!
Dead
7.2.
Protocol Violations / Deviations
Protocol violations / deviations will be summarized and listed by assigned dose level for the FAS
population.
A protocol violation / deviation is defined as any departure from the approved protocol that:  
!
Impacts the safety, rights, and/or welfare of the subject; 
!
Negatively impacts the quality or completeness of the data; or
!
Makes the informed consent document/form inaccurate. 
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Protocol violation / deviation will be monitored and reported throughout the study. Data of 
protocol violation / deviation will be finalized prior to database lock by clinical team with 
EXCEL sheet
&(/*(1(35235,(7$5<,1)250$7,21


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Celgene Corporation
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25
8.
DEMOGRAPHICS AND BASELINE CHARACTERISTICS
Summaries for the demographics and baseline characteristics will be analyzed by assigned dose level for 
the safety population. For clinical characteristics, the baseline values are the last value collected on or 
before the start of study therapy. When there are retested values, the retest values will be used for the 
analysis. Continuous variables will be presented with descriptive statistics (N, Mean (SD), Median, 
Minimum and Maximum). Categorical variables will be presented with counts and percentages.
8.1.
Demographics
Subject age, height, and weight will be presented as continuous variables. Gender, Race, and
Race/Ethnicity will be presented as categorical variables.
8.2.
Baseline Disease Characteristics
Baseline disease characteristics are:
!
Previous therapies for MDS: yes, no;
!
Number of previous therapies for MDS: 0, 1, 2, 3, 4, 5, >5;
!
Time from MDS diagnosis (years): as a continuous variable;
!
Time from MDS diagnosis (<=2 years vs. >2 years from diagnosis).
!
RBC transfusion burden (56 days prior to randomization/dosing): as a continuous 
variable
!
RBC transfusion burden categories (units during 56 days prior to 
randomization/dosing): (<4, ≥ 4);
!
WHO Subtype classification: Refractory Cytopenia with 2 Unlineage Dysplasia 
(RCUD), Refractory Anemia with Ringed Sideroblasts (RARS), Refractory 
Cytopenia with Multilineage Dysplasia (RCMD), Refractory Anemia with Excess 
Blasts - 1 (RAEB-1), Refractory Anemia with Excess Blasts - 2 (RAEB-2), 
Myelodysplastic Syndrome - Unclassified (MDS-U), CMML non proliferative 
(CMML), MDS Associated with Isolated del (5q); 
!
RCUD Subtype (For subjects with WHO Subtype RCUD): Refractory Anemia, 
Refractory Neutropenia, Refractory Thrombocytopenia;
!
Marrow blasts measured from a BMA smear (%): as a continuous variable;
!
Karyotype IPSS: good, intermediate, poor;
!
Number of Cytopenias;
!
ECOG  performance status: 0, 1 or 2 ;
8.3.
Baseline Laboratories
Baseline value is defined as the last non-missing measurement on/before the first dose of the 
study drug, unless otherwise specified. Baseline Laboratories are:
!
Hemoglobin (mg/dl): as a continuous variable;
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8.3.


Sotatercept (ACE-011)
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!
Serum erythropoietin level : as a continuous variable;
!
Serum erythropoietin level : >500 mU/mL,250 -500, < 250 mU/mL;
Category variables will be summarized using a frequency distribution by treatment group and 
overall. Continuous variables will be summarized using descriptive statistics in the same way as 
continuous demographic variables in Section 8.1. All baseline characteristics will be provided in 
subject listings.
8.4.
Medical History
Medical history data will be summarized using frequency tabulations by system organ class and 
preferred term by dose level for the safety population.
8.5.
Prior MDS Therapy
Prior ESA and Non ESA medications with ATC code will be summarized and listed by assigned 
dose level for the safety population. The Anatomical Therapeutical Chemical (ATC) coding 
scheme of the World Health Organization (WHO) will be used to group medications into 
relevant categories for these tabulations.
8.6.
Prior and Concomitant Medications
Prior medications are defined as non-study medications that were started before the start of the 
study treatment (regardless of whether they are stopped before the start of the study treatment or 
they continue to be used on or after the start of therapy). Prior medications that are ongoing at 
the start date of study treatment will be also reported as concomitant medications.
Concomitant mediations are defined as non-study medications that are started on or after the start 
of the study treatment, or started before the start of the study treatment and ended or were
ongoing during the study treatment.
All prior and concomitant medications (summarized separately) will be summarized in frequency 
tabulations by assigned dose level.  The Anatomical Therapeutical Chemical (ATC) coding 
scheme of the World Health Organization (WHO) will be used to group medications into 
relevant categories for these tabulations.
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9.
STUDY TREATMENTS AND EXTENT OF EXPOSURE
9.1.
Treatment Duration
The treatment duration of sotatercept will be calculated in weeks and is defined as:
[(Study Treatment End Date) – (Study Treatment Start Date) + 1]/7
For interim analyses, the treatment duration of sotatercept for subjects still on treatment will be 
calculated in weeks and is defined as:
[(End Date of the last cycle) – (Study Treatment Start Date) + 1]/7
The number of cycles received will also be summarized for the safety population by assigned dose level.
See sections 6.4.1, 6.4.2 and 6.4.3 for definitions of Study Treatment Start Date, Study Treatment End 
Date, and End Date of last cycle, respectively. 
9.2.
Dose Modification
Dose reductions/interruptions will be summarized by assigned dose level. Summaries include 
subjects who had at least one dose reduction/interruption.
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10.
EFFICACY ANALYSIS
All efficacy analyses will be carried out in the EE population unless otherwise specified. All 
analyses will be presented by assigned dose level of sotatercept.
10.1.
RBC-Transfusion Analysis
The RBC-Transfusion analysis will be performed for subjects that require a transfusion of ≥ 4 
units of RBCs in the eight weeks prior to randomization (Part 1) or start of therapy (Part 2), i.e. 
the TDE population.
Baseline RBC transfusion burden is the number of units of RBCs transfused in the 8 weeks 
immediately prior to the start of dosing (Study days -55 to 1). All RBC-transfusion records after 
the first dose of study drug will be used to assess the response.
Responder for Reduction in RBC-Transfusion Rate
The HI-E response is defined as a ≥ 4 unit decrease of RBCs transfused over a period of 8 weeks, 
relative to the number of units of RBCs transfused in the 8 weeks immediately prior and 
including Day 1 during any consecutive 56 days during the treatment period starting on Studyday 
2, i.e. Study days 2 to 57, Study days 3 to 58,  . . . etc.
The series of 56 day intervals which will be evaluated will begin with the interval that starts on 
Study day 2 and will end with the interval in which Study day 56 occurs on the last day of study 
therapy. If any of these intervals has a decrease ≥ 4 units of RBCs relative to the baseline RBC-
transfusion burden, the subject is a responder. Subjects who do not achieve the response will be 
counted as non-responders. Subjects who discontinue from the study early without achieving the 
clinical response will be counted as non-responders regardless of how long the subject 
participates in the study.
Responder for RBC-Transfusion Independence
The response for RBC-Transfusion independence will be done similarly except a response occurs 
if no RBC-transfusions occur in a 56 day interval instead of a decrease of ≥ 4 units of RBCs
relative to the baseline RBC-transfusion burden.
Time to HI-E Response
The Time to HI-E Response for subjects who respond is the time between the randomization date 
(subjects in Part 1) or the start date of therapy (subjects in Part 2) to the start date of the first 56 
day interval that the subject was evaluated to be in response. For subjects who do not respond, 
the time to HI-E response is censored at the treatment discontinuation date.
Duration of HI-E Response
The Duration of HI-E Response is the end date of the first response period minus the start date of 
the first response period plus 1. The end date of the first response period is determined by 
extending the first 56 day interval until a decrease of ≥ 4 units (adjusted to 56 days) of RBCs
relative to the baseline RBC-transfusion burden is no longer true and then using the previous 
date. The end date should be one day prior to a transfusion. If the first response does not end or 
the end date of the first response is beyond the end of treatment date, the end of treatment date is 
used.
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Sotatercept (ACE-011)
Statistical Analysis Plan: ACE-011-MDS-001
Celgene Corporation
Confidential and Proprietary
29
10.2.
Hemoglobin Analysis
The hemoglobin (Hgb) analysis will be performed for subjects that require a transfusion of < 4 
units of RBCs) in the eight weeks prior to randomization (Part 1) or start of therapy (Part 2), i.e. 
the NTDE population. 
Only Hgb measurements from the local laboratory page (and not the RBC-Transfusion page) will 
be used. Also, Hgb measurements taken within 2 weeks (inclusive) after an RBC-transfusion will 
not be used. Hgb measurements taken after the last dose of study treatment will not be used.
Baseline Hgb measurement is the last measurement taken prior to study drug excluding 
measurements taken within 2 weeks after an RBC-transfusion.
Responder for increase in Hemoglobin 
HI-E is an Hgb increase ≥ 1.5 g/dL relative to baseline, sustained (i.e. consecutive Hgb 
measurements) over a period ≥56 days in the absence of RBC transfusion. The ≥56 day period 
must start after the start of treatment, i.e. the date of the first on-treatment Hgb measurement, and 
cannot extend beyond the end of study treatment date.
Time to HI-E Response
Time to HI-E Response for subjects who respond is the time between the randomization date 
(subjects in Part 1) or start date of therapy (subjects in Part 2) to the first Hgb measurement of 
the first HI-E response. For subjects who do not respond, the time to HI-E response is censored 
at treatment discontinuation date.
Duration of HI-E Response
Duration of HI-E Response for subjects who respond is the last date of the consecutive Hgb 
measurements of the first ≥56 day interval minus the first date of the consecutive Hgb 
measurements of the ≥56 day interval plus 1.
10.3.
Time to Progression to AML and Time to Progression of higher risk 
MDS
The number and percent of subjects who progress to AML within the treatment phase and within 
the entire study will be tabulated, respectively, by assigned dose level. The time to AML 
progression will be assessed using the time between the randomization date (subjects in Part 1) 
or start date of therapy (subjects in Part 2) to the date of AML was diagnosed. The subjects who 
have AML will be considered to have the events. Subjects who died without AML will be 
censored at the date of death. Subjects who are lost to follow-up will be censored at the last 
known date when subjects did not have AML. Subjects who do not progress to AML by the last 
follow-up contact will be censored at the date of the last follow-up contact.   
Time to progression to AML will be listed and Kaplan-Meier graphs by assigned dose level will 
be provided if sufficient events occur.
Time to progression of higher risk MDS will be done similarly to time to progression to AML 
except the assessment of progression of higher risk MDS will be used.
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me t


Sotatercept (ACE-011)
Statistical Analysis Plan: ACE-011-MDS-001
Celgene Corporation
Confidential and Proprietary
30
10.4.
Progression Free Survival (PFS)
The number and percent of subjects with disease progression within the treatment phase and 
during the entire study will each be tabulated by assigned dose level. The time to disease 
progression will be assessed using the time between the randomization date (subjects in Part 1) 
or the start date of therapy (subjects in Part 2) and the date of disease progression (AML or high 
risk MDS). Subjects who have disease progression will be considered to have events. Subjects 
who died without AML will also be considered to have events with the event date as the date of 
death. Subjects who do not have disease progression and who are lost to follow-up will be 
censored at the last known disease progression assessment date. Subjects in the follow-up stage 
without disease progression at the last follow-up contact will be censored at the date of the last 
follow-up contact date.   
Time to PFS will be listed and Kaplan-Meier graphs by assigned dose level will be provided if 
sufficient events occur.
10.5.
Overall Survival
Overall survival will be assessed using the time between start of treatment and the 
death/censored date. Subjects who died (regardless of the cause of death) will be considered to 
have an event. Subjects who are alive at the end of the study, and subjects who are lost to follow-
up, will be censored at the last date when subjects are known to be alive.
Time to overall survival will be listed and Kaplan-Meier graphs by treatment will be provided if 
sufficient events occur.
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35,(


Sotatercept (ACE-011)
Statistical Analysis Plan: ACE-011-MDS-001
Celgene Corporation
Confidential and Proprietary
31
11.
PHARMACOKINETIC ANALYSIS
11.1.
Pharmacokinetic Analysis
11.1.1.
Data Handling
Predose concentrations that are below the limit of quantitation (BLQ) or missing will be assigned 
a numerical value of zero for PK analysis.  Postdose concentrations that are BLQ and occur 
before the first quantifiable concentration will also be treated as zero for PK analysis. Postdose 
concentrations that are BLQ but occur after the first quantifiable concentration on each day will 
be treated as missing for PK analysis.  
Concentrations assigned a value of missing will be omitted from the calculation of descriptive 
statistics.  A concentration value of zero will be excluded from the computation of geometric 
mean (geometric CV%).
In tables and listings for the derived PK data, there should be 4 decimal places for numerical 
values below 1, 3 decimal places for numeric values below 10 but above 1, and 2 decimal places 
for numeric values above 10.  However, the listings of raw data should not have more decimal 
places than the actual data.
11.1.2.
Pharmacokinetic Parameters
Pharmacokinetic parameters of sotatercept will be derived using a one-compartment model with 
first order absorption and elimination.  All sotatercept serum concentration values obtained from 
Cycle 1 Day 1 to the end of study will be included in this analysis.  Actual sampling and dosing 
times will be used in this analysis.  
The model will be parameterized in terms of the absorption rate constant (k01), apparent 
clearance (CL/F), and apparent volume of distribution (V/F).  Other parameters will be derived 
from the established model.  The main compartmental pharmacokinetic parameters to be 
estimated are outlined as following:
k01
Absorption rate constant
CL/F
Apparent clearance from the central compartment
V/F
Apparent volume of distribution of the central compartment
Tmax
Time to maximum serum concentration, calculated as ln(k01/k10)/(k01-k10), 
where k10 = (CL/F)/(V/F)
Cmax
Maximum serum concentration for the starting dose, predicted at Tmax
AUC
Area under the serum concentration-time from time zero to infinity (or at the 
steady-date) for the starting dose, calculated as (Starting Dose)/(CL/F). 
t1/2
Elimination half-life, calculated as (ln2)/k10
Additional pharmacokinetic parameters may be determined when appropriate.
All sotatercept serum concentrations will be listed by dose group, subject, and scheduled time  
(visit and study day).  The sotatercept serum concentrations will be summarized by dose group 
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onstant
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t1/2
1


Sotatercept (ACE-011)
Statistical Analysis Plan: ACE-011-MDS-001
Celgene Corporation
Confidential and Proprietary
32
and scheduled time, including N (number of observations), arithmetic mean, arithmetic standard 
deviation (SD), arithmetic coefficient of variation (CV%), geometric mean, geometric CV%, 
minimum, median, and maximum.  Mean (SD) serum concentration-time profiles will be 
presented on linear scales by dose group for the first 4 weeks.  Individual concentration plots will 
be provided by presenting the observed concentration data along with the one-compartment 
model-predicted concentration-time profile on the linear scale using actual sampling times and 
multiple dose data.
Pharmacokinetic parameters will be listed by dose group and subject, and they will be 
summarized descriptively by dose group (N, mean, SD, minimum, median, maximum, CV%, 
geometric mean, and geometric CV%).  Dose proportionality may be assessed using the 
exposure data (e.g., Cmax, AUC).    
11.2.
PK Analysis
ACE-011 plasma concentrations will be summarized by scheduled visits and treatment , and PK 
parameters will be summarized by treatment using descriptive statistics (N, mean, SD, 
coefficient of variation [CV%], geometric mean, geometric CV%, median, Min, and Max).  
Mean (±SD) and individual plot of plasma concentrations will be presented in both linear scale 
and semi-logarithmic scales. 
Dose-proportionality may be evaluated using AUC and Cmax data from Cycle 1.
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be presente
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Cmax data 
Cmax dat


Sotatercept (ACE-011)
Statistical Analysis Plan: ACE-011-MDS-001
Celgene Corporation
Confidential and Proprietary
33
12.
SAFETY ANALYSIS
Safety analyses will be conducted using the safety population and analyses will be presented by assigned 
dose level of sotatercept.
12.1.
Dose-limiting Toxicity 
Definition of Dose-Limiting Toxicity (DLT)
Dose-limiting Toxicity (DLT)
Definition
Hemoglobin
Hgb > 12 g/dL (not influenced by transfusions) 
sustained for ≥ 7 days, confirmed by 2 
assessments ≥ 1 week apart.
Hypertension*
Subjects within normal limits (WNL) and not 
receiving antihypertensive treatment at baseline
≥ Grade 2 (140 mmHg systolic or 90 mmHg 
diastolic) according to the National Cancer 
Institute Common Terminology Criteria for 
Adverse Events (NCI-CTCAE) Version 4.0 
(current active minor version) (Appendix F)
Prehypertensive subjects (systolic BP 120 - 139 
mmHg or diastolic 80-89 mmHg) and not 
receiving antihypertensive treatment at baseline
Systolic ≥ 140 or diastolic ≥ 90 mmHg
AND:
Introduction of anti-hypertensive treatment
OR
An increase of > 20 mmHg (systolic or diastolic) 
from baseline
For patients with blood pressure controlled on 
antihypertensive treatment at baseline
Systolic BP ≥ 140 or diastolic ≥ 90 mmHg AND:
More intensive antihypertensive treatment than 
previously used at baseline
OR
Additional antihypertensive treatment than 
previously used at baseline.
Any other treatment-related (suspected) toxicity
≥ Grade 2 per NCI-CTCAE Version 4.0 (current 
active minor version)
* Blood pressure values should be confirmed by mean of two readings obtained approximately 5 minutes apart with 
the patient seated for approximately 10 minutes prior to the initial reading.
A summary table of DLT will be presented by assigned dose level using the Safety Population.
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Sotatercept (ACE-011)
Statistical Analysis Plan: ACE-011-MDS-001
Celgene Corporation
Confidential and Proprietary
34
12.2.
Adverse Events
Adverse events (AEs) will be coded according to the Medical Dictionary for Regulatory 
Activities (MedDRA) Version 18.0.  The intensity of AEs will be graded according to the NCI-
CTCAE Version 4.0. AEs, SAEs, and death will be summarized using the Safety Population. 
Treatment-emergent adverse events (TEAEs) are defined as any AE occurring or worsening on 
or after the first treatment of the study medication and within 42 days after the last dose. TEAEs, 
AEs leading to study medication discontinuation, AEs leading to dose reduction/interruption, 
AEs related to study medication, and serious AEs will be summarized by system organ class and 
preferred term for each assigned dose level. A summary of AEs with NCI-CTCAE Grade 3 or 
higher, as well as the most frequent preferred terms, will be provided. If a subject experiences 
the same preferred term multiple times then the event will be counted only once and by greatest 
severity. All deaths and reasons for death will be summarized.
Listings for the corresponding summary tables will be presented.
12.3.
Clinical Laboratory Evaluations  
Clinical laboratory values will be graded according to NCI-CTC Version 4.0 for applicable tests.
Shift from baseline to the worst grade observed during the treatment for selected laboratory 
results will be provided.
Separate listings will be provided for laboratory values. 
12.4.
Vital Sign Measurements
For vital signs, shift from baseline to worst during the treatment in below, within, and above the 
normal ranges will be displayed in cross–tabulations.  Summary statistics (N, Mean, Standard 
Deviation, Median, Minimum, and Maximum) of observed and change from baseline values will 
be presented.
12.5.
Electrocardiogram
The overall ECG interpretation will be summarized by presenting the number and percentage of 
subjects with ‘Normal’, ‘Abnormal, not clinically significant’ and ‘Abnormal, clinically 
significant’.  Shift from baseline to worst during the treatment in the overall ECG interpretation 
will be displayed in cross–tabulations.
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by greates
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on 4.0 f
4.0
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ment for se
during the
during the
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l’, ‘Abno
from basel
from basel
ed in cross
d in cross


Sotatercept (ACE-011)
Statistical Analysis Plan: ACE-011-MDS-001
Celgene Corporation
Confidential and Proprietary
35
13.
REFERENCES
Not Applicable
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Sotatercept (ACE-011)
Statistical Analysis Plan: ACE-011-MDS-001
Celgene Corporation
Confidential and Proprietary
36
14.
APPENDICES 
14.1.
Date Imputation Guideline
14.1.1.
Impute Missing AE/ Prior or Concomitant Medications Start Dates
If the stop date is non-missing and the imputed start date is after the stop date, the start date will 
be imputed by the stop date.
Missing day and month
!
If the year is same as the year of first day on study medication, then the day and month of the 
start date of study medication will be assigned to the missing fields
!
If the year is prior to the year of first day on study medication, then December 31 will be 
assigned to the missing fields.
!
If the year is after the year of first day on study medication, then January 1 will be assigned to 
the missing fields.
Missing day only 
!
If the month and year are same as the year and month of first day on study medication, then the 
start date of study medication will be assigned to the missing day.
!
If the month and year are before the year and month of first day on study medication, then the 
last day of the month will be assigned to the missing day.
!
If the month and year are after the year and month of first day on study medication, then the first 
day of the month will be assigned to the missing day.
Missing day, month, and year
!
Included as TEAE
14.1.2.
Impute Missing AE/ Prior or Concomitant Medications Stop Dates
If the imputed stop date is before the start date then the imputed stop date will be equal to the start date.
Missing day and month
!
If the year of the incomplete stop date is the same as the year of the last dose date of study 
medication, then the day and month of the last dose date will be assigned to the missing fields. 
!
If the year of the incomplete stop date is prior to the year of the last dose date, then December 31 
will be assigned to the missing fields. 
!
If the year of the incomplete stop date is after the year of the last dose date of study medication, 
then January 1 will be assigned to the missing fields.
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th of the
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missing da
month of firs
month of firs
missing day
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medic
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I


Confidential and Proprietary
37
Missing day only 
!
If the month and year of the incomplete stop date are the same as the month and year of the last 
dose date of study medication, then the day of the last dose date will be assigned to the missing 
day. 
!
If the month and year of the incomplete stop date are before the month and year of the last dose 
date of the study medication, then the last day of the month will be assigned to the missing day. 
!
If the month and year of the incomplete stop date are after the month and year of the last dose 
date of study medication, then the first day of the month will be assigned to the missing day.
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y.
dose
dose
g day.
g day.


Confidential and Proprietary
38
14.2.
Schedule of Assessments
Schedule of Assessments
Period
Screening
Treatment
End of 
Treatment 
Period or 
Early 
Termination Extensionr
End of 
Extension 
Period
Follow
-up
Cycle
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Cycle 5 (6-8 
for potential 
late 
respondersr)
After 
Completion 
of 
Treatment 
Period
Daya
-28 to 0
1
8
15
1
8
15
1
8
15
1
8
15
1
8
15
Randomize subject to sotatercept in 
IVRS system
•
Administer sotatercept
•
•
•
•
•
•
Medical history, Height
•
Record prior meds and treatments
•
MDS disease history and baseline 
assessment and prior therapyb
•
RBC transfusion log
•
•
•
•
•
•
•
•
•
• t
Record current therapies (including 
concomitant medications)/procedures
•
•
•
•
•
•
•
•
•
• t
Record adverse eventsc
Record on an ongoing basis.
Physical examd
•
•
•
•
•
•
•
•
•
Vital signs, weightd
•
• • • • •
•
• •
•
• •
•
• •
•
•
•
•
CCI
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After
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Confidential and Proprietary
39
Schedule of Assessments (Continued)
Period
Screening
Treatment
End of 
Treatment 
Period or 
Early 
Termination Extensionr
End of 
Extension 
Period
Follow
-up
Cycle
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Cycle 5 (6-8 
for potential 
late 
respondersr)
After 
Completion 
of 
Treatment 
Period
Daya
-28 to 0
1
8
15
1
8
15
1
8
15
1
8
15
1
8
15
Blood Pressured
•
• • • • •
•
• •
•
• •
•
• •
•
•
•
•
ECGd
•
•
•
•
ECOG performance statusd
•
•
•
•
•
•
•
•
•
Hematologye assessed prior to each 
treatment
Include CBC with diff and retic count
•
• • • • •
•
• •
•
• •
•
• •
•
•
•
•
•e
Serum chemistryf
•
• • • •
•
•
•
•
•
•
Urinalysish
•
•
•
•
•
•
•
•
•
Serum Erythropoietin
•
• • • •
•
•
•
•
Pregnancy testingi
•
•
•
•
•
•
•
•
•
•i
Pharmacokineticsj
• • • • •
•
•
•
•
•
•
•
•j
Antidrug antibody (ADA)k
•
•
•
•
•
•
•
•
•k
CCI
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Confidential and Proprietary
40
Schedule of Assessments (Continued)
Period
Screening
Treatment
End of 
Treatment 
Period or 
Early 
Termination Extensionr
End of 
Extension 
Period
Follow
-up
Cycle
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Cycle 5, (6-8 
for potential 
late 
respondersr)
After 
Completion 
of 
Treatment 
Period
Daya
-28 to 0
1
8
15
1
8
15
1
8
15
1
8
15
1
8
15
MDS response assessmentl
•
•
•s
Bone marrow aspirate, standardm
Peripheral blood smearn
•
•
•
a Variations of ±5 business days of the scheduled visit are permitted.  An unscheduled visit can occur at any time during the study.  Source documents for unscheduled visits must 
be maintained.  The date of the visit and data generated must be recorded on the appropriate CRF.  In the Follow-Up Period (for those visits not requiring sample collection 
only), a variation of ±15 business days of the schedule visit are permitted.
b MDS disease history and baseline assessment and prior therapy - to include date of diagnosis, WHO subtype, IPSS, and blast percent, cytopenia and karyotype at original 
diagnosis and at study baseline (assessed during the screening period prior to Day 1 dosing); and record of prior therapy for MDS including history of administration of 
erythropoiesis stimulating agents.  For baseline MDS disease assessment, if bone marrow biopsy and/or aspirate results within 90 days prior to screening period are available,
they may be used contingent that subject had no additional treatment (including ESAs and steroids) since sample obtainment.  Supportive care (i.e. transfusions) since 
sample obtainment is acceptable.  
c Record on an ongoing basis from the time of provision of written informed consent to participate in this study to 42 days after the last treatment.  Beyond 42 after the last 
treatment, any SAE related to treatment should be reported.
d If physical examination, vital signs (except blood pressure), weight, or ECOG performance status were done within 7 days of Day 1, they do not need to be repeated at Study 
Day 1.  Blood pressure should be monitored during screening, prior to each study drug administration, and on a weekly basis during the first 5 cycles.  In addition, blood pressure 
should be assessed approximately 24 hours after the initial study drug administration during Cycle 1.  On study drug dosing days, blood pressure must be assessed within 8 hours 
prior to study drug administration.  Monitoring of blood pressure may be performed at home on nondosing days.  For home monitoring, a plan with instructions and thresholds 
regarding when to contact the investigator in the event significant increases are observed should be established with the subject.  In the absence of clinically significant changes 
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in blood pressure after 5 cycles of treatment, monitoring frequency may decrease to once per cycle at the investigator’s discretion.  ECG should be performed during screening, 
Cycle 3 Day 1, Cycle 5 Day 1, and at the End of Treatment Period.  In the absence of clinically significant changes in ECG readings after completion of 5 cycles of treatment, 
ECGs will no longer be required until the End of Treatment Period unless deemed necessary by the investigator.  
e Hematology, including CBC with differential and reticulocyte count are done at baseline and weekly during the treatment period.  In the Follow-Up Period, Hematology values
(ie, Hgb levels) will be collected approximately 28 days after the last treatment and repeated once per month until 3 months after the last treatment or until the start of the next 
treatment, whichever occurs first, to assess potential late response to sotatercept after discontinuation.  
f Serum chemistry includes sodium, potassium, chloride, CO2 (bicarbonate), calcium, magnesium, phosphorus, BUN, creatinine, glucose, amylase, lipase, albumin, total protein, 
alkaline phosphatase, bilirubin (total and direct), AST/SGOT, ALT/SGPT, LDH, creatinine clearance (per Cockcroft-Gault formula).
h Urinalysis includes albumin (quantitative), bilirubin, creatinine (quantitative), glucose, Hgb, total protein (quantitative), ketones, pH, albumin/creatinine ratio, protein/creatinine 
ratio, 
.
i Pregnancy tests for females of childbearing potential.  A female of childbearing potential is a sexually mature female who: 1) has not undergone hysterectomy or bilateral 
oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (ie, has had menses at any time in the preceding 24 consecutive months).  Urine or 
serum pregnancy tests must occur within 3 days prior to sotatercept for Cycle 1.  Urine or serum pregnancy tests must occur immediately prior to each treatment; approximately 
every 28 days during delays in treatment; at discontinuation of treatment; and approximately 28 days after the last treatment.
Note:  Local laboratory assessments are allowed in cases when timely results are needed (eg, randomization, study treatment dosing decisions, hematology assessments between 
clinic visits).  Whenever possible a “split” sample should also be forwarded to the central laboratory for analysis.  Local laboratory data should be collected in the eCRF. 
j Pharmacokinetics - Blood samples will be collected for assessment of pharmacokinetics in all subjects as per schedule.  On days of treatment administration the sample must be 
collected prior to administration of sotatercept.  During the Extension Period the sample must be collected prior to every other administration of sotatercept on days of treatment 
administration as per the schedule for assessment of ADA.  A blood sample will be collected for the assessment of pharmacokinetics at the end of the Extension period.  During 
the Follow-up Period a blood sample will be collected for assessment of pharmacokinetics at a single timepoint 3 months after the last treatment. At each pharmacokinetics time 
point, approximately 3 mL blood will be collected and serum prepared.
k Antidrug antibody (ADA) - Blood samples will be collected for assessment of ADA in all subjects.  During the Treatment Period the sample must be collected prior to each 
administration of sotatercept on days of treatment administration.  During the Extension Period the sample must be collected prior to every other administration of sotatercept on 
days of treatment administration as per the schedule of assessment of pharmacokinetics.  A blood sample will be collected for the assessment of ADA at the end of the Extension 
period.  At the end of the treatment, assessment of ADA will be repeated every 3 months until 1 year after the last treatment.  If a serum sample is provided for assessment of 
pharmacokinetics, the assay for ADA will be performed on that serum sample and an additional sample need not be provided.  If a serum sample is not provided for assessment 
of pharmacokinetics (ie, during the Follow-up Period) a serum sample 
; prepare serum must be provided for the assay of ADA.
l MDS response assessment - per International Working Group (IWG) Response Criteria in Myelodysplasia, to include best response at end of treatment.
m Bone marrow aspirate, standard - for: local assessment of cytogenetics employing standard banding overall and FISH for d5q only; preparation of smear with Wright and Giemsa
stain for local and central assessment of cell differential, morphology, and cellularity; standard assessment by flow cytometry.  During screening, if cytogenetic results from 
within 90 days of Screening Period are available, they may be used contingent subject did not receive treatment (including ESAs and steroids) since sample obtainment.  
Supportive care (ie, ESAs and transfusions) since sample obtainment is acceptable.
n Peripheral blood smear - <0.1 ml of peripheral blood for preparation of smear with Wright and Giemsa stain for local and central assessment of cell morphology.
 
 
 
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Confidential and Proprietary
42
r After completing the Treatment Period, subjects who qualify for the Extension Period may continue therapy until PD or treatment failure in the Extension Phase.  Subjects who 
have a sustained Hgb increase or a decreased transfusion burden by the end of Cycle 5 but for a period less than or equal to 8 consecutive weeks (potential late responders) may 
continue treatment for up to an additional 3 cycles (Cycles 6-8) for the purpose of meeting response criteria.
s MDS Response Assessment during Follow-up Period to include only progression to AML and OS assessed every 6 months up to 2 years following the first administration of 
sotatercept. 
t Assessment of efficacy (ie, Hgb levels, transfusions) to continue approximately 28 days after the last treatment and repeated once per month until 3 months after the last 
treatment or until the start of the next treatment, whichever occurs first, to assess potential late response to sotatercept  after discontinuation.
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