A Phase-2 Study To Determine Efficacy and Safety of Luspatercept in Subjects With Myeloproliferative Neoplasm-Associated Myelofibrosis and Anemia With or Without Red Blood Cell-Transfusion Dependence
Phase: PHASE2
Conditions: Primary Myelofibrosis, Anemia
Sponsor: Celgene

Official Title of Study: 
A Phase 2, Multicenter, Open-Label Study to Evaluate the Efficacy and Safety of Luspatercept 
(ACE-536) in Subjects With Myeloproliferative Neoplasm-Associated Myelofibrosis and 
Anemia With and Without Red Blood Cell-Transfusion Dependence 
 
PROTOCOL(S) ACE-536-MF-001 
 
NCT Number: NCT03194542 
  
Document Date (Date in which document was last revised): February 19, 2020 

EDMS Doc. Number: 24487940 - 21868350
Luspatercept (ACE-536)
Protocol ACE-536-MF-001
Celgene Corporation
Confidential and Proprietary
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ACE-536-MF-001 Amendment 4 Final: 19 Feb 2020
TITLE PAGE
A PHASE 2, MULTICENTER, OPEN-LABEL STUDY TO 
EVALUATE THE EFFICACY AND SAFETY OF 
LUSPATERCEPT (ACE-536) IN SUBJECTS WITH 
MYELOPROLIFERATIVE NEOPLASM-ASSOCIATED 
MYELOFIBROSIS AND ANEMIA WITH AND 
WITHOUT RED BLOOD CELL-TRANSFUSION 
DEPENDENCE
PROTOCOL NUMBER:
ACE-536-MF-001
DATE FINAL:
17 May 2017
AMENDMENT 1 DATE:
21 Mar 2018
AMENDMENT 2 DATE:
18 Dec 2018
AMENDMENT 3 DATE:
01 Aug 2019
AMENDMENT 4 DATE
19 Feb 2020
EudraCT NUMBER:
2017-000322-35
IND NUMBER:
112,562
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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Luspatercept (ACE-536)
Protocol ACE-536-MF-001
Celgene Corporation
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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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Luspatercept (ACE-536)
Protocol ACE-536-MF-001
Celgene Corporation
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CELGENE THERAPEUTIC AREA HEAD SIGNATURE PAGE
{See appended electronic signature page}
Signature of Celgene Therapeutic Area Head
dd mmm yyyy
Printed Name of Celgene Therapeutic Area Head and Title
By my signature, I indicate I have reviewed this protocol and find its content to be 
acceptable.  
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Luspatercept (ACE-536)
Protocol ACE-536-MF-001
Celgene Corporation
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SITE PRINCIPAL INVESTIGATOR SIGNATURE PAGE
Signature of Site Principal Investigator
dd mmm yyyy
Printed Name of Site Principal Investigator
Institution Name: _______________________________________
By my signature, I agree to personally supervise the conduct of this study at my study 
site and to ensure its conduct is in compliance with the protocol, informed consent, 
Institutional Review Board (IRB)/Ethics Committee (EC) procedures, instructions from
Celgene representatives, the Declaration of Helsinki, International Council for
Harmonisation (ICH) Good Clinical Practices Guidelines, and local regulations 
governing the conduct of clinical studies.
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Luspatercept (ACE-536)
Protocol ACE-536-MF-001
Celgene Corporation
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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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Luspatercept (ACE-536)
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PROTOCOL SUMMARY
Study Title
A Phase 2, Multicenter, Open-Label Study to Evaluate the Efficacy and Safety of Luspatercept
(ACE-536) in Subjects With Myeloproliferative Neoplasm-Associated Myelofibrosis and 
Anemia With and Without Red Blood Cell-Transfusion Dependence
Indication
Treatment of anemia associated with myeloproliferative neoplasm (MPN)-associated 
myelofibrosis in subjects with and without red blood cell (RBC)-transfusion dependence
Objectives
The primary objective of this study is:
-
to evaluate the efficacy and safety of luspatercept for the treatment of anemia in subjects 
with MPN-associated myelofibrosis with and without RBC-transfusion dependence.
The secondary objectives of this study are:

To evaluate the safety of luspatercept in MPN-associated myelofibrosis 

To evaluate the effect of luspatercept in MPN-associated myelofibrosis: 
o
on the time to and duration of anemia response
o
on frequency of RBC transfusions and transfusion dependence 
o
on symptom response improvement via the Myeloproliferative Neoplasms 
Symptom Assessment Form Total Symptom Score (MPN-SAF TSS)
o
on health-related quality of life (HRQoL) via the EQ-5D-5L and Functional 
Assessment of Cancer Therapy – Anemia (FACT-An) questionnaires 
o
on the changes in hemoglobin and mean hemoglobin increase 

To evaluate population pharmacokinetics of luspatercept in subjects with MPN-
associated myelofibrosis with and without RBC-transfusion dependence
 
 
 
 
 
 
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Luspatercept (ACE-536)
Protocol ACE-536-MF-001
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Study Population and Design
This is a Phase 2, multicenter, multicohort, open-label study that will be conducted in 
compliance with International Council for Harmonisation (ICH) Good Clinical Practices (GCPs).  
Subjects satisfying the eligibility criteria will be assigned to 1 of the following cohorts:
Cohort 1: will contain up to 20 subjects with anemia only that are not currently receiving 
RBC transfusions (these subjects will be referred to as “anemia only” throughout the 
protocol, defined as 0 RBC units/84 days immediately prior to the C1D1 date)
Cohort 2: will contain up to 20 subjects that are RBC-transfusion dependent (these 
subjects will be referred to as “RBC-transfusion dependent” throughout the protocol, 
defined as an average RBC transfusion frequency of 2 to 4 RBC units/28 days over at 
least the 84 days immediately up to the C1D1 date)
Cohort 3A: will contain ≥10 subjects who meet the eligibility criteria for Cohort 1 
(anemia only) while being on a stable dose of ruxolitinib for at least 112 days
immediately prior to the enrollment date
Cohort 3B: will contain approximately 46 subjects who meet the eligibility criteria for 
Cohort 2 (RBC-transfusion dependent) while being on a stable dose of ruxolitinib for at 
least 112 days immediately prior to the enrollment date. Effective from Protocol 
Amendment 3, additional subjects for this cohort must also have a minimum prior 
treatment with ruxolitinib per their local standard-of-care for at least 280 days (40 weeks)
without interruptions exceeding 2 consecutive weeks, while being on a stable ruxolitinib 
dose for at least 112 days (16 weeks) immediately prior to the enrollment date.
Overall, the study will enroll approximately 100 subjects worldwide across these parallel-
enrolling cohorts.  
The study will consist of a:

Maximum 28-day Screening Period 

Up to a 2-year Treatment Period (consisting of a 168-day Primary Phase, a Day 169 
Disease Response Assessment, and approximately 2-years or more for Extension 
Phase following the Cycle 1 Day 1 (C1D1) date, defined as the date of first dose of 
luspatercept) 

At least a 3-year Posttreatment Follow-up Period (consisting of 42-Day Follow-up 
Period and Long-term Follow-up Period) 
Refer to Section 3.1 for more information.  
Length of Study
The expected duration of the study for an individual subject is up to 5 years, consisting of a 
maximum 28-day Screening Period, a Primary Phase of Treatment Period of 168 days, a 
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Protocol ACE-536-MF-001
Celgene Corporation
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potential Extension Phase of Treatment Period for approximately 2 years or more (if the subject
continues to receive clinical benefit) from first dose of luspatercept, and a Posttreatment Follow-
up Period of 3 years. A roll-over study will provide continued access for subjects benefiting from 
luspatercept in the Extension Phase of the Treatment Period and ensures the Posttreatment
Follow-up Period will also be captured. 
The expected total study duration is approximately 6 years, which includes an enrollment period 
of approximately 26 months. 
The Screening Period 
Screening procedures are to take place over a maximum of 28 days immediately prior to the 
enrollment date, which is defined as the date in which subjects have been assigned a treatment cohort 
via Integrated Response Technology (IRT).  
Review of historical bone marrow biopsy information will be used to confirm MPN-associated 
myelofibrosis diagnosis.  The report(s) should come from the most recent local bone marrow 
biopsy performed and should contain the mutational status of the disease (eg, Janus kinase 2
[JAK2] gene, calreticulin [CALR] gene, and thrombopoietin receptor [MPL] gene).  
Transfusion history must be available for at least the 84 days immediately prior to the subject’s 
C1D1 date.  Transfusion data should include, but not be limited to, the number of units, volume 
of transfusion, pretransfusion hemoglobin (Hgb) values, and date of transfusion.  Red blood cell 
transfusions given at outside local institutions must also be collected.  
Primary Phase of Treatment Period: Day 1 to Day 168 
The first dose of luspatercept should be administered as soon as possible (at the latest 3 calendar 
days) following the enrollment date and will be given on Day 1 of each 21-day treatment cycle 
(unless there are dose delays).  In all cohorts, best supportive care (BSC) may be used in 
combination with study treatment when clinically indicated per Investigator. 
Day 169 Disease Response Assessment 
The Day 169 Disease Response Assessment visit should be completed 169 days after the date of 
first dose, regardless of dose delays.  
Extension Phase of Treatment Period: Day 169 through approximately 2 years or more from the 
date of C1D1, if the subject continues to receive clinical benefit
Subjects who meet the clinical benefit criteria (refer to Section 6.2.2 for more information) to 
remain on luspatercept treatment may continue dosing on Day 1 of each 21-day treatment cycle 
in the Extension Phase of the Treatment Period for approximately 2 years or more until the 
subject is no longer receiving clinical benefit, experiences unacceptable toxicities, has disease 
progression, withdraws consent, or meets any other discontinuation criteria (refer to Section 11
for more information).  Best supportive care (BSC) may continue to be used in combination with 
study treatment when clinically indicated per Investigator.  
The Disease Response Assessment should be completed on Day 1 of every Cycle in the 
Extension Phase until the subject is discontinued from treatment or withdraws consent.  
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Serial measurements of safety and efficacy will continue on scheduled study visits in the 
Extension Phase of the Treatment Period.  Refer to Section 6 for full list of study 
procedures/assessments.  
The same dose titration, delay and/or reduction, and treatment discontinuation criteria will still 
apply in the Extension Phase of the Treatment Period.  See Section 7.3 for dose modification 
rules and Section 11 for discontinuation criteria.  
All subjects who have received at least 1 dose of study treatment should undergo end of 
treatment (EOT) evaluations when luspatercept is discontinued.  
Posttreatment Follow-up Period 
The Posttreatment Follow-up Period includes a 42-Day Follow-up Period and Long-term 
Follow-up Period, beginning from the date of last dose of luspatercept. 
42-Day Follow-up Period
All adverse events (AEs) will be recorded by the Investigator from the time the subject signs 
informed consent until 42 days after the last dose of luspatercept including serious adverse 
events (SAEs) made known to the Investigator at any time thereafter that are suspected of 
being related to luspatercept. 
Long-term Follow-up Period 
For all subjects who receive at least 1 dose of luspatercept, continuation of monitoring for 
transformation to blast phase will occur in the Posttreatment Follow-up Period along with 
data collection of subsequent MPN-associated myelofibrosis therapies, and overall survival 
for at least 3 years from the date of last dose of luspatercept unless the subject withdraws 
consent from the study, dies, or is lost to follow up.  Refer to Section 6.5 for additional 
details.
The End of Trial is defined as either the date of the last visit of the last subject to complete the 
Posttreatment Follow-up Period, or the date of receipt of the last data point from the last subject 
that is required for primary, secondary 
 analysis, as prespecified in the 
protocol, whichever is the later date.
Refer to Section 3.1 for more information.  
Study Treatments
Each subject will receive a starting dose level of luspatercept at 1.0 mg/kg subcutaneous 
injection every 3 weeks (administered on Day 1 of each 21-day treatment cycle).  The starting 
dose can be titrated (increased) during the Treatment Period (Primary Phase and Extension 
Phase) to 1.33 mg/kg, up to a maximum of 1.75 mg/kg, provided that the subject meets the 
appropriate criteria (refer to Section 7.3).  The subject’s dose may also be delayed, reduced, or 
discontinued, depending on the specific criteria (refer to Section 7.3).  
Subjects enrolling into Cohort 3B following implementation of Protocol Amendment 3 will 
begin luspatercept treatment at a starting dose of 1.33 mg/kg and can have their dose increased to 
a maximum dose of 1.75 mg/kg (with the total dose not to exceed 168 mg). 
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Overview of Key Efficacy Assessments
Key efficacy assessments include:
-
RBC transfusions
-
Hematology parameters (eg, Hgb)
-
HRQoL information 
-
Disease Response Assessment 
Overview of Key Safety Assessments
Key safety assessments include:
-
AE/SAE reporting
-
Concomitant medications/procedures
-
Hematology parameters 
-
Serum chemistry 
-
Urinalysis
-
Pregnancy testing 
-
12-lead electrocardiogram (ECG)
-
Physical examination 
-
Eastern Cooperative Oncology Group (ECOG) performance status 
-
Vital signs and body weight 
Statistical Methods
For more specific information, please refer to Section 9 of the protocol.  
The analysis populations for this protocol are the intent-to-treat (ITT) population, the efficacy 
evaluable (EE) population, and the safety population.  
A sample size of approximately 100 subjects will be enrolled as follows:
-
Cohort 1: approximately 20 subjects, but no less than 14 EE subjects
-
Cohort 2: approximately 20 subjects
-
Cohort 3: up to 60 subjects 
A subject who meets all of the inclusion/exclusion criteria will be considered “efficacy 
evaluable” upon receiving ≥ 3 cycles of luspatercept and remain in the study for ≥ 21 days 
following the third dose of luspatercept.  Subjects who attain Hgb values > 13 g/dL in < 3 cycles 
will also be considered efficacy evaluable.  Subjects not considered “efficacy evaluable” are in 
general those that receive < 3 cycles of luspatercept in which luspatercept is held or discontinued 
or who receive < 3 cycles due to a treatment-emergent adverse event (TEAE) or discontinued 
treatment for any other reason (these subjects will be scored as a nonresponder).
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Subjects will become nonefficacy evaluable in certain cases (eg, prohibited concomitant 
medication/s was/were used during the study).  Subjects specifically in Cohort 3 become 
nonefficacy evaluable in certain cases (eg, the ruxolitinib dose was modified during the study).  
The study steering committee will review the allocation of all subjects to the EE population. 
The Sponsor estimates that out of 20 enrolled subjects in Cohort 1, at least 14 will become 
efficacy evaluable.  For Cohort 1, the probability of observing no responses among 14 subjects is 
less than 0.05 if the response probability is greater than 20%.  If no responses are observed in the 
first 14 evaluable subjects, the trial will be stopped because it can be concluded that the response 
rate for the primary endpoint is less than 20% in Cohort 1, and not worthy of further 
investigation.  Cohorts 2 and 3 will also be stopped due to clinical considerations. 
The sample size of Cohort 3 is increased to approximately 60 ITT subjects by the addition of up 
to 27 additional subjects (a total of approximately 46 subjects) in Cohort 3B. The sample size of 
Cohort 3A remains the same. A total of 46 subjects in Cohort 3B would provide for 80% power 
to detect a 15% increase in response rate for luspatercept over a null response rate of 17%. This 
assumes a one-sided z test of a binomial proportion (with a 5% significance level).
All efficacy analyses will be conducted primarily in the ITT population.  Confirmatory analyses 
will be conducted in the EE population. 
The primary efficacy endpoint is the proportion of subjects that achieved anemia response as 
defined below: 
Cohorts 1 (anemia only) and 3A: 
Proportion of subjects achieving ≥1.5 g/dL hemoglobin increase from baseline over any 
consecutive 84-day period without an RBC transfusion from Day 1 up through and including 
Day 168.  This 84-day period will begin as soon as the ≥1.5 g/dL hemoglobin increase is 
detected.  There must be ≥ 3 determinations of ≥1.5 g/dL hemoglobin increase from baseline
in this interval with no value showing a < 1.5 g/dL hemoglobin increase from baseline and no 
2 measurements are ≥ 42 days apart.
Cohorts 2 (RBC-transfusion dependent) and 3B: 
Proportion of subjects who become RBC-transfusion free over any consecutive 84-day 
period from Day 1 up through and including Day 168.  This 84-day period will begin from 
the date of the prior RBC transfusion that is given for a Hgb value ≤9.5 g/dL.
Anemia response rate, together with a 95% confidence interval, will be calculated for each 
cohort. 
Secondary efficacy endpoint analyses will include:
Time to anemia response will be summarized only for subjects who achieved anemia 
response. It is defined as time from first dose to first onset of anemia response, calculated 
from Day 1 through and including Day 168. 
Duration of anemia response will be summarized only for subjects who achieved anemia 
response. It is defined as maximum duration of modified anemia response, calculated from 
Day 1 through end of treatment.
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Frequency of RBC transfusions will be assessed for Cohort 2 subjects and RBC-transfusion 
dependent subjects in Cohort 3B.  It is defined as the mean number of RBC units transfused 
per subject per 28 days. It will be calculated from Day 1 through and including Day 168 and 
Day 1 through end of treatment. 
Frequency of RBC transfusion dependence will be assessed for Cohort 2 subjects and 
RBC-transfusion dependent subjects in Cohort 3B.  It is defined as the proportion of subjects 
who reduce their transfusion burden by ≥ 50% from baseline over any consecutive 84-day 
period.  It will be calculated from Day 1 through and including Day 168 and Day 1 through 
end of treatment. 
Symptoms response improvement will be assessed using the proportion of subjects who 
achieve ≥50% reduction in fatigue symptom as measured by the MPN-SAF TSS, calculated 
from Day 1 through and including Day 168 and Day 1 through end of treatment.  The 
proportion of subjects who achieve ≥50% reduction in total symptom score (TSS) will also 
calculated. 
Health-related quality of life (HRQoL) will be assessed via the mean changes in domain 
scores over the study compared to baseline using the FACT-An and EQ-5D-5L, calculated 
from Day 1 through and including Day 168 and Day 1 through end of treatment.  
Changes in hemoglobin will be assessed for Cohorts 1 and 3A subjects over the study 
compared to baseline in the absence of RBC transfusions, calculated from Day 1 through and 
including Day 168 and Day 1 through end of treatment.  
Mean hemoglobin increase of ≥ 1.5 g/dL from baseline over any consecutive 84-day period 
without an RBC transfusion will be assessed for Cohorts 1 and 3A subjects, calculated from 
Day 1 through and including Day 168 and Day 1 through end of treatment.  
No formal interim analysis is planned for the study.  
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TABLE OF CONTENTS
TITLE PAGE..............................................................................................................................1
PROTOCOL SUMMARY ..........................................................................................................6
1.
INTRODUCTION..................................................................................................20
1.1.
Myeloproliferative Neoplasm-associated Myelofibrosis..........................................20
1.1.1.
Signs and Symptoms...............................................................................................20
1.1.2.
Prognosis................................................................................................................20
1.2.
Treatment of MPN-associated Myelofibrosis ..........................................................21
1.2.1.
Treatment for Anemia.............................................................................................21
1.2.1.1.
Erythropoiesis Stimulating Agents..........................................................................22
1.2.1.2.
Androgenic Steroids ...............................................................................................22
1.2.1.3.
Corticosteroids........................................................................................................22
1.2.1.4.
Thalidomide, Lenalidomide, and Pomalidomide .....................................................22
1.2.1.5.
Sotatercept..............................................................................................................23
1.3.
Luspatercept Background .......................................................................................23
1.3.1.
Summary of Nonclinical Studies with Luspatercept................................................24
24
1.3.2.
Summary of Clinical Experience ............................................................................25
1.3.3.
Potential Risks of Human Use ................................................................................26
1.4.
Rationale ................................................................................................................26
1.4.1.
Study Rationale and Purpose ..................................................................................26
1.4.2.
Rationale for the Study Design ...............................................................................27
27
 
28
2.
STUDY OBJECTIVES AND ENDPOINTS...........................................................30
3.
OVERALL STUDY DESIGN ................................................................................34
3.1.
Study Design ..........................................................................................................34
3.2.
Study Duration for Subjects....................................................................................37
3.3.
End of Trial ............................................................................................................38
4.
STUDY POPULATION.........................................................................................39
4.1.
Numbers of Subjects...............................................................................................39
4.2.
Inclusion Criteria....................................................................................................39
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4.3.
Exclusion Criteria...................................................................................................41
5.
TABLE OF EVENTS.............................................................................................44
6.
PROCEDURES......................................................................................................51
6.1.
Screening Period.....................................................................................................51
6.2.
Treatment Period ....................................................................................................55
6.2.1.
Primary Phase of the Treatment Period...................................................................55
6.2.2.
Day 169 Disease Response Assessment ..................................................................56
6.2.3.
Extension Phase of the Treatment Period................................................................58
6.3.
Dose Delays in Treatment Period............................................................................60
6.4.
End of Treatment Visit ...........................................................................................60
6.5.
Posttreatment Follow-up Period..............................................................................61
6.5.1.
42-Day Follow-up Period (referred to as the Safety Follow-up) ..............................61
6.5.2.
Long-term Follow-up and End of Study..................................................................62
6.6.
Unscheduled Visits.................................................................................................63
6.7.
Pharmacokinetics....................................................................................................63
6.7.1.
Unscheduled Pharmacokinetic Visits ......................................................................63
6.8.
Antidrug Antibody..................................................................................................63
64
6.10.
Subject Reported Outcomes or Quality of Life Measurements ................................64
6.11.
Screen Failures .......................................................................................................65
7.
DESCRIPTION OF STUDY TREATMENTS........................................................66
7.1.
Description of Investigational Product(s)................................................................66
7.2.
Treatment Administration and Schedule .................................................................66
7.3.
Dose Modifications: Dose Titration, Dose Reduction, and Dose Delay ...................66
7.3.1.
Dose Titration.........................................................................................................67
7.3.2.
Dose Reduction and Dose Delay.............................................................................67
7.4.
Overdose ................................................................................................................69
7.5.
Method of Treatment Assignment...........................................................................70
7.6.
Packaging and Labeling..........................................................................................70
7.7.
Investigational Product Accountability and Disposal ..............................................70
7.8.
Investigational Product Compliance........................................................................70
8.
CONCOMITANT MEDICATIONS AND PROCEDURES....................................72
8.1.
Permitted Concomitant Medications and Procedures...............................................72
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8.2.
Prohibited Concomitant Medications and Procedures..............................................73
8.3.
Required Concomitant Medications and Procedures................................................73
9.
STATISTICAL CONSIDERATIONS ....................................................................74
9.1.
Overview................................................................................................................74
9.2.
Study Population Definitions ..................................................................................74
9.3.
Sample Size and Power Considerations...................................................................75
9.4.
Background and Demographic Characteristics........................................................76
9.5.
Subject Disposition.................................................................................................76
9.6.
Efficacy Analysis....................................................................................................76
9.6.1.
Primary Efficacy Analysis ......................................................................................76
9.6.2.
Secondary Efficacy Analyses..................................................................................77
9.7.
Safety Analysis.......................................................................................................78
9.8.
Timing of Analyses ................................................................................................78
9.8.1.
Interim Analysis .....................................................................................................78
9.8.2.
Final Analysis.........................................................................................................78
9.9.
Other Topics...........................................................................................................78
9.9.1.
Pharmacokinetic Analysis.......................................................................................78
79
9.9.3.
Steering Committee ................................................................................................79
10.
ADVERSE EVENTS..............................................................................................80
10.1.
Monitoring, Recording and Reporting of Adverse Events .......................................80
10.2.
Evaluation of Adverse Events.................................................................................80
10.2.1.
Seriousness.............................................................................................................80
10.2.2.
Severity/Intensity....................................................................................................82
10.2.3.
Causality ................................................................................................................82
10.2.4.
Duration .................................................................................................................83
10.2.5.
Action Taken..........................................................................................................83
10.2.6.
Outcome.................................................................................................................83
10.3.
Adverse Events of Special Interest..........................................................................83
10.4.
Abnormal Laboratory Values..................................................................................84
10.5.
Pregnancy...............................................................................................................84
10.5.1.
Females of Childbearing Potential: .........................................................................84
10.5.2.
Male Subjects.........................................................................................................85
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10.6.
Reporting of Serious Adverse Events......................................................................85
10.6.1.
Safety Queries ........................................................................................................86
10.7.
Expedited Reporting of Adverse Events..................................................................86
10.8.
Monitoring of Toxicity and Study Stopping Rules ..................................................86
11.
DISCONTINUATIONS .........................................................................................88
11.1.
Treatment Discontinuation......................................................................................88
11.2.
Study Discontinuation ............................................................................................89
12.
EMERGENCY PROCEDURES.............................................................................90
12.1.
Emergency Contact.................................................................................................90
12.2.
Emergency Identification of Investigational Products .............................................90
13.
REGULATORY CONSIDERATIONS...................................................................91
13.1.
Good Clinical Practice............................................................................................91
13.2.
Investigator Responsibilities ...................................................................................91
13.3.
Subject Information and Informed Consent.............................................................92
13.4.
Confidentiality........................................................................................................92
13.5.
Protocol Amendments.............................................................................................92
13.6.
Institutional Review Board/Independent Ethics Committee Review and 
Approval ................................................................................................................92
13.7.
Ongoing Information for Institutional Review Board/ Ethics Committee ................93
13.8.
Termination of the Study ........................................................................................93
14.
DATA HANDLING AND RECORDKEEPING.....................................................95
14.1.
Data/Documents .....................................................................................................95
14.2.
Data Management...................................................................................................95
14.3.
Record Retention....................................................................................................95
15.
QUALITY CONTROL AND QUALITY ASSURANCE........................................97
15.1.
Study Monitoring and Source Data Verification......................................................97
15.2.
Audits and Inspections............................................................................................97
15.3.
Product Quality Complaint .....................................................................................97
16.
PUBLICATIONS ...................................................................................................99
17.
REFERENCES.....................................................................................................100
18.
APPENDICES......................................................................................................104
Appendix A:
Table of Abbreviations ....................................................................................104
Appendix B:
Eastern Cooperative Oncology Group (ECOG) Performance Status Scale........107
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Appendix C:
National Cancer Institute (NCI) Common Terminology Criteria for 
Adverse Events (CTCAE), Version 4.03...............................................................108
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LIST OF TABLES
Table 1:
Study Objectives.....................................................................................................30
Table 2:
Study Endpoints .....................................................................................................31
Table 3:
Table of Events.......................................................................................................44
Table 4:
Starting Dose Level with Dose Reductions and Dose Titration................................67
Table 5:
Dose Modification: Dose Delay, Dose Reduction, and Discontinuation 
Guidelines ..............................................................................................................68
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LIST OF FIGURES
Figure 1:
Luspatercept Schematic Representation and Mechanism of Action .........................24
Figure 2:
Study Design ..........................................................................................................37
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1.
INTRODUCTION 
1.1.
Myeloproliferative Neoplasm-associated Myelofibrosis
Myeloproliferative neoplasm (MPN)-associated myelofibrosis is a clonal myeloid neoplasm 
characterized by defective bone marrow function, bone marrow fibrosis, extramedullary 
hematopoiesis, a propensity for transformation to blast phase, and an inflammatory state.  Levels 
of hematopoietic stem and progenitor cells in the blood are increased, reflecting abnormal 
homing of hematopoietic stem and progenitor cells.  Hematopoiesis in MPN-associated 
myelofibrosis is clonal arising from a transformed multipotent hematopoietic progenitor cell.
The cause of MPN-associated myelofibrosis is unknown and there are no known etiological 
factors.  About 50% of patients with MPN-associated myelofibrosis have a mutation in the Janus 
kinase 2 (JAK2) gene, about 33% of patients have a mutation in the calreticulin (CALR) gene,
and about 5% of patients have a mutation in the thrombopoietin receptor (MPL) gene.  About 
25% of patients have no detectable mutation and are referred to as triple-negative.  Mutations in 
other genes such as TET2, ASXL1 and DMT3A are also sometimes found and can precede or 
follow development of the driver mutations.  
Myeloproliferative neoplasm (MPN)-associated myelofibrosis can develop directly (primary 
myelofibrosis [PMF]) or evolve from other MPNs, including polycythemia vera (PV) and 
essential thrombocythemia (ET).  For purposes of this study, MPN-associated myelofibrosis is 
defined as PMF, post-polycythemia vera myelofibrosis (post-PV MF), and post-essential 
thrombocythemia myelofibrosis (post-ET MF).  
1.1.1.
Signs and Symptoms 
Myeloproliferative neoplasm (MPN)-associated myelofibrosis is predominately a disease of the 
elderly with a median age at onset in a range of 69 to 76 years (Moulard, 2013).  Erythropoiesis 
is qualitatively and quantitatively abnormal resulting in anemia in about 30% of affected patients 
at diagnosis.  However, eventually all affected patients develop anemia.  Anemia is often 
confounded by comorbidities typical of an older population like atherosclerotic cardiovascular 
disease and cerebrovascular disease.  Severe anemia unresponsive to therapy can be fatal.  
Myelopoiesis is also qualitatively and quantitatively abnormal resulting in decreased or increased 
granulocytes and/or platelets.  Infection risk is increased because of decreased numbers of and/or 
dysfunctional granulocytes.  Furthermore, there may be bleeding from decreased numbers of 
and/or dysfunctional platelets.  Extramedullary hematopoiesis, typical of MPN-associated 
myelofibrosis, results in spleen and liver enlargement (splenomegaly and hepatomegaly, 
respectively) in about 60% of affected patients at diagnosis resulting in early satiety, weight loss, 
and constitutional symptoms.  Myeloproliferative neoplasm (MPN)-associated myelofibrosis is a 
progressive disorder such that many of the signs and symptoms discussed above will develop
with time even in patients in whom they are absent at diagnosis.  
1.1.2.
Prognosis 
Median survival of patients with MPN-associated myelofibrosis is 5 to 6 years from diagnosis.  
Several prognostic scores are used that combine independent prognostic variables including age, 
gender, spleen and/or liver enlargement, hemoglobin (Hgb) level, red blood cell (RBC)-
transfusion dependence, numbers of leukocytes and/or platelets, numbers of monocytes or 
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immature myeloid cells, clonal cytogenetic abnormalities and bone marrow histology (Cervantes, 
2009; Dupriez, 1996; Tefferi, 2007; Tefferi, 2009).  In a recent study involving > 1000 subjects,
multivariate analysis of parameters obtained at diagnosis identified age > 65 years, constitutional 
symptoms, hemoglobin concentration < 10 g/dL, leukocyte levels > 25 x 109/L and blood 
myeloblasts ≥1% as predictors of shortened survival.  Several of these parameters are also 
associated with an increased risk of transformation to blast phase.  In this study, the yearly 
incidence rates for transformation to blast phase was 3.7% and deaths due to transformation to 
blast phase within a 10-year period was 18% (Quintas-Cardama, 2013; updated by personal 
communication with Srdan Verstovsek 01 May 2017).  
Patients developing MPN-associated myelofibrosis after PV or ET have the same prognosis to 
those with PMF.
Recently, associations are reported between prognosis and mutational landscape.  For example, 
patients with CALR mutations have the best prognosis whereas those with no detectable mutation 
(triple negative) have the worst prognosis.  The concomitant presence of non-driver mutations,
such as those in ASXL1, TET2 and DNMT3A, are also associated with a worse prognosis.
1.2.
Treatment of MPN-associated Myelofibrosis 
Two types of therapies are used in MPN-associated myelofibrosis: (1) targeting the cancer clone 
and (2) targeting signs and symptoms of the disease.  Current therapies have little impact on 
survival.  Commonly used therapies include drugs to reverse anemia (refer to below), drugs to 
decrease the size of the neoplastic clone, and anti-inflammatory drugs, where sometimes these 
targets overlap.  Splenectomy and/or spleen radiation are also sometimes done, whereas 
hematopoietic cell transplants are rarely used because of advanced age and co-morbidities.
In 2011 and 2012, the Food and Drug Administration (FDA) and European Medicines Agency 
(EMA), respectively, approved ruxolitinib, a Janus kinase (JAK) inhibitor intended for therapy of 
MPN-associated myelofibrosis.  Currently, it is the standard of care for treating splenomegaly 
and constitutional symptoms, offering significant improvements in spleen shrinkage, symptom 
mitigation, and overall survival.  However, therapy-induced cytopenias like anemia may impair 
administration of optimal therapeutic doses as they can occur transiently.
Several other JAK or signal transducers and activators of transcription (STAT) inhibitors are 
currently in development, and though they are not targeted, they are effective in reducing 
splenomegaly and constitutional symptoms in patients with and without the JAK2 mutation.  
However, there is controversy whether they improve survival. Several other drug classes are in 
development including telomerase inhibitors and anti-fibrotic drugs (eg, pentraxin).  
1.2.1.
Treatment for Anemia 
Anemia is present at diagnosis in about 30% of patients with MPN-associated myelofibrosis and 
develops in almost all patients.  The etiology of anemia in MPN-associated myelofibrosis is 
complex, as several mechanisms may operate in an affected person (Barosi, 2010).  Some drugs 
used to treat MPN-associated myelofibrosis, such as hydroxyurea (hydroxycarbamide) and 
ruxolitinib, worsen anemia.  
Overall, anemia and RBC-transfusion dependence are strong, independent prognostic variables 
for survival and for risk of transformation to blast phase (Passamonti, 2010; Elena, 2011). 
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Therapy of anemia in MPN-associated myelofibrosis is problematic, and there are no proven or 
approved therapies.  Currently, there are no FDA- or EMA-approved drugs for the treatment of 
anemia with or without RBC-transfusion dependence in patients with MPN-associated 
myelofibrosis, but commonly used interventions include therapies such as corticosteroids, 
androgenic steroids, erythropoietin, thalidomide, and pomalidomide.  None have been proven
effective in an adequately powered, double-blind, randomized clinical trial.  A recent large 
randomized trial of pomalidomide reported no benefit, but other investigational studies of 
pomalidomide and corticosteroids report contradictory data (Tefferi, 2017; Schlenk, 2016).
In summary, no therapy has been proven safe and effective to treat anemia in patients with MPN-
associated myelofibrosis.  
1.2.1.1.
Erythropoiesis Stimulating Agents 
Erythropoiesis stimulating agents (ESAs) are widely used for the treatment of anemia associated 
with both lymphoid and myeloid neoplasms.  In general, serum erythropoietin (EPO) levels in 
patients with MPN-associated myelofibrosis are elevated for the degree of anemia and 
exogenous use of ESAs are of limited value (Barosi, 1993). 
Some patients with EPO levels < 500 IU/L receive pharmacological doses of recombinant human 
EPO.  Response rates are < 20% and complete responses are uncommon, while most responses 
are transient.  Currently, there are no randomized clinical trials of recombinant human EPO in 
patients with MPN-associated myelofibrosis who are RBC-transfusion dependent.  Retrospective 
series in such patients treated with EPO or darbepoetin reported occasional response (Cervantes, 
2004; Cervantes, 2006; Rodriguez, 1998; Tsiara, 2007).  The data suggest ESAs have limited 
therapeutic activity in RBC-transfusion dependent patients with MPN-associated myelofibrosis 
and anemia regardless of serum EPO levels (Huang, 2009).
1.2.1.2.
Androgenic Steroids 
Androgenic steroids are sometimes used to treat anemia in patients with MPN-associated 
myelofibrosis.  A retrospective analysis of case reports identified 5 of 27 (18%) subjects with 
MPN-associated myelofibrosis and RBC-transfusion-dependence responding to treatment with 
danazol (Cervantes, 2015).  Complete responses are uncommon and often transient, which are in 
line with earlier studies.  Additionally, androgenic steroids are associated with risks of liver 
toxicity and liver and prostate cancers.  Based on these data, use of androgenic steroids in this 
setting is not proven safe and effective in patients with MPN-associated myelofibrosis who are 
RBC-transfusion dependent (Branda, 1977; Brubaker, 1982; Cervantes, 2005; Levy, 1996).
1.2.1.3.
Corticosteroids 
Corticosteroids do not produce sustained improvement in hemoglobin concentrations in patients 
with MPN-associated myelofibrosis.  Corticosteroids are poorly-tolerated, especially in older
patients, and increase infection risk in patients with decreased normal spleen function and in 
patients who have been splenectomized (Odenike, 2005).  
1.2.1.4.
Thalidomide, Lenalidomide, and Pomalidomide 
Thalidomide and other immunomodulatory compounds, such as lenalidomide and
pomalidomide, modulate levels of cytokines and growth factors in the bone marrow and may be 
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of benefit in patients with MPN-associated myelofibrosis.  Thalidomide and lenalidomide are 
reported to improve outcomes with MPN-associated myelofibrosis in nonrandomized clinical 
trials. However, the efficacy of thalidomide and lenalidomide are severely limited by adverse 
effects, toxicities that are uncommon with pomalidomide.  Furthermore, pomalidomide is more 
active in modulating levels of inflammatory cytokines and growth factors.  Data from 
experimental models and a Celgene-sponsored trial indicate pomalidomide increases
erythropoiesis in mice with sickle cell disease and humans with MPN-associated myelofibrosis.  
A randomized Phase 3 study showed no benefit of low-dose pomalidomide over placebo in 
subjects with RBC-transfusion dependence (Tefferi, 2017).  However, a Phase 2 study of a 
higher dose of pomalidomide combined with prednisone reported activity (Schlenk, 2016).
1.2.1.5.
Sotatercept
Sotatercept (ACE-011) is a novel soluble receptor fusion protein (activin receptor type IIA 
linked to Fc fragment of human immunoglobulin [Ig]G1) that “traps” ligands that bind to the 
activin type IIA receptor.  
Sotatercept is extensively studied in humans and is active in treating anemia in patients 
associated with β-thalassemia and myelodysplastic syndrome (MDS).  Like luspatercept, 
sotatercept targets molecules in the transforming growth factor-beta (TGF-β) superfamily, but 
sotatercept contains the human activin type IIA receptor whereas luspatercept contains the 
activin type IIB receptor.
Sotatercept is currently being studied in subjects with MPN-associated myelofibrosis and anemia 
receiving or not receiving ruxolitinib.  Preliminary results suggest sotatercept improves anemia 
and RBC-transfusion dependence in patients with MPN-associated myelofibrosis and is well-
tolerated (Bose, 2016).
1.3.
Luspatercept Background
Luspatercept (ACE-536) is a recombinant fusion protein consisting of a modified form of the 
extracellular domain (ECD) of the human activin receptor type IIB (ActRIIB) linked to the IgG1 
Fc domain (Figure 1A). The ActRIIB receptor and its ligands are members of the transforming 
growth factor-β (TGF-β) superfamily, a group of proteins involved in the development, 
differentiation, and/or maturation of various tissues.  No species differences have been described 
in the ligand-receptor interactions among members of the TGF-β family as the ligands and 
receptors are highly conserved across species (Massague, 1998).  Thus, observations from 
pharmacology studies of luspatercept or its murine ortholog RAP-536 in animal models provide 
significant insight into the potential of luspatercept to treat human disease. 
Members of the TGF-β ligands, through their binding to activin receptors, are involved in 
modulating the differentiation of late-stage erythrocyte precursors (normoblasts) in the bone 
marrow. In particular, luspatercept acts as a ligand trap for growth differentiation factor 11 
(GDF11) and other TGF-β family ligands to suppress Smad2/3 signaling. In nonclinical 
experiments, luspatercept has been shown to bind with high affinity to some TGF-β ligands (eg, 
GDF11, bone morphogenetic protein 6 [BMP6] and activin B) but substantially less to others 
(eg, bone morphogenetic protein 9 [BMP9] and activin A). The mechanism of action of 
luspatercept is independent from that of erythropoietin (EPO) (Suragani, 2014). While EPO 
stimulates proliferation and differentiation of early erythroid progenitors, luspatercept promotes 
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stimulation of the later, maturation phase of erythroblast differentiation and maturation in the 
bone marrow (refer to Figure 1B).
During normal erythropoiesis, GDF11 appears to inhibit differentiation and maintain the survival 
of immature erythroid progenitors, but its expression is decreased as cells mature, and thus its 
effect is transient. In a mouse model of thalassemia, defects in erythroid differentiation led to an 
accumulation of GDF11 expressing cells that maintained their own survival (Dussiot, 2014). 
Recent studies (Dussiot, 2014; Suragani, 2014) identified GDF11 as a regulator of erythropoiesis 
and showed that its inhibition in mouse models of anemia with ineffective erythropoiesis restores 
normal erythropoietic differentiation and improves anemia.
Figure 1:
Luspatercept Schematic Representation and Mechanism of Action
A 
B
ActRIIB = activin receptor type IIB; ECD = extracellular domain; EPO = erythropoietin; GDF11 = growth 
differentiation factor 11; IgG1 = immunoglobulin G1; RBC = red blood cell; TGF-b = transforming growth factor-
beta.  
Please refer to the Investigator’s Brochure for detailed information concerning the available 
pharmacology, toxicology, drug metabolism, clinical studies, and adverse event profile of 
luspatercept.
1.3.1.
Summary of Nonclinical Studies with Luspatercept 
A brief summary of key findings from pharmacology and toxicology studies is provided below. 
Please refer to the Investigator’s Brochure (IB) for detailed information concerning the available 
pharmacology, toxicology, drug metabolism, clinical studies, and adverse event profile of 
luspatercept.  The most recent version of the luspatercept IB should be reviewed prior to 
initiating the study.
 
 
 
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1.3.2.
Summary of Clinical Experience
Luspatercept is currently in Phase 3 of clinical development in MDS and beta-thalassemia. 
Luspatercept is currently being assessed in two Phase 2 studies in subjects with MDS.  In these 
studies, the preliminary International Working Group (IWG) hematologic improvement –
erythroid (HI-E) response for subjects treated with luspatercept dose levels of ≥ 0.75 mg/kg in 
the base study (A536-03) and the extension study (A536-05) respectively were seen in 18 out of 
29 (62%) and 19 out of 23 (83%) subjects with ring sideroblasts (RS+) with EPO levels < 200 
U/L, as well as 5 out of 11 (46%) and 7 out of 8 (88%) RS+ subjects with EPO levels 200 to 500
U/L. Subjects were also evaluated on the basis of whether they achieved RBC-transfusion
independence (RBC-TI) for ≥8 weeks. The RBC-TI response for subjects treated with 
luspatercept dose levels of ≥0.75 mg/kg in the base study and extension study respectively were 
seen in 13 out of 19 (68%) and 10 out of 14 (71%) RS+ subjects with EPO levels < 200 U/L, as 
well as 3 out of 9 (33%) and 3 out of 5 (60%) RS+ subjects with EPO levels 200 to 500
U/L. Furthermore, in the extension study, 17 out of 28 (61%) subjects overall had achieved 
transfusion independence, in which the longest duration of erythroid response was up to 22 
months (treatment ongoing) (Platzbecker, 2016).
Preliminary data for RS- subjects is encouraging for both HI-E response and RBC-TI.
In a Phase 3 (MEDALIST) trial, luspatercept resulted in a significantly reduced transfusion 
burden compared with placebo in patients with anemia due to Revised International Prognostic 
Scoring System (IPSS-R) very low-, low-, or intermediate-risk MDS with ring sideroblasts who 
require RBC transfusions, and overall, was generally well tolerated. Data demonstrated that 58 
out of 153 (37.9%) subjects in the luspatercept arm achieved RBC transfusion independence for 
≥ 8 weeks compared to 10 out of 76 (13.2%) subjects in the placebo arm (Fenaux, 2018).
Luspatercept is currently being assessed in two Phase 2 studies in subjects with β-thalassemia.  
In these studies, 25 out of 31 (81%) transfusion-dependent (TD) subjects treated with ≥ 
0.6 mg/kg had a ≥20% reduction and 17 out of 31 subjects (55%) had a ≥50% reduction in 
transfusion burden over any 12-week period during the 3-month study (A536-04). For 
nontransfusion dependent (NTD) subjects treated with ≥0.6 mg/kg, 7 out of 21 subjects (33%)
achieved an increase in Hgb ≥1.5 g/dL sustained for ≥14 days and 13 out of 21 subjects (62%)
achieved a mean increase in Hgb ≥1.0 g/dL sustained for ≥12 weeks in the 3-month treatment 
study (Piga, 2016).
In a Phase 3 (BELIEVE) trial, luspatercept resulted in significantly reduced transfusion burden in 
adults with transfusion-dependent β-thalassemia, and overall, was generally well tolerated.  Data 
demonstrated that 48 out of 224 (21.4%) subjects in the luspatercept arm achieved a ≥ 33% 
reduction from baseline in transfusion burden during weeks 13 to 24 compared to 5 out of 112 
(4.5%) subjects in the placebo arm (Cappellini, 2018).
Until now, no clinical trials investigating the efficacy of luspatercept in MPN-associated 
myelofibrosis have been initiated/completed.  
Additional information regarding clinical experience with luspatercept is summarized in the 
current version of the luspatercept IB.
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1.3.3.
Potential Risks of Human Use 
Increases in hematologic parameters (ie, RBC, Hgb, hematocrit, reticulocytes) are expected 
pharmacologic effects of luspatercept treatment.  Increases in systolic and diastolic blood 
pressures may occur in concert with increases in hemoglobin values.  Excessive or rapid 
increases in hemoglobin or blood pressure may occur and will be monitored.  Dose modification 
rules for individual subjects, including dose delay and/or dose reduction, will be utilized to 
minimize risks associated with increased RBC parameters. 
Adverse events observed in the Phase 1 study in healthy volunteers and the ongoing Phase 2 
studies that were considered probably or possibly related to investigational product included 
injection site reactions (hemorrhage, pruritus, rash), skin rash, hyperesthesia, muscle spasms, 
myalgia, pruritus, and hyperkalemia.
As with all biologics, there is the potential for antidrug antibodies (ADA) that can be associated 
with increased drug clearance and hypersensitivity reactions.  Antidrug antibody (ADA)
formation against luspatercept as well as human ActRIIB protein will be monitored in the initial
clinical studies. 
Luspatercept has exhibited maternal and developmental toxicity in reproductive toxicity studies 
in preclinical species and therefore luspatercept should not be administered to pregnant or 
nursing women.  Male and female subjects of childbearing potential participating in studies of 
luspatercept must be willing to abstain from sexual intercourse or use adequate contraception 
during the treatment and follow-up period of the study.  Please refer to the IB for additional 
information regarding findings from toxicology studies.  It is unknown if humans will experience 
any of the effects of luspatercept that were noted in the rat and monkey toxicology studies.  
Safety effects will be monitored closely through adverse event (AE) reporting, clinical laboratory 
tests, vital signs, and physical examinations. 
A comprehensive review of luspatercept, as well as details regarding the information 
summarized above, is provided in the IB.  The most recent version of the luspatercept IB should 
be reviewed prior to initiating the study.
1.4.
Rationale
1.4.1.
Study Rationale and Purpose
Anemia and related symptoms are important features of MPN-associated myelofibrosis.  Patients 
with anemia and those receiving RBC transfusions have significantly worse survival and an 
increased risk of transformation to blast phase. Therapies such as ESAs, androgenic steroids,
and corticosteroids are rarely effective with most responses transient, while data regarding 
efficacy of pomalidomide is controversial.  No drug is approved to treat anemia in patients with 
MPN-associated myelofibrosis.  
Luspatercept is a novel recombinant fusion protein consisting of a modified form of the 
extracellular domain (ECD) of the human activin receptor type IIB (ActRIIB).  Luspatercept 
stimulates the later, maturation phase of erythropoiesis and improves anemia in patients with 
MDS and beta-thalassemia.  Sotatercept, active in patients with MPN-associated myelofibrosis 
and anemia, is structurally similar to luspatercept.  
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The purpose of this Phase 2 study is to evaluate safety and efficacy of luspatercept in subjects 
with MPN-associated myelofibrosis and anemia with and without RBC-transfusion dependence. 
1.4.2.
Rationale for the Study Design
This study is a multicenter, multicohort, parallel-enrolling, single-arm, Phase 2 study of anemia 
response, where the multicenter nature of the study provides assurance that the results are likely 
to have applicability for planning a confirmatory Phase 3 study.
Three cohorts with distinct entry criteria are included.  The rationale for each of the cohorts is as 
follows:

Cohort 1 (anemia only): 
 
 

Cohort 2 (RBC-transfusion dependent):
 
 
 

Cohort 3 (subjects on ruxolitinib as part of their standard-of-care therapy):
 
 
  
Beginning with Protocol Amendment 3, in addition to RBC-transfusion dependent subjects with 
a defined average RBC-transfusion frequency of 6 to 12 RBC units/84 days, subjects with an 
RBC transfusion burden of 4 to 5 RBC units/84 days may also be eligible for enrollment.
Eligibility criteria are consistent with those in other studies of this population.  Safety is assessed 
by evaluating adverse events and laboratory data.  Adverse events and abnormal laboratory value 
severity will be graded using version 4.03 of the National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI CTCAE).
 
 
 
 
 
 
 
 
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EDMS Doc. Number: 24487940 - 21868350
Luspatercept (ACE-536)
Protocol ACE-536-MF-001
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2.
STUDY OBJECTIVES AND ENDPOINTS
Table 1:
Study Objectives
Primary Objective
The primary objective of the study is to evaluate the efficacy and safety of luspatercept for the 
treatment of anemia in subjects with myeloproliferative neoplasm (MPN)-associated 
myelofibrosis with and without red blood cell (RBC)-transfusion dependence.
Secondary Objectives
The secondary objectives of the study are:
-
To evaluate the safety of luspatercept in MPN-associated myelofibrosis 
-
To evaluate the effect of luspatercept in MPN-associated myelofibrosis:
o
on the time to and duration of anemia response
o
on frequency of RBC transfusions and transfusion dependence
o
on symptom response improvement via the Myeloproliferative Neoplasm 
Symptom Assessment Form Total Symptom Score (MPN-SAF TSS) 
o
on health-related quality of life (HRQoL) via the EQ-5D-5L and Functional 
Assessment of Cancer Therapy – Anemia (FACT-An) questionnaires 
o
on the changes in hemoglobin and mean hemoglobin increase 
-
To evaluate population pharmacokinetics of luspatercept in subjects with MPN-
associated myelofibrosis with and without RBC-transfusion dependence 
 
 
 
 
 
 
 
 
Approved
9.0
v
Approved
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EDMS Doc. Number: 24487940 - 21868350
Luspatercept (ACE-536)
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Table 2:
Study Endpoints
Endpoint
Name
Description
Timeframe
Primary 
Endpoint 
*refer to 
Section 3.1 for 
more 
information 
on each 
cohort 
Anemia response as it relates 
to hemoglobin (Hgb) increase 
and red blood cell (RBC)-
transfusion independence
Cohorts 1 and 3A*: 
Proportion of subjects 
achieving ≥1.5 g/dL 
hemoglobin increase from 
baseline over any consecutive 
84-day period without an 
RBC transfusion 
Any consecutive 
“rolling” 84-day period 
from Day 1 through 
and including Day 168
Cohorts 2 and 3B*: 
Proportion of subjects who 
become RBC-transfusion free 
over any consecutive 84-day 
period
Any consecutive 
“rolling” 84-day period 
from Day 1 through
and including Day 168
Secondary 
Endpoints 
Time to anemia response 
Time from first luspatercept 
dose to first onset of anemia 
response in each of the 
cohorts
Day 1 through and 
including Day 168
Duration of anemia response 
Maximum duration of anemia 
response in each of the 
cohorts
Day 1 through end of 
treatment
Frequency of RBC 
transfusions 
Cohorts 2 and 3B:
Mean number of RBC units 
transfused per subject per 28 
days 
Day 1 through and 
including Day 168;
Day 1 through end of 
treatment
Frequency of RBC-
transfusion dependence 
Cohorts 2 and 3B: 
Proportion of RBC-
transfusion dependent 
subjects who reduce their 
transfusion burden by ≥50% 
from baseline over any 
consecutive 84-day period 
Day 1 through and 
including Day 168;
Day 1 through end of 
treatment
Symptoms response 
improvement 
Proportion of subjects who 
achieve ≥50% reduction in 
fatigue symptom as measured 
by the Myeloproliferative 
Neoplasms Symptom 
Assessment Form Total 
Symptom Score (MPN-SAF 
TSS)
The proportion of subjects 
who achieve ≥50% reduction 
in total symptom score (TSS)
Day 1 through and 
including Day 168;
Day 1 through end of 
treatment
Approved
9.0
v
Approved
1.0
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EDMS Doc. Number: 24487940 - 21868350
Luspatercept (ACE-536)
Protocol ACE-536-MF-001
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Confidential and Proprietary
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ACE-536-MF-001 Amendment 4 Final: 19 Feb 2020
Table 2:
Study Endpoints (Continued)
Endpoint
Name
Description
Timeframe
Health-related quality of life 
(HRQoL) improvement via 
the Functional Assessment of 
Cancer Therapy – Anemia 
(FACT-An) and EQ-5D-5L 
questionnaires 
Mean changes in HRQoL 
domain scores over the study 
compared to baseline
Day 1 through and 
including Day 168;
Day 1 through end of 
treatment
Safety
Type, frequency, severity of 
AEs and relationship of AEs 
to luspatercept
Screening through 42 
days post last dose
A population 
pharmacokinetic (PK) model
A population PK model that 
describes the PK exposure 
data of luspatercept and 
associated variability
Day 1 up to 1 year
Antidrug antibodies (ADA) 
Frequency of antidrug 
antibodies and effects on 
efficacy, safety, or PK
Day 1 up to 1 year for 
ADA-negative 
subjects; Day 1 up to 2 
years for ADA-positive 
subjects
Changes in hemoglobin  
Cohorts 1 and 3A:
Changes in hemoglobin over 
the study compared to 
baseline in the absence of 
RBC transfusions
Day 1 through and 
including Day 168;
Day 1 through end of 
treatment
Mean hemoglobin increase
Cohorts 1 and 3A: 
Proportion of subjects 
achieving a mean ≥ 1.5 g/dL 
hemoglobin increase from 
baseline over any consecutive 
84-day period without an 
RBC transfusion
Any consecutive 
“rolling” 84-day period 
from Day 1 through 
and including Day 168;
Day 1 through end of 
treatment
Approved
9.0
v
Approved
1.0
v

EDMS Doc. Number: 24487940 - 21868350
Luspatercept (ACE-536)
Protocol ACE-536-MF-001
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Confidential and Proprietary
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ACE-536-MF-001 Amendment 4 Final: 19 Feb 2020
Table 2:
Study Endpoints (Continued)
Endpoint
Name
Description
Timeframe
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Approved
9.0
v
Approved
1.0
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EDMS Doc. Number: 24487940 - 21868350
Luspatercept (ACE-536)
Protocol ACE-536-MF-001
Celgene Corporation
Confidential and Proprietary
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ACE-536-MF-001 Amendment 4 Final: 19 Feb 2020
3.
OVERALL STUDY DESIGN
3.1.
Study Design
The study will be conducted in compliance with the International Council for Harmonisation 
(ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use/Good 
Clinical Practice (GCP) and applicable regulatory requirements.
This is a Phase 2, multicenter, open-label study to evaluate the efficacy and safety of luspatercept 
in subjects with MPN-associated myelofibrosis and anemia with and without RBC-transfusion 
dependence.  The study is divided into a Screening Period, a Treatment Period (consisting of a 
Primary Phase, a Day 169 Disease Response Assessment, and an Extension Phase), followed by 
a Posttreatment Follow-up Period.  The overall study design is described in Figure 2, with more 
detailed descriptions for each phase of the study design found in Section 6.
Subjects satisfying the eligibility criteria will be assigned to 1 of the following cohorts (which 
are enrolling in parallel) based on their eligibility: 

Cohort 1: will contain up to 20 subjects with anemia only that are not currently 
receiving RBC transfusions (these subjects will be referred to as “anemia only” 
throughout the protocol, defined as 0 RBC units/84 days immediately up to the C1D1
date)

Cohort 2: will contain up to 20 subjects that are RBC-transfusion dependent (these 
subjects will be referred to as “RBC-transfusion dependent” throughout the protocol, 
defined as an average RBC transfusion frequency of 2 to 4 RBC units/28 days over at 
least the 84 days immediately up to the C1D1 date)

Cohort 3A: will contain ≥ 10 subjects who meet the eligibility criteria for Cohort 1 
(anemia only) while being on a stable dose of ruxolitinib for at least 112 days
immediately prior to the enrollment date

Cohort 3B: will contain approximately 46 subjects who meet the eligibility criteria 
for Cohort 2 (RBC-transfusion dependent) while being on a stable dose of ruxolitinib 
for at least 112 days immediately prior to the enrollment date. Effective from Protocol 
Amendment 3, additional subjects for this cohort must also have a minimum prior 
treatment with ruxolitinib per their local standard-of-care for at least 280 days (40 
weeks) without interruptions exceeding 2 consecutive weeks, while being on a stable 
ruxolitinib dose for at least 112 days (16 weeks) immediately prior to the enrollment 
date.
Refer to the eligibility criteria (Section 4) for full cohort specifications.  
The subject must be enrolled at the latest 28 days from signing the informed consent form (ICF), 
designated as the enrollment date.  The first dose of luspatercept (designated as Cycle 1 Day 1 
[C1D1]) should be administered as soon as possible (at the latest 3 calendar days) following the 
enrollment date (but can occur on the same day as the enrollment date).
Subjects across each cohort will receive a starting dose level of luspatercept at 1.0 mg/kg 
subcutaneous injection every 3 weeks (administered on Day 1 of each 21-day treatment cycle).  
Approved
9.0
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Approved
1.0
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EDMS Doc. Number: 24487940 - 21868350
Luspatercept (ACE-536)
Protocol ACE-536-MF-001
Celgene Corporation
Confidential and Proprietary
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ACE-536-MF-001 Amendment 4 Final: 19 Feb 2020
Subjects enrolling into Cohort 3B following implementation of Protocol Amendment 3 will 
begin luspatercept treatment at a starting dose of 1.33 mg/kg and can have their dose increased to 
a maximum dose of 1.75 mg/kg (with the total dose not to exceed 168 mg).
The starting dose can be titrated (increased), reduced, or delayed during the Treatment Period 
(Primary Phase and Extension Phase).  Please refer to Section 7.3 for more information regarding 
dose modifications.  
During the Primary Phase of the Treatment Period, subjects will receive luspatercept on Day 1 of 
each 21-day treatment cycle (unless there are dose delays) through at least Day 168 following the 
C1D1 date unless the subject experiences unacceptable toxicities, withdrawsconsent, or meets 
any other treatment discontinuation criteria (Section 11.1) prior to the Day 169 Disease Response 
Assessment. 
At the Day 169 Disease Response Assessment, which should be completed 169 days after the 
C1D1 date regardless of dose delays, subjects will be assessed by the Investigator to see if they 
may continue receiving luspatercept treatment in the Extension Phase of the Treatment Period.  
The following criteria must be met: 
Cohorts 1 (anemia only) and 3A
Subjects with ≥3 determinations showing a ≥1.5 g/dL hemoglobin increase above the 
baseline value (defined as the subject’s Hgb value observed on the C1D1 date prior to 
luspatercept administration) absent of RBC transfusions over a consecutive ≥84-day period 
with no 2 measurements ≥42 days apart (and no determination < 1.5 g/dL above the baseline 
value) at the time of the Day 169 Disease Response Assessment will have the opportunity to 
move into the Extension Phase of the Treatment Period.  The subject may remain on 
treatment for approximately 2 years or more from date of C1D1, until a determination shows 
a value < 1.5 g/dL hemoglobin increase above the baseline value (absent of bleeding or 
infection), there is receipt of an RBC transfusion, disease progression, or any of the other 
criteria for treatment discontinuation are met.  
If, at the Day 169 Disease Response Assessment, the subject has ≥3 determinations showing 
a ≥1.5 g/dL hemoglobin increase above the baseline value with no 2 measurements ≥42 
days apart (and no determination < 1.5 g/dL above the baseline value) in the absence of RBC 
transfusions over the preceding 56 days, the subject may continue on in the Extension Phase 
of the Treatment Period for an additional 28 days. If, after this additional 28 days, the 
subject meets the response criteria, the subject can continue on in the Extension Phase of the 
Treatment Period and remain on treatment at the Investigator’s discretion for approximately 
2 years or more from the date of C1D1, until a determination shows a value < 1.5 g/dL 
hemoglobin increase above the baseline value (absent of bleeding or infection), there is
receipt of an RBC transfusion, disease progression, or any of the other criteria for treatment 
discontinuation are met.
Cohorts 2 (RBC-transfusion dependent) and 3B
Subjects who are transfusion free over ≥84 consecutive days at the time of the Day 169 
Disease Response Assessment can enter the Extension Phase of the Treatment Period and 
remain on treatment for approximately 2 years or more from the C1D1 date at the 
Approved
9.0
v
Approved
1.0
v

EDMS Doc. Number: 24487940 - 21868350
Luspatercept (ACE-536)
Protocol ACE-536-MF-001
Celgene Corporation
Confidential and Proprietary
36
ACE-536-MF-001 Amendment 4 Final: 19 Feb 2020
Investigator’s discretion, until they receive the next RBC transfusion (absent of bleeding or 
infection), disease progression, or meet other criteria for treatment discontinuation.  
If, at the Day 169 Disease Response Assessment, the subject is RBC-transfusion free for the 
preceding 56 days, they may continue on in the Extension Phase of the Treatment Period for 
an additional 28 days. If, after this additional 28 days, the subject meets the response criteria, 
they can continue on in the Extension Phase of the Treatment Period and remain on treatment 
for approximately 2 years or more from the C1D1 date at Investigator’s discretion until the 
subject receives an RBC transfusion (absent of bleeding or infection), disease progression, or 
meets of other criteria for treatment discontinuation.
Should subjects from each respective cohort not meet the clinical benefit criteria outlined above, 
they should discontinue treatment with luspatercept and enter the Posttreatment Follow-up 
Period.  Otherwise, subjects may begin luspatercept treatment in the Extension Phase of the 
Treatment Period, receiving luspatercept on Day 1 of each 21-day treatment cycle (unless there 
are dose delays), and remain on treatment at the Investigator’s discretion for approximately 2 
years or more (if the subject continues to receive benefit) following the C1D1 date or until the 
next RBC transfusion, disease progression, or any of the other criteria for treatment 
discontinuation are met.  If, according to the assessment of the investigator, the subject is 
benefiting from treatment not reflected by the criteria above (eg, a clinically significant reduction 
of the transfusion burden or clinically significant improvement of a subject’s symptom burden),
this should be discussed with the Medical Monitor for the potential continuation of the subject in 
the Extension Phase.
Subjects will enter the Posttreatment Follow-up Period following the last dose of luspatercept for 
at least 3 years.  This Posttreatment Follow-up Period will be inclusive of a 42-Day Follow-up 
Period and Long-term Follow-up Period.
In all cohorts throughout the Treatment Period, best supportive care (BSC) may be used in 
combination with study treatment when clinically indicated per Investigator. Best supportive 
care includes, but is not limited to, antibiotic, antiviral and/or antifungal therapy, and nutritional 
support as needed.  Best supportive care forthis study excludes the use of ESAs.  Refer to 
Section 8 for additional details.
A steering committee (SC) will be established by charter for this study, in which SC members 
will have the opportunity to review efficacy and safety data on an ongoing basis. The SC will 
serve in an advisory capacity to the Sponsor.  Please refer to Section 9.9.3 for additional details.
Approved
9.0
v
Approved
1.0
v

EDMS Doc. Number: 24487940 - 21868350
Luspatercept (ACE-536)
Protocol ACE-536-MF-001
Celgene Corporation
Confidential and Proprietary
37
ACE-536-MF-001 Amendment 4 Final: 19 Feb 2020
Figure 2:
Study Design
28-Day Screening 
Period
Treatment Period
(for approximately 2 years or more, from C1D1)
Posttreatment Follow-up 
Period
End of 
Study
AEs = adverse events; Approx. = approximately; Avg. = average; C1D1 = Cycle 1 Day 1; 
Discon. = discontinuation; RBC = red blood cell; tx = treatment.
3.2.
Study Duration for Subjects 
After a Screening Period of at most 28 days immediately prior to their enrollment date, eligible 
subjects should receive luspatercept treatment through at least the first 168 days of the study 
unless the subject experiences unacceptable toxicities, has disease progression, withdraws 
consent, or meets any other discontinuation criteria (refer to Section 11).
Subjects who experience clinical benefit or become responders (refer to Section 6.2.2 for 
detailed definition) as determined by the Day 169 Disease Response Assessment may continue 
luspatercept treatment beyond the Day 169 visit (ie, in the Extension Phase of the Treatment 
Period) for approximately 2 years or more from the C1D1 date or until the subject is no longer 
Subjects 
who 
provide 
signed 
informed 
consent 
and meet 
eligibility
Cohort 1 
(anemia only)
0 RBC units/84 days up to 
and on C1D1 
(n = 20 for 14 efficacy 
evaluable subjects)
Cohort 2
(RBC-transfusion 
dependent)
Avg. 2-4 RBC units/28 days 
(n = 20)
Cohort 3 
(subjects on ruxolitinib as 
part of their standard-of-
care therapy)
Anemia only and RBC-
transfusion dependent 
subjects
If clinical 
benefit:
continue tx for 
approx. 1.5 
additional 
years or more
until loss of 
response or 
meeting 
protocol tx 
discon. criteria
If no clinical 
benefit: 
discontinue 
treatment 
DAY 169
Disease 
Response 
Assessment 
Luspatercept (in Treatment Period): starting dose 1.0 
mg/kg subcutaneous injection on Day 1 of each 21-day 
treatment cycle (subject to dose modifications per 
Section 7.3)
Follow-Up
AEs will be reported 
(regardless of causality) 
until 42 days post last 
dose of luspatercept.
Transformation to blast 
phase and other 
malignancies/premaligna
ncies will be monitored 
for at least up to 3 years 
post last dose of 
luspatercept.
Transfusion data will be 
collected for up to 42 
days post last dose of 
luspatercept. 
Subjects who remain on 
study may be enrolled 
into the luspatercept roll-
over study, ACE-536-
LTFU-001.
Study
Discon.
Approved
9.0
v
Approved
1.0
v

EDMS Doc. Number: 24487940 - 21868350
Luspatercept (ACE-536)
Protocol ACE-536-MF-001
Celgene Corporation
Confidential and Proprietary
38
ACE-536-MF-001 Amendment 4 Final: 19 Feb 2020
receiving clinical benefit, experiences unacceptable toxicities, has disease progression, 
withdraws consent, or meets any other discontinuation criteria (refer to Section 11).
For all subjects who receive at least 1 dose of luspatercept, continuation of monitoring for 
transformation to blast phase will occur in the Posttreatment Follow-up Period, along with data 
collection of subsequent MPN-associated myelofibrosis therapies and overall survival for at least 
3 years from the date of last dose of luspatercept unless the subject withdraws consent from the 
study, dies, or is lost to follow up.  Refer to Section 6 for additional details.
3.3.
End of Trial
The End of Trial is defined as either the date of the last visit of the last subject to complete the 
Posttreatment Follow-up Period, or the date of receipt of the last data point from the last subject 
that is required for primary, secondary 
 analysis, as prespecified in the 
protocol, whichever is the later date.
The Sponsor may end the trial when all key endpoints and objectives of the study have been 
analyzed.
At the End of Trial, any subjects who remain on study may be consented and enrolled on the 
luspatercept roll-over study, ACE-536-LTFU-001.  This study is intended to evaluate long-term 
safety (including progression to acute myeloid leukemia [AML] and/or other malignancies/pre-
malignancies) of luspatercept.  The roll-over study will also provide continued access for 
subjects on luspatercept treatment who continue to receive benefit. Additionally, subjects who
have completed the Primary Phase of the Treatment Period and the Day 169 Disease Response 
Assessment may be considered for consent and transition over to the ACE-536-LTFU-001 study
prior to the End of Trial if agreed to by the Sponsor.
Approved
9.0
v
Approved
1.0
v

EDMS Doc. Number: 24487940 - 21868350
Luspatercept (ACE-536)
Protocol ACE-536-MF-001
Celgene Corporation
Confidential and Proprietary
39
ACE-536-MF-001 Amendment 4 Final: 19 Feb 2020
4.
STUDY POPULATION
4.1.
Numbers of Subjects 
Approximately 100 subjects with MPN-associated myelofibrosis (primary myelofibrosis [PMF], 
post-polycythemia vera myelofibrosis [post-PV MF], or post-essential thrombocythemia 
myelofibrosis [post-ET MF]) with or without RBC-transfusion dependence will be enrolled 
worldwide.  Refer to Section 3.1 for additional information regarding subject enrollment in each 
cohort.  
4.2.
Inclusion Criteria
Subjects must satisfy the following criteria to be enrolled in the study (with the enrollment date 
defined as the date in which the subject is assigned a cohort in Integrated Response Technology 
[IRT]) and receive their first dose of luspatercept:
1. Subject is ≥18 years of age at the time of signing the informed consent form (ICF).
2. Subject has MPN-associated myelofibrosis (PMF, post-PV MF, and/or post-ET MF) as 
confirmed from the most recent local bone marrow biopsy report according to the World 
Health Organization 2016 criteria (Arber, 2016).  
3. Subject has anemia defined as:
a. Cohorts 1 and 3A
i. Obtain ≥3 Hgb levels of ≤9.5 g/dL recorded on ≥3 different days, including the 
day of dosing, in the 84-day period immediately up to the C1D1 date.  There must 
be ≥14 days in between each Hgb measurement.  No subjects with an interval ≥
42 days between hemoglobin measurements will be enrolled.  
ii. There must not be any RBC transfusions within the 84-day period immediately up 
to the C1D1 date.
b. Cohorts 2 and 3B
i. Average RBC-transfusion frequency: 4 to 12 RBC units/84 days immediately up 
to the C1D1 date.  There must be no interval > 56 days without ≥1 RBC
transfusion.
ii. Subjects must have a Hgb value of < 13 g/dL on C1D1 prior to luspatercept 
administration. 
iii. Only RBC transfusions given when the Hgb ≤9.5 g/dL are scored in determining 
eligibility.  
iv. RBC transfusions given because of bleeding, infection, or chemotherapy-induced 
anemia are not scored in determining eligibility.
4. Subject has an Eastern Cooperative Oncology Group (ECOG) performance score of ≤2.
5. Subject is not anticipated during the 6 months from the C1D1 date to receive a 
hematopoietic cell transplant.  
Approved
9.0
v
Approved
1.0
v

EDMS Doc. Number: 24487940 - 21868350
Luspatercept (ACE-536)
Protocol ACE-536-MF-001
Celgene Corporation
Confidential and Proprietary
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ACE-536-MF-001 Amendment 4 Final: 19 Feb 2020
6. A female of childbearing potential (FCBP) for this study is defined as a female who: 1) 
has achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral 
oophorectomy or 3) has not been naturally postmenopausal (amenorrhea following cancer 
therapy does not rule out childbearing potential) for at least 24 consecutive months (ie, 
has had menses at any time in the preceding 24 consecutive months). FCBP participating 
in the study must:
a.
Have 2 negative pregnancy tests as verified by the Investigator prior to starting study 
therapy. She must agree to ongoing pregnancy testing during the course of the study, 
and after end of study treatment. This applies even if the subject practices true 
abstinence* from heterosexual contact.
b. Either commit to true abstinence* from heterosexual contact (which must be 
reviewed on a monthly basis and source documented) or agree to use, and be able to 
comply with, effective contraception** without interruption, 28 days prior to starting 
investigational product, during the study therapy (including dose interruptions), and 
for 12 weeks (approximately 5 times the mean terminal half-life of luspatercept based 
on multiple-dose pharmacokinetics [PK] data) after discontinuation of study therapy.
7. Male subjects must:
a.
Practice true abstinence* (which must be reviewed on a monthly basis) or agree to 
use a condom during sexual contact with a pregnant female or a female of 
childbearing potential** while participating in the study, during dose interruptions 
and for at least 12 weeks (approximately 5 times the mean terminal half-life of 
luspatercept based on multiple-dose PK data) following investigational product 
discontinuation, even if he has undergone a successful vasectomy
* True abstinence is acceptable when it is in line with the preferred and usual lifestyle of the subject. 
[Periodic abstinence (eg, calendar, ovulation, symptothermal, postovulation methods) and withdrawal 
are not acceptable methods of contraception.]
** Agreement to use highly effective methods of contraception that alone or in combination resulting 
in a failure rate of a Pearl index of less than 1% per year when used consistently and correctly 
throughout the course of the study. Such methods include: Combined (estrogen and progestogen 
containing) hormonal contraception:  Oral; Intravaginal; Transdermal; Progestogen-only hormonal 
contraception associated with inhibition of ovulation:  Oral; Injectable hormonal contraception; 
Implantable hormonal contraception; Placement of an intrauterine device (IUD); Placement of an 
intrauterine hormone-releasing system (IUS); Bilateral tubal occlusion; Vasectomized partner; Sexual 
Abstinence.
8. Subject must understand and voluntarily sign an ICF prior to any study-related 
assessments/procedures being conducted. 
9. Subject is willing and able to adhere to the study visit schedule and other protocol 
requirements.
Approved
9.0
v
Approved
1.0
v

EDMS Doc. Number: 24487940 - 21868350
Luspatercept (ACE-536)
Protocol ACE-536-MF-001
Celgene Corporation
Confidential and Proprietary
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ACE-536-MF-001 Amendment 4 Final: 19 Feb 2020
4.3.
Exclusion Criteria
The presence of any of the following will exclude a subject from enrollment (with the enrollment 
date defined as the date in which the subject is assigned a cohort in IRT):
1. Subject use of hydroxyurea or other drugs with potential effects on hematopoiesis (refer 
to Section 8.2 for prohibited medications) or ongoing adverse events from previous 
treatment ≤112 days immediately up to the enrollment date.
a.
Systemic corticosteroids are permitted for nonhematological conditions providing the 
subject is receiving a stable or decreasing dose for ≥ 84 days immediately up to 
enrollment and is receiving a constant dose equivalent to ≤ 10 mg prednisone for the 
28 days immediately up to enrollment.
2. Cohort 1 and 2 only: subjects treated with JAK2 inhibitors ≤112 days immediately up to
the enrollment date or if anticipated/substantial likelihood for subject to receive 
ruxolitinib within the first 168 days on the study.  
3. Cohort 3 only: subjects not receiving ruxolitinib:  
a.
for at least 280 days (40 weeks) without interruptions exceeding 2 consecutive
weeks
b. on a stable daily dose for at least 112 days (16 weeks)
immediately up to the enrollment date as part of their standard-of-care therapy.
4. Subject use of ESAs or androgenic steroids ≤112 days immediately up to the enrollment 
date.  
5. Starting iron chelation therapy (ICT) or changing the ICT dose within ≤ 112 days up to 
the enrollment date.
6. Subject with anemia from iron deficiency, B12 and folate deficiencies, hemolytic anemia,
infection, or bleeding.
7. Pregnant or breastfeeding females.
8. Subject with blood myeloblasts ≥ 5%.
9. Subject with major surgery within 8 weeks up to the enrollment date. Subject must have 
completely recovered from any previous surgery immediately up to the enrollment date.
10. Subject with prior history of malignancies, other than disease under study, unless the 
subject has been free of the disease for ≥5 years. However, subject with the following 
history/concurrent conditions is allowed:

Basal or squamous cell carcinoma of the skin

Carcinoma in situ of the cervix

Carcinoma in situ of the breast

Incidental histologic finding of prostate cancer (T1a or T1b using the tumor, 
nodes, metastasis [TNM] clinical staging system)
11. Subject with prior therapy of luspatercept or sotatercept.  
Approved
9.0
v
Approved
1.0
v

EDMS Doc. Number: 24487940 - 21868350
Luspatercept (ACE-536)
Protocol ACE-536-MF-001
Celgene Corporation
Confidential and Proprietary
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ACE-536-MF-001 Amendment 4 Final: 19 Feb 2020
12. Subject participation in any other clinical protocol or investigational trial that involves 
administration of experimental therapy and/or therapeutic devices within 30 days 
immediately up to the enrollment date.  
13. Subject with prior hematopoietic cell transplant.
14. Subject with any of the following laboratory abnormalities at screening:

Neutrophils < 1 x 109/L

White blood count (WBC) > 100 x 109/L

Platelets 
i. Cohorts 1 and 2: < 25 x 109/L 
ii. Cohort 3A and 3B: < 50 x 109/L 
iii. All Cohorts: > 1000 x 109/L

Estimated glomerular filtration rate < 45 mL/min/1.73 m2 (via the 4-variable 
modification of diet in renal disease [MDRD] formula)

Aspartate aminotransferase (AST) or alanine transaminase (ALT) > 3.0 x upper 
limit of normal (ULN)

Direct bilirubin ≥2 x ULN
i. higher levels are acceptable if these can be attributed to active red blood 
cell precursor destruction within the bone marrow (ie, ineffective 
erythropoiesis) 

Uncontrolled hyperthyroidism or hypothyroidism
15. Subject with stroke, deep venous thrombosis, pulmonary or arterial embolism within 6 
months immediately up to the enrollment date.
16. Subject with diastolic blood pressure ≥ 90 mmHg or systolic blood pressure ≥ 140 mmHg 
measured during the Screening Period despite appropriate treatment.  
17. Subject with inadequately controlled heart disease and/or have a known left ventricular 
ejection fraction < 35%.
18. Subject with history of severe allergic or anaphylactic reactions or hypersensitivity to 
recombinant proteins or excipients in the investigational product (see luspatercept IB).
19. Subject with uncontrolled systemic fungal, bacterial, or viral infection (defined as 
ongoing signs/symptoms related to the infection without improvement despite 
appropriate antibiotics, antiviral therapy, and/or other treatment).
20. Subject with human immunodeficiency virus (HIV), evidence of active infectious 
Hepatitis B (HepB), and/or evidence of active Hepatitis C (HepC).  
21. Subject with any significant medical condition, laboratory abnormality, psychiatric 
illness, or is considered vulnerable by local regulations (eg, imprisoned or 
institutionalized) that would prevent the subject from participating in the study.
Approved
9.0
v
Approved
1.0
v

EDMS Doc. Number: 24487940 - 21868350
Luspatercept (ACE-536)
Protocol ACE-536-MF-001
Celgene Corporation
Confidential and Proprietary
43
ACE-536-MF-001 Amendment 4 Final: 19 Feb 2020
22. Subject with any condition including the presence of laboratory abnormalities, which
places the subject at unacceptable risk if he/she were to participate in the study.
23. Subject with any condition or concomitant medication that confounds the ability to 
interpret data from the study.
24. Subject on anticoagulant therapy not under appropriate control or subject not on a stable 
dose of anticoagulant therapy for ≥8 weeks up to the enrollment date.
25. Subject on anagrelide within 28 days immediately up to the enrollment date. 
26. Subject with a major bleeding event (defined as symptomatic bleeding in a critical area or 
organ and/or bleeding causing a decrease in Hgb of ≥ 2 g/dL or leading to transfusion of 
≥ 2 units of packed red cells) in the last 6 months prior to enrollment.
Approved
9.0
v
Approved
1.0
v

EDMS Doc. Number: 24487940 - 21868350
Luspatercept (ACE-536)
Protocol ACE-536-MF-001
Celgene Corporation
Confidential and Proprietary
44
ACE-536-MF-001 Amendment 4 Final: 19 Feb 2020
5.
TABLE OF EVENTS
Table 3:
Table of Events
Screening 
Perioda
Treatment Period
Posttreatment Follow-up Period
(± 14 days)
42-Day Follow-up Period = Occurs 
42 days from last dose of 
luspatercept
Long-term Follow-up Period =
Occurs every 3 months after 42-Day 
Follow-up until at least 3 years post 
last dose of luspatercept
Primary Phase
First 168 days of treatment
Up to maximum of 8 Treatment 
Cycles 
(if no dose delays)
(± 3 days)
Day 169b
Assessment
169 calendar 
days after 
C1D1 
regardless of 
dose delays
(± 14 days)
Extension Phase 
Continuation of treatment 
beyond Day 169 
(± 3 days)
EOT
Visitb
Day -28
Every 
Cycle
(ie, 1,
2, 3+ 
up to 
max 8 
cycles
Every 
Other 
Cycle
Only) 
(ie, 1, 3, 
5, 7)
Cycles 
1 and 
5
Only
Cycle 
1
Only
Every 
Cycle;
X, 
X+1, 
etc.
Every 
4th 
Cycle; 
X, X+4, 
etc.
Every 
8th 
Cycle; 
X, X+8, 
etc.
42-Day 
Follow-up
Period
Long-
term 
Follow-up
Period
End of 
Study 
Reference 
Section
to 
Enrollment Day 1
Day 1
Day 8 Day 15
Day 1
Day 1
Day 1
STUDY ENTRY AND GENERAL ASSESSMENTS
Informed consent
6.1
X
--
--
--
--
--
--
--
--
--
--
--
--
Inclusion/Exclusion 
evaluations
6.1
X
--
--
--
--
--
--
--
--
--
--
--
--
Physical examination 
(including liver/spleen 
assessment)
6.1
X
X
--
--
--
X
X
--
--
X
--
--
--
Demographics 
6.1
X
--
--
--
--
--
--
--
--
--
--
--
--
Medical history
6.1
X
--
--
--
--
--
--
--
--
--
--
--
--
Prior anemia treatment
6.1
X
--
--
--
--
--
--
--
--
--
--
--
--
Prior RBC transfusions
6.1
X
--
--
--
--
--
--
--
--
--
--
--
--
INVESTIGATIONAL PRODUCT 
Luspatercept administration 
and accountabilityc
6.2
--
X
--
--
--
--
X
--
--
--
--
--
--
Approved
9.0
v
Approved
1.0
v

EDMS Doc. Number: 24487940 - 21868350
Luspatercept (ACE-536)
Protocol ACE-536-MF-001
Celgene Corporation
Confidential and Proprietary
45
ACE-536-MF-001 Amendment 4 Final: 19 Feb 2020
Table 3:
Table of Events (Continued)
Screening 
Perioda
Treatment Period
Posttreatment Follow-up Period
(± 14 days)
42-Day Follow-up Period = Occurs 
42 days from last dose of 
luspatercept
Long-term Follow-up Period =
Occurs every 3 months after 42-Day 
Follow-up until at least 3 years post 
last dose of luspatercept
Primary Phase
First 168 days of treatment
Up to maximum of 8 Treatment 
Cycles 
(if no dose delays)
(± 3 days)
Day 169b
Assessment
169 calendar 
days after 
C1D1 
regardless of 
dose delays
(± 14 days)
Extension Phase 
Continuation of treatment 
beyond Day 169 
(± 3 days)
EOT
Visitb
Day -28
Every 
Cycle
(ie, 1, 
2, 3+ 
up to 
max 8 
cycles
Every 
Other 
Cycle
Only) 
(ie, 1, 3, 
5, 7)
Cycles 
1 and 
5
Only
Cycle 
1
Only
Every 
Cycle;
X, 
X+1, 
etc.
Every 
4th 
Cycle; 
X, X+4, 
etc.
Every 
8th 
Cycle; 
X, X+8, 
etc.
42-Day 
Follow-up 
Period
Long-
term 
Follow-up 
Period 
End of 
Study 
Reference 
Section
to 
Enrollment Day 1
Day 1
Day 8 Day 15
Day 1
Day 1
Day 1
SAFETY ASSESSMENTS
ECOG performance status 
6.1
X
--
X
--
--
X
Ext. C1D1, then D1 of 
every other cycle until 
treatment discontinuation
(eg, Ext. C1D1, C3D1, etc.)
X
--
--
--
Urinalysis
6.1
X
C1D1 and D1 of every 4th cycle 
thereafter (eg, C1D1, C5D1, etc.)
X
--
X
--
X
--
--
--
Assessment of 
HIV/HepB/HepC statusd
6.1
X
--
--
--
--
--
--
--
--
--
--
--
--
Electrocardiogram (ECG), 
12-lead
6.1
X
--
--
C5D8 
only
--
--
--
--
--
X
--
--
--
Pregnancy testing
6.1
X
X
--
--
--
X
X
--
--
X
--
--
--
Adverse events 
6.1
Continuous, from signing informed consent until 42 days after last luspatercept administratione
--
--
Prior and concomitant 
medications/procedures 
6.1
X
Continuous until 42 days after last luspatercept administration or until the EOT visit, whichever occurs 
later
--
--
Approved
9.0
v
Approved
1.0
v

EDMS Doc. Number: 24487940 - 21868350
Luspatercept (ACE-536)
Protocol ACE-536-MF-001
Celgene Corporation
Confidential and Proprietary
46
ACE-536-MF-001 Amendment 4 Final: 19 Feb 2020
Table 3:
Table of Events (Continued)
Screening 
Perioda
Treatment Period
Posttreatment Follow-up Period
(± 14 days)
42-Day Follow-up Period = Occurs 
42 days from last dose of 
luspatercept
Long-term Follow-up Period =
Occurs every 3 months after 42-Day 
Follow-up until at least 3 years post 
last dose of luspatercept
Primary Phase
First 168 days of treatment
Up to maximum of 8 Treatment 
Cycles 
(if no dose delays)
(± 3 days)
Day 169b
Assessment
169 calendar 
days after 
C1D1 
regardless of 
dose delays
(± 14 days)
Extension Phase 
Continuation of treatment 
beyond Day 169 
(± 3 days)
EOT
Visitb
Day -28
Every 
Cycle
(ie, 1, 
2, 3+ 
up to 
max 8 
cycles
Every 
Other 
Cycle
Only) 
(ie, 1, 3, 
5, 7)
Cycles 
1 and 
5
Only
Cycle 
1
Only
Every 
Cycle;
X, 
X+1, 
etc.
Every 
4th 
Cycle; 
X, X+4, 
etc.
Every 
8th 
Cycle; 
X, X+8, 
etc.
42-Day 
Follow-up 
Period
Long-
term 
Follow-up 
Period 
End of 
Study 
Reference 
Section
to 
Enrollment Day 1
Day 1
Day 8 Day 15
Day 1
Day 1
Day 1
Vital signs, height (measured 
at screening), weight 
(measured at screening and 
prior to every luspatercept 
administration) 
6.1
X
X
--
X
X
X
X
--
--
X
--
--
--
Serum chemistry
6.1
X
X
--
--
--
X
X
--
--
X
--
--
--
EFFICACY ASSESSMENTS
Hematologyc
6.1
X
X
--
X
X
X
X
--
--
X
--
--
--
Serum erythropoietin (EPO)
6.1
X
--
X
--
--
X
--
--
--
X
--
--
--
Serum ferritin
6.1
X
X
--
--
--
X
--
X
--
X
--
--
--
Transfusion data collection 
and assessmentf
6.2, 6.5
--
Assess and record on ongoing basis (prior to each dose of luspatercept) until end of treatment or 42 days 
after last dose of luspatercept, whichever occurs later.
--
--
Disease response assessmentg
6.2.2
--
--
--
--
--
X
X
--
--
X
--
--
--
Approved
9.0
v
Approved
1.0
v

EDMS Doc. Number: 24487940 - 21868350
Luspatercept (ACE-536)
Protocol ACE-536-MF-001
Celgene Corporation
Confidential and Proprietary
47
ACE-536-MF-001 Amendment 4 Final: 19 Feb 2020
Table 3:
Table of Events (Continued)
Screening 
Perioda
Treatment Period
Posttreatment Follow-up Period
(± 14 days)
42-Day Follow-up Period = Occurs 
42 days from last dose of 
luspatercept
Long-term Follow-up Period =
Occurs every 3 months after 42-Day 
Follow-up until at least 3 years post 
last dose of luspatercept
Primary Phase
First 168 days of treatment
Up to maximum of 8 Treatment 
Cycles 
(if no dose delays)
(± 3 days)
Day 169b
Assessment
169 calendar 
days after 
C1D1 
regardless of 
dose delays
(± 14 days)
Extension Phase 
Continuation of treatment 
beyond Day 169 
(± 3 days)
EOT
Visitb
Day -28
Every 
Cycle
(ie, 1, 
2, 3+ 
up to 
max 8 
cycles
Every 
Other 
Cycle
Only) 
(ie, 1, 3, 
5, 7)
Cycles 
1 and 
5
Only
Cycle 
1
Only
Every 
Cycle;
X, 
X+1, 
etc.
Every 
4th 
Cycle; 
X, X+4, 
etc.
Every 
8th 
Cycle; 
X, X+8, 
etc.
42-Day 
Follow-up 
Period
Long-
term 
Follow-up 
Period 
End of 
Study 
Reference 
Section
to 
Enrollment Day 1
Day 1
Day 8 Day 15
Day 1
Day 1
Day 1
PK and ADA
PK sample collection 
6.7
--
C1, 
C2, 
C4, 
C5, 
C6, C8
Only
--
X
X
X
D1 of every 4th Extension 
Cycle thereafter (eg, Ext. 
C4, C8, etc.) for up to 1-
year post first dose of 
luspatercept.
X
--
--
--
Approved
9.0
v
Approved
1.0
v

EDMS Doc. Number: 24487940 - 21868350
Luspatercept (ACE-536)
Protocol ACE-536-MF-001
Celgene Corporation
Confidential and Proprietary
48
ACE-536-MF-001 Amendment 4 Final: 19 Feb 2020
Table 3:
Table of Events (Continued)
Screening 
Perioda
Treatment Period
Posttreatment Follow-up Period
(± 14 days)
42-Day Follow-up Period = Occurs 
42 days from last dose of 
luspatercept
Long-term Follow-up Period =
Occurs every 3 months after 42-Day 
Follow-up until at least 3 years post 
last dose of luspatercept
Primary Phase
First 168 days of treatment
Up to maximum of 8 Treatment 
Cycles 
(if no dose delays)
(± 3 days)
Day 169b
Assessment
169 calendar 
days after 
C1D1 
regardless of 
dose delays
(± 14 days)
Extension Phase 
Continuation of treatment 
beyond Day 169 
(± 3 days)
EOT
Visitb
Day -28
Every 
Cycle
(ie, 1, 
2, 3+ 
up to 
max 8 
cycles
Every 
Other 
Cycle
Only) 
(ie, 1, 3, 
5, 7)
Cycles 
1 and 
5
Only
Cycle 
1
Only
Every 
Cycle;
X, 
X+1, 
etc.
Every 
4th 
Cycle; 
X, X+4, 
etc.
Every 
8th 
Cycle; 
X, X+8, 
etc.
42-Day 
Follow-up 
Period
Long-
term 
Follow-up 
Period 
End of 
Study 
Reference 
Section
to 
Enrollment Day 1
Day 1
Day 8 Day 15
Day 1
Day 1
Day 1
ADA sample collection
6.8
--
C1, 
C2, 
C4, 
C6, C8 
Only
(collect 
C1D1 
sample 
prior to 
luspat-
ercept 
dose)
--
--
--
--
D1 of every 4th Cycle 
thereafter (eg, Ext. C4, C8, 
C12, C16+, etc.) for up to 1
year post first dose of 
luspatercept
X
ADA sample collection to 
continue every 12 weeks 
for positive subjects for 
up to 2 years post first 
dose of luspatercept or 
until return to baseline, 
whichever comes first.
--
QUALITY OF LIFE
EQ-5D-5L and FACT-An 
questionnaire completion
6.10
--
--
X
--
--
X
Day 1 of Every Other 
Cycle
(X, X+2, etc.)
X
--
--
--
MPN-SAF TSS completion
6.10
--
Completed weekly during the first 
6 months of treatment
X
Day 1 of Every Other 
Cycle
(X, X+2, etc.)
X
--
--
--
Approved
9.0
v
Approved
1.0
v

EDMS Doc. Number: 24487940 - 21868350
Luspatercept (ACE-536)
Protocol ACE-536-MF-001
Celgene Corporation
Confidential and Proprietary
49
ACE-536-MF-001 Amendment 4 Final: 19 Feb 2020
Table 3:
Table of Events (Continued)
Screening 
Perioda
Treatment Period
Posttreatment Follow-up Period
(± 14 days)
42-Day Follow-up Period = Occurs 
42 days from last dose of 
luspatercept
Long-term Follow-up Period =
Occurs every 3 months after 42-Day 
Follow-up until at least 3 years post 
last dose of luspatercept
Primary Phase
First 168 days of treatment
Up to maximum of 8 Treatment 
Cycles 
(if no dose delays)
(± 3 days)
Day 169b
Assessment
169 calendar 
days after 
C1D1 
regardless of 
dose delays
(± 14 days)
Extension Phase 
Continuation of treatment 
beyond Day 169 
(± 3 days)
EOT
Visitb
Day -28
Every 
Cycle
(ie, 1, 
2, 3+ 
up to 
max 8 
cycles
Every 
Other 
Cycle
Only) 
(ie, 1, 3, 
5, 7)
Cycles 
1 and 
5
Only
Cycle 
1
Only
Every 
Cycle;
X, 
X+1, 
etc.
Every 
4th 
Cycle; 
X, X+4, 
etc.
Every 
8th 
Cycle; 
X, X+8, 
etc.
42-Day 
Follow-up 
Period
Long-
term 
Follow-up 
Period 
End of 
Study 
Reference 
Section
to 
Enrollment Day 1
Day 1
Day 8 Day 15
Day 1
Day 1
Day 1
FOLLOW UP
Monitoring for 
transformation to blast phase 
and other malignancies/
Premalignanciesh
6.1, 6.5
After signing ICF and until at least 3 years post last dose of luspatercept or until death, lost to follow up, withdrawal of consent for further data 
collection.
Posttreatment myelofibrosis 
therapiesh
6.5
--
--
--
--
--
--
--
--
--
--
X
X
X
Survival follow uph
6.5
--
--
--
--
--
--
--
--
--
--
X
X
X
ADA = antidrug antibody; C1D1 = Cycle 1 Day 1; ECOG = Eastern Cooperative Oncology Group; EOT = End of Treatment; FACT-An = Functional Assessment of Cancer 
Therapy – Anemia; Hgb = hemoglobin; HepB = Hepatitis B; HepC = Hepatitis C; HIV = human immunodeficiency virus; MPN-SAF TSS = Myeloproliferative Neoplasm 
Symptom Assessment Form Total Symptom Score; 
; PK = pharmacokinetic; RBC = red blood cell; TSS = total symptom score; 
WBC = white blood count.  
a If screening assessments are performed within 72 hours of the C1D1 date, safety laboratory and physical examinations would not need to be repeated during the C1D1 date, with 
the exception of blood pressure measurements, hematology, serum ferritin, and serum EPO sample collections.  
b Day 169 and beyond visit procedures/assessments may not need to be repeated if previously performed within ± 7 days of the scheduled visit.  End of Treatment (EOT) Visit 
procedures/assessments will be performed as soon as possible for subjects who are withdrawn from treatment for any reason as soon as possible (but, at the latest, at the next 
projected planned study visit) after the decision to permanently discontinue treatment has been made.  Furthermore, the EOT evaluations may not need to be repeated if 
previously performed within ± 7 days of EOT visit (with the exception of blood pressure assessment and sample collection for hematology, chemistry, and urinalysis).  If a 
subject is discontinued during a regular scheduled visit, all EOT procedures should be completed at that visit.  
Approved
9.0
v
Approved
1.0
v

EDMS Doc. Number: 24487940 - 21868350
Luspatercept (ACE-536)
Protocol ACE-536-MF-001
Celgene Corporation
Confidential and Proprietary
50
ACE-536-MF-001 Amendment 4 Final: 19 Feb 2020
c On dosing days, local laboratory sample should be collected, with white blood count (WBC) and Hgb levels assessed prior to each luspatercept administration to ensure dose 
modification rules are followed.  Blood myeloblasts should also be assessed prior to luspatercept dosing.  In case a subject had an elevated blood myeloblast percentage at the 
previous treatment cycle (≥ 10%), the blood myeloblast percentage needs to be assessed within a week prior to the next treatment cycle.  In these circumstances, a split sample 
should also be collected and sent to the central laboratory for analysis.  Subjects must have blood pressure assessed prior to each luspatercept administration.  Should a dose 
delay occur on the day of dosing, refer to Section 7.3 for more information.
d Central assessments are not required when local test results confirming HIV, HepB, Hep C are available within 8 weeks immediately prior to the enrollment date. If beyond this 
window, additional central laboratory testing will be requested.
e Only serious adverse events (SAEs) related to luspatercept will be captured post the 42-Day Follow-up Period.
f Clinical site staff should confirm if any transfusions were received by the subject (including any at outside institutions in between study visits) prior to each dose of luspatercept
via use of a transfusion diary or other local procedure in place at the investigational site.  Subjects should record information relating to transfusions (eg, date of transfusion, 
pretransfusion Hgb levels, number of units transfused, volume of transfusion, etc.) they may have received outside the study site.  In addition to local procedures that may be in 
place at the site to capture this information, a transfusion diary will be provided to all subjects and will be reviewed by the site when/if returned by the subject.
g During the Treatment Period, the Day 169 Disease Response Assessment should be completed by the Investigator.  At Day 169, based on the outcome of the Disease Response 
Assessment, subjects will either be discontinued from treatment and enter the Posttreatment Follow-up Period or continue treatment with luspatercept in the Extension Phase of 
the Treatment Period.  
h The Long-term Follow-up Period for transformation to blast phase, other malignancies/premalignancies, and data collection for subsequent myelofibrosis therapies may be 
conducted by record review (including public records if allowed by local regulations) and/or telephone contact with the subject, family, or the subject’s treating physician.  The 
Investigator must make every effort to obtain information regarding the subject’s survival status before determining the subject is lost to follow up.
Approved
9.0
v
Approved
1.0
v

EDMS Doc. Number: 24487940 - 21868350
Luspatercept (ACE-536)
Protocol ACE-536-MF-001
Celgene Corporation
Confidential and Proprietary
51
ACE-536-MF-001 Amendment 4 Final: 19 Feb 2020
6.
PROCEDURES
Any questions regarding the protocol should be directed to the Celgene Medical Monitor or 
designee.
All of the protocol required assessments are listed in Section 5, Table 3, with an “X” indicating 
at which visits the assessments are to be performed. All data obtained from these assessments 
must be recorded in the subject’s source documentation.  Except for the Day 169 Disease 
Response Assessment, all study visits during the Treatment Period (both Primary and Extension 
Phases) must occur within ± 3 days of the scheduled day.  A 14-day window is allowed for the 
Day 169 Disease Response Assessment and Posttreatment Follow-up Period assessments (ie, 
transformation to blast phase, posttreatment myelofibrosis therapies).  Procedures are described 
in detail below.
Safety laboratory analyses and all laboratory assessments will be performed centrally (except 
otherwise stated in this section) during the Treatment Period.  
Local laboratories are only allowed in cases when timely results are needed (eg, study treatment 
dosing decisions, hematology assessments between clinic visits, adverse events).  In these 
circumstances, a split sample should still be collected and sent to the central laboratory for 
analysis.  Local laboratory data should be collected in the electronic case report form (eCRF) if 
relevant to dose administration, dose modification, an AE, or when no central laboratory results 
were obtained.  
Refer to the eCRF completion guidelines for additional information related to data entry 
requirements of local laboratories.  
Sample collection, processing, storage, and shipment procedures will be provided in the Study 
Laboratory Manual.
6.1.
Screening Period
Upon giving written informed consent, subjects enter the Screening Period to determine 
eligibility. Subject screening procedures (performed locally/centrally) are to take place over a 
maximum of 28 days immediately prior to their enrollment date, which will be defined in this protocol 
as the date in which they have been assigned a treatment cohort via IRT.  The first dose of 
luspatercept (designated as the C1D1 date) should be administered as soon as possible (at the 
latest 3 calendar days) following the enrollment date. During the Screening Period, the subject 
will undergo safety and other assessments to determine eligibility for the study.  Screening 
laboratory values must demonstrate subject eligibility but may be repeated within the screening 
window if clinically justified.  Subjects that have met all eligibility criteria during the Screening 
Period will be eligible for enrollment.  
Review of historical bone marrow biopsy information will be used to confirm MPN-associated 
myelofibrosis diagnosis.  The report should come from the most recent local bone marrow 
biopsy performed and should contain the mutational status of the disease (eg, JAK2, MPL, and 
CALR).
Approved
9.0
v
Approved
1.0
v

EDMS Doc. Number: 24487940 - 21868350
Luspatercept (ACE-536)
Protocol ACE-536-MF-001
Celgene Corporation
Confidential and Proprietary
52
ACE-536-MF-001 Amendment 4 Final: 19 Feb 2020
These data will be recorded in the subject’s electronic case report form (eCRF).  Subjects who do 
not meet the eligibility criteria prior to enrollment will be considered screening failures and will 
not be eligible for enrollment.  Subjects who fail screening may undergo rescreening.
Screening evaluations will be performed (locally/centrally) for all subjects to determine study 
eligibility. These evaluations must be completed within the 28 days prior to the enrollment date
(refer to Table of Events, Section 5, Table 3 for further information) unless noted otherwise 
below.
Waivers to the protocol eligibility criteria will not be granted during the conduct of this trial.
The following will be performed during the 28-day Screening Period as specified in the Table of 
Events (Section 5, Table 3) after informed consent has been obtained:

Assessment of inclusion/exclusion criteria for study eligibility 
Screening evaluations will be performed for all subjects to determine eligibility.  
Screening laboratory values must demonstrate subject eligibility, but may be repeated 
within the screening window, if necessary.  

Physical examination
Information about the physical examination (which will also include liver and spleen 
palpation, as well as spleen size assessment) to be captured in the eCRF. 

Demographics and medical history 
Information about the subject’s demographics (if allowed per local country 
regulations; including, but not limited to: date of birth, sex, race, and ethnicity) to be 
recorded on the appropriate eCRF.
Complete medical history documenting specific information regarding all relevant 
medical conditions diagnosed (occurring prior to Screening Period) to be recorded on 
the appropriate eCRF. 

Prior anemia treatment
Information on therapies to treat anemia prior to the Screening Period to be recorded 
on the appropriate eCRF.  Refer to Section 8 for more information.  

RBC transfusion history 
Information regarding RBC transfusion history (≥84 days prior to and including the
C1D1 date), including, but not limited to, pretransfusion Hgb levels, number of units 
transfused, volume of transfusion, and dates of transfusions, will be collected and 
reported in the appropriate eCRF. Any transfusions given at outside institutions must 
also be collected.  Source documentation of RBC transfusion history must be 
available for source document verification.  Transfusions given when Hgb ≤9.5 g/dL 
will be counted towards eligibility, while transfusions given because of bleeding, 
infection, or chemotherapy-induced anemia will not be counted towards eligibility.  

Eastern Cooperative Oncology Group (ECOG) performance status 
Performance status will be assessed by the Investigator using the ECOG criteria 
provided in Appendix B.  
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
Urinalysis 
Information regarding urinalysis to include microscopic, quantitative analysis of urine 
(eg, albumin, protein, creatinine, albumin/creatinine ratio), and will be tested by the 
central laboratory.  

Human immunodeficiency virus (HIV), Hepatitis B (HepB), and Hepatitis C
(HepC)
Testing for HIV, HepB, and HepC will be completed by the central laboratory unless 
local lab results are available within 8 weeks immediately prior to the enrollment 
date.  If beyond this window, additional central laboratory testing will be requested.

Electrocardiogram (ECG)
A 12-lead ECG to be performed locally at site.  The following ECG parameters will 
be recorded on the respective eCRF(s): heart rate (HR), PR interval, QRS duration, 
QT, QTc.  The Investigator will review the results and assess as normal, abnormal –
not clinically significant, or abnormal – clinically significant, and report the abnormal 
finding(s) on the appropriate eCRF.  If the ECG is abnormal, the Investigator should 
consult a cardiologist if deemed appropriate.  

Pregnancy testing 
Pregnancy testing (conducted at the central laboratory or locally) to be completed for 
all female subjects of childbearing potential (FCBP), in which the serum beta subunit 
of the human chorionic gonadotropic (β-hCG) pregnancy test (which must be 
negative) with a minimum sensitivity of 25 mIU/mL will be performed.  This 
assessment will be used to confirm eligibility.  Urine (or serum) pregnancy test will 
be performed to assess subject eligibility within 72 hours prior to the C1D1 date, if 
the initial serum pregnancy test did not already occur with 72 hours of dosing 
(negative results required for luspatercept administration).  During the Treatment 
Period, a urine or serum pregnancy test is allowed.  The Investigator will appraise a
female subject as a FCBP according to the definition provided in Section 4.2.  
Justification must be recorded in the eCRF and the source document. Pregnancy 
testing is not required for non-FCBP subjects.  

Adverse event assessment 
Information regarding adverse event assessment and reporting initiated from the time 
the subject signs the informed consent form will occur on an ongoing basis and must 
be documented on the appropriate eCRF.  Refer to Section 10 for more information. 

Prior/concomitant medications and procedures
Information relating to prior/concomitant medications and procedures to be reported 
on the appropriate eCRF.  Refer to Section 8 for more information. 

Vital signs, height, and weight 
Information regarding vital signs including height (measured only during screening), 
weight (measured during screening and prior to each luspatercept administration), 
seated blood pressure (documented as mean of 2 readings obtained approximately 10 
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Confidential and Proprietary
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minutes apart with the subject seated for approximately 10 minutes prior to initial 
reading; on dosing days, blood pressure must be assessed prior to luspatercept 
administration), temperature, heart rate, and respiratory rate are to be reported on the 
appropriate eCRF.

Serum chemistry
Information regarding serum chemistry including labs such as sodium, potassium, 
chloride, bicarbonate (if available), calcium, magnesium, phosphorus, blood urea 
nitrogen, creatinine and creatinine clearance,glucose, albumin, total protein, alkaline
phosphatase, direct/indirect total bilirubin, AST/serum glutamic oxaloacetic 
transaminase (SGOT) or ALT/serum glutamic pyruvic transaminase (SGPT), lactate
dehydrogenase, and uric acid are to be reported on the appropriate eCRF and will be 
tested by the central laboratory.  

Hematology 
Information regarding hematology assessments including red blood cell (RBC) count, 
complete blood count, white blood count (WBC) with differential (including 
myeloblasts), Hgb, hematocrit, nucleated red blood cells, absolute reticulocyte count, 
platelet count, mean corpuscular volume, mean corpuscular hemoglobin, mean 
corpuscular hemoglobin concentration, and red blood cell distribution width are to be 
reported on the appropriate eCRF and will be tested by the central laboratory.  

Serum erythropoietin (EPO) 
Serum EPO collected during the Screening Period should be collected on the same
day as a planned RBC transfusion, prior to the transfusion, or 7 days after any RBC 
transfusion due to possible reduction of the serumlevel related to the hemoglobin 
level achieved after the last transfusion.  Serum EPO samples will be analyzed by the 
central laboratory.  

Serum ferritin 
Serum ferritin should be collected within the Screening Period and analyzed by the 
central laboratory.  Historic serum ferritin levels from previous local laboratory 
reports (within the 84-day window prior to and including the enrollment date) should 
be collected, if available in the medical records, and entered on the appropriate eCRF.  
On dosing days, serum ferritin samples should be collected prior to luspatercept
administration and analyzed by the central laboratory.  

 

Monitoring for transformation to blast phase and other 
malignancies/premalignancies
Monitoring for transformation to blast phase as per International Working Group-
Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) criteria (Tefferi, 
2013) will be included as part of the safety assessment throughout the course of the 
study.  Transformation to blast phase should be monitored from time of signing of 
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ACE-536-MF-001 Amendment 4 Final: 19 Feb 2020
informed consent through at least 3 years after last dose of luspatercept or until death, 
lost to follow up, or withdrawal of consent from the study, whichever occurs first.  
The occurrence of a new malignancy or premalignant lesion will be monitored as an 
event of interest and should be included as part of the assessment of adverse events 
throughout the course of the study. Investigators are to report the development of any 
new malignancy or premalignant lesion as a serious adverse event, regardless of 
causal relationship to luspatercept, occurring at any time for the duration of the study, 
from the time of signing the ICF for up to and including at least 3 years of long-term 
follow up, or until death, lost to follow up, or withdrawal of consent for further data 
collection.  Documentation supporting the diagnosis of transformation to blast phase
and other malignancies/pre-malignancies (eg, confirmatory histology or cytology 
results) may be requested.  Appropriate information related to the diagnosis of 
transformation to blast phase and other malignancies/premalignancies should be 
captured on the eCRF and in the subject’s source documents. 
6.2.
Treatment Period
The subject will be enrolled into the study following Sponsor review of eligibility.
The subject must be enrolled at the latest 28 days from signing the ICF.  The first dose of 
luspatercept (designated as C1D1) should be administered as soon as possible (at the latest 3
calendar days) following the enrollment date. In case a subject should become ineligible after 
being enrolled but prior to receiving the first dose of luspatercept, they must be discontinued 
from the study.  These subjects will be replaced.  
If screening assessments are performed within 72 hours of the C1D1 date, safety laboratory and 
physical examinations would not need to be repeated during the C1D1 date, with the exception 
of blood pressure measurements, hematology, serum ferritin, and serum EPO sample collections.  
On dosing days, local laboratory WBC and Hgb levels should be assessed prior to each 
luspatercept administration. In case a subject had an elevated blood myeloblast percentage at the 
previous treatment cycle, the blood myeloblast percentage needs to be assessed within a week 
prior to the next treatment cycle.  These parameters are to ensure the dose modification rules are 
followed as outlined in Section 7.
In these circumstances, a split sample should also be collected and sent to the central laboratory 
for analysis.  Subjects should also have blood pressure assessed (as detailed in Section 6.1) and 
the clinical site must confirm with the subject if any transfusions were received at outside local 
centers in between study visits prior to each luspatercept administration.
6.2.1.
Primary Phase of the Treatment Period
Subjects will receive luspatercept on Day 1 of each 21-day treatment cycle (unless there are dose 
delays) through at least Day 168 following the C1D1 date unless the subject experiences 
unacceptable toxicities, withdrawsconsent, or meets any other treatment discontinuation criteria 
(refer to Section 11.1) prior to the Day 169 Disease Response Assessment.  Treatment cycles are 
21 days in duration.  
The following procedures/evaluations will be performed at the frequency specified in the Table 
of Events (Table 3) during the Primary Phase of the Treatment Period.  The 
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Celgene Corporation
Confidential and Proprietary
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ACE-536-MF-001 Amendment 4 Final: 19 Feb 2020
procedures/evaluations should be performed prior to dosing on the visit day, unless otherwise 
specified:

Physical examination (as detailed in Section 6.1)

Administration/accountability of luspatercept 

ECOG performance status

Urinalysis (as detailed in Section 6.1)

12-lead electrocardiogram (ECG) to be performed locally 

Pregnancy testing (as detailed in Section 6.1)

Adverse event assessment and reporting on an ongoing basis 

Concomitant medications and procedures on an ongoing basis 

Vital signs (as detailed in Section 6.1) 

Serum chemistry (as detailed in Section 6.1)

Hematology assessments (as detailed in Section 6.1) 

Serum EPO level 

Serum ferritin level 

Transfusion data collection and assessment 
During the study, the following, but not limited to, information will be recorded for 
all transfusions (including any transfusions received at outside institutions in between 
study visits) the subject receives starting from the C1D1 date until end of treatment or 
end of the 42-Day Follow-up Period, whichever occurs later: date of transfusion, 
pretransfusion Hgb levels, number of units transfused, and volume of transfusion.  In 
addition to local procedures that may be in place at the site to capture this 
information, a transfusion diary will be provided to all subjects and will be reviewed 
by the site when/if returned by the subject.  Source documentation of transfusions 
given during the study must be available for source document verification.


PK and ADA sample collection (as detailed in Sections 6.7 and 6.8)

Subject reported outcomes via the EQ-5D-5L, FACT-An, and MPN-SAF TSS (as 
detailed in Section 6.10)

Monitoring for transformation to blast phase and other malignancies/premalignancies 
6.2.2.
Day 169 Disease Response Assessment 
The Day 169 Disease Response Assessment should be completed 169 days after the C1D1 date, 
regardless of dose delays.  As central laboratory results and assessments are required for the Day 
169 Disease Response Assessment, a 14-day window is allowed for the Day 169 Disease 
Response Assessment.
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EDMS Doc. Number: 24487940 - 21868350
Luspatercept (ACE-536)
Protocol ACE-536-MF-001
Celgene Corporation
Confidential and Proprietary
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In order for subjects to remain on luspatercept treatment beyond Day 169, the following criteria 
must be confirmed upon the completion of the Disease Response Assessment by the Investigator 
at the Day 169 visit:
Cohorts 1 (anemia only) and 3A 
Subjects with ≥3 determinations showing a ≥1.5 g/dL hemoglobin increase above the 
baseline value (defined as the subject’s Hgb value observed on the C1D1 date prior to 
luspatercept administration) absent of RBC transfusions over a consecutive ≥84-day period 
with no 2 measurements ≥42 days apart (and no determination < 1.5 g/dL above the baseline 
value) at the time of the Day 169 Disease Response Assessment will have the opportunity to 
move into the Extension Phase of the Treatment Period. The subject may remain on 
treatment for approximately 2 years or more from date of C1D1 at the Investigator’s 
discretion until a determination shows a value < 1.5 g/dL hemoglobin increase from the 
baseline value (absent of bleeding or infection), there is receipt of an RBC transfusion, 
disease progression, or any of the other criteria for treatment discontinuation are met.  
If, at the Day 169 Disease Response Assessment, the subject has ≥3 determinations showing 
a ≥1.5 g/dL hemoglobin increase above the baseline value with no 2 measurements ≥42 
days apart (and no determination < 1.5 g/dL above the baseline value) in the absence of RBC 
transfusions over the preceding 56 days, the subject may continue on in the Extension Phase 
of the Treatment Period for an additional 28 days. If, after this additional 28 days, the 
subject meets the response criteria, the subject can continue on in the Extension Phase of the 
Treatment Period and remain on treatment for approximately 2 years or more from the C1D1 
date at the Investigator’s discretion until a determination shows a value < 1.5 g/dL 
hemoglobin increase above the baseline value (absent of bleeding or infection), there is
receipt of an RBC transfusion, disease progression, or any of the other criteria for treatment 
discontinuation are met.
Cohorts 2 (RBC-transfusion dependent) and 3B 
Subjects who are transfusion-free over ≥84 consecutive days at the time of the Day 169 
Disease Response Assessment can enter the Extension Phase of the Treatment Period and 
remain on treatment for approximately 2 years or more from the C1D1 date at the 
Investigator’s discretion until they receive the next RBC transfusion (absent of bleeding or 
infection), disease progression, or meet other criteria for treatment discontinuation.  
If, at the Day 169 Disease Response Assessment, the subject is RBC-transfusion free for the 
preceding 56 days, they may continue on in the Extension Phase of the Treatment Period for 
an additional 28 days. If, after this additional 28 days, the subject meets the response criteria, 
they can continue on in the Extension Phase of the Treatment Period and remain on treatment 
for approximately 2 years or more from the C1D1 date at Investigator’s discretion until the 
subject receives an RBC transfusion (absent of bleeding or infection), disease progression, or 
meets of other criteria for treatment discontinuation.
Should subjects from each respective cohort not meet the clinical benefit criteria outlined above,
they should discontinue treatment with luspatercept and enter the Posttreatment Follow-up 
Period. Otherwise, subjects may begin luspatercept treatment in the Extension Phase of the 
Treatment Period to remain on treatment at the Investigator’s discretion until the next RBC
transfusion, disease progression, or any of the other criteria for treatment discontinuation are 
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Protocol ACE-536-MF-001
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Confidential and Proprietary
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met.  If, according to the assessment of the investigator, the subject is benefiting from treatment 
not reflected by the criteria above (eg, a clinically significant reduction of the transfusion burden 
or clinically significant improvement of a subject’s symptom burden), this should be discussed 
with the Medical Monitor for the potential continuation of the subject in the Extension Phase.
The following procedures/evaluations will be performed at the Day 169 Disease Response 
Assessment visit: 

Physical examination (as detailed in Section 6.1)

ECOG performance status

Urinalysis (as detailed in Section 6.1)

Pregnancy testing (as detailed in Section 6.1)

Adverse event assessment and reporting on an ongoing basis 

Concomitant medications and procedures on an ongoing basis 

Vital signs (as detailed in Section 6.1)

Serum chemistry (as detailed in Section 6.1)

Hematology assessments (as detailed in Section 6.1) 

Serum EPO level 

Serum ferritin level 

Transfusion data collection and assessment 
During the study, the following, but not limited to, information will be recorded for 
all transfusions (including any transfusions received at outside institutions in between 
study visits) the subject receives starting from the C1D1 date until end of treatment or 
end of the 42-Day Follow-up Period, whichever occurs later: date of transfusion, 
pretransfusion Hgb levels, number of units transfused, and volume of transfusion.  In 
addition to local procedures that may be in place at the site to capture this 
information, a transfusion diary will be provided to all subjects and will be reviewed 
by the site when/if returned by the subject.  Source documentation of transfusions 
given during the study must be available for source document verification.


PK sample collection (as detailed in Sections 6.7 and 6.8)

Subject reported outcomes via the EQ-5D-5L, FACT-An, and MPN-SAF TSS (as 
detailed in Section 6.10)

Monitoring for transformation to blast phase and other malignancies/premalignancies
will occur on an ongoing basis 
6.2.3.
Extension Phase of the Treatment Period 
Subjects who meet the criteria to remain on luspatercept treatment after completion of the Day 
169 Disease Response Assessment may continue dosing on Day 1 of each 21-day treatment cycle 
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EDMS Doc. Number: 24487940 - 21868350
Luspatercept (ACE-536)
Protocol ACE-536-MF-001
Celgene Corporation
Confidential and Proprietary
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ACE-536-MF-001 Amendment 4 Final: 19 Feb 2020
in the Extension Phase of the Treatment Period for approximately 2 years or more from the 
C1D1 date until the subject is no longer receiving clinical benefit according to the Investigator’s
assessment (eg, loss of ≥ 50%  reduction of transfusion burden from baseline), experiences 
unacceptable toxicities, has disease progression, withdraws consent, or meets any other 
discontinuation criteria (Section 11).  
The Disease Response Assessment should be completed on Day 1 of every treatment cycle in the 
Extension Phase of the Treatment Period until the subject is discontinued from treatment and 
should confirm continued clinical benefit per the criteria outlined in Section 6.2.2.
All subjects who have received at least 1 dose of study treatment should undergo end of 
treatment (EOT) evaluations when luspatercept is discontinued (refer to Section 6.4 for more 
information).  The reason for discontinuation will be recorded in the eCRF pages and in the 
source documents.
Serial measurements of safety and efficacy will continue on scheduled study visits in the 
Extension Phase of the Treatment Period, of which the following procedures/evaluations should 
be performed prior to dosing on the visit day, unless otherwise specified:  

Physical examination (as detailed in Section 6.1)

Administration/accountability of luspatercept on Day 1 of each treatment cycle 

ECOG performance status

Urinalysis (as detailed in Section 6.1)

Pregnancy testing (as detailed in Section 6.1)

Adverse event assessment and reporting on an ongoing basis 

Concomitant medications and procedures on an ongoing basis 

Vital signs (as detailed in Section 6.1)

Serum chemistry (as detailed in Section 6.1)

Hematology assessments (as detailed in Section 6.1) 

Serum ferritin level assessed on Day 1 of every 4th Extension Phase treatment cycle 

Transfusion data collection and assessment 
During the study, the following, but not limited to, information will be recorded for 
all transfusions (including any transfusions received at outside institutions in between 
study visits) the subject receives starting from the C1D1 date until end of treatment or 
end of the 42-Day Follow-up Period, whichever occurs later: date of transfusion, 
pretransfusion Hgb levels, number of units transfused, and volume of transfusion.  In 
addition to local procedures that may be in place at the site to capture this 
information, a transfusion diary will be provided to all subjects and will be reviewed 
by the site when/if returned by the subject.  Source documentation of transfusions 
given during the study must be available for source document verification.

PK and ADA sample collection (as detailed in Sections 6.7 and 6.8)
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EDMS Doc. Number: 24487940 - 21868350
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Protocol ACE-536-MF-001
Celgene Corporation
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ACE-536-MF-001 Amendment 4 Final: 19 Feb 2020

Subject reported outcomes via the EQ-5D-5L, FACT-An, and MPN-SAF TSS (as 
detailed in Section 6.10)

Monitoring for transformation to blast phase and other malignancies/premalignancies
will occur on an ongoing basis 
6.3.
Dose Delays in Treatment Period 
On days when subjects return to the investigational site for luspatercept administration, but 
luspatercept is not administered (eg, due to protocol dose modification, dose delay rules 
[Section 7.3]), all required assessments and procedures should be performed, regardless if 
luspatercept is administered. During the time period of dose delay, the following 
assessments/procedures should be performed:

If dose delay is due to a laboratory or vital signs abnormality, the assessment that was the 
reason for the dose delay should be repeated at least on a weekly basis.

If dose delay is due to increased Hgb level, perform hematology assessments at least 
weekly.

If dose delay is due to an AE, perform hematology, serum chemistry, and serum ferritin 
assessments at least every 3 weeks thereafter and before next dose administration. 

Pharmacokinetic (PK)/ADA samples should be collected on the first day of dose delay 
and prior to luspatercept administration on day dosing resumes.
Refer to the eCRF completion guidelines for detailed instructions related to eCRF data entry.
6.4.
End of Treatment Visit 
An end of treatment (EOT) evaluation will be performed as soon as possible for subjects who are 
withdrawn from treatment for any reason (but, at the latest, at the next projected planned study 
visit) after the decision to permanently discontinue treatment has been made.  Evaluations will be 
performed as specified in Table 3.
If a subject is discontinued during a regular scheduled visit, all EOT procedures should be 
completed at that visit. If a procedure had been performed within ± 7 days of the EOT visit, it 
does not need to be repeated unless clinically indicated per Investigator discretion (with the 
exception of blood pressure assessment and sample collection for hematology, chemistry, and 
urinalysis).  
The reason for discontinuation will be recorded in the eCRF and in the source document for all 
enrolled subjects, regardless of whether they are dosed or not. Reasons for treatment 
discontinuation are provided in Section 11.
The following procedures/evaluations (including a Disease Response Assessment evaluation) 
should be performed:

Physical examination (as detailed in Section 6.1)

ECOG performance status

Urinalysis (as detailed in Section 6.1)
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EDMS Doc. Number: 24487940 - 21868350
Luspatercept (ACE-536)
Protocol ACE-536-MF-001
Celgene Corporation
Confidential and Proprietary
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
12-lead electrocardiogram (ECG) to be performed locally 

Pregnancy testing (as detailed in Section 6.1)

Adverse event assessment and reporting on an ongoing basis 

Concomitant medications and procedures on an ongoing basis 

Vital signs (as detailed in Section 6.1)

Serum chemistry (as detailed in Section 6.1)

Hematology assessments (as detailed in Section 6.1) 

Serum EPO level 

Serum ferritin level 

Transfusion data collection and assessment 
During the study, the following, but not limited to, information will be recorded for 
all transfusions (including any transfusions received at outside institutions in between 
study visits) the subject receives starting from the C1D1 date until end of treatment or 
end of the 42-Day Follow-up Period, whichever occurs later: date of transfusion, 
pretransfusion Hgb levels, number of units transfused, and volume of transfusion.  In 
addition to local procedures that may be in place at the site to capture this 
information, a transfusion diary will be provided to all subjects and will be reviewed 
by the site when/if returned by the subject.  Source documentation of transfusions 
given during the study must be available for source document verification.

Disease response assessment (as detailed in Section 6.2.2)


PK and ADA sample collection (as detailed in Sections 6.7 and 6.8)

Subject reported outcomes via the EQ-5D-5L, FACT-An, and MPN-SAF TSS (as 
detailed in Section 6.10)

Monitoring for transformation to blast phase and other malignancies/pre-malignancies
will occur on an ongoing basis 
6.5.
Posttreatment Follow-up Period 
The Posttreatment Follow-up Period will be inclusive of a 42-Day Follow-up Period and a Long-
term Follow-up Period, beginning from the date of last dose of luspatercept.
6.5.1.
42-Day Follow-up Period (referred to as the Safety Follow-up)
All AEs (including serious adverse events [SAEs]), regardless of causal relationship to 
luspatercept, will be recorded by the Investigator from the time the subject signs informed 
consent until 42 days after the last dose of luspatercept.  
Females of childbearing potential (FCBPs) will be advised to avoid becoming pregnant during 
study and for 12 weeks after the last dose of luspatercept.  Males will be advised to use a latex 
condom during any sexual contact with an FCBP prior to study entry and continue for 12 weeks 
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following the last dose of luspatercept, even if he has undergone a successful vasectomy.  Refer 
to Section 10.5.
Antidrug antibodies (ADA) sample(s) may be required in the Posttreatment Follow-up Period if 
a subject is ADA positive at the time of treatment discontinuation.  Refer to Section 6.8.
Additionally, the following should also be captured:

Concomitant medications and procedures 

Transfusion data collection and assessment 
During the study, the following, but not limited to, information will be recorded for 
all transfusions (including any transfusions received at outside institutions in between 
study visits) the subject receives starting from the C1D1 date until end of treatment or 
end of the 42-Day Follow-up Period, whichever occurs later: date of transfusion, 
pretransfusion Hgb levels, number of units transfused, and volume of transfusion.  In 
addition to local procedures that may be in place at the site to capture this 
information, a transfusion diary will be provided to all subjects and will be reviewed 
by the site when/if returned by the subject.  Source documentation of transfusions 
given during the study must be available for source document verification.

Monitoring for transformation to blast phase and other malignancies/pre-malignancies 

Post-luspatercept treatment MPN-associated myelofibrosis therapies

Survival follow up
6.5.2.
Long-term Follow-up and End of Study 
After the 42-Day Follow-up Period, only those serious adverse events (SAEs) made known to 
the Investigator that are suspected of being related to luspatercept will be recorded by the 
Investigator.
Females of childbearing potential (FCBPs) will be advised to avoid becoming pregnant during 
study and for 12 weeks after the last dose of luspatercept.  Males will be advised to use a latex 
condom during any sexual contact with an FCBP prior to study entry and continue for 12 weeks 
following the last dose of luspatercept, even if he has undergone a successful vasectomy.  Refer 
to Section 10.5.
For all subjects who receive at least 1 dose of luspatercept, continuation of monitoring for 
transformation to blast phase will occur in the Posttreatment Follow-up Period, along with data 
collection of new MPN-associated myelofibrosis disease therapies and overall survival for at 
least 3 years from the date of last dose of luspatercept unless the subject withdraws consent from 
the study, dies, or is lost to follow up, whichever occurs first.  This information will be collected 
until the End of Study and recorded in the eCRF.  During this time, all subjects will be followed 
approximately every 3 months following the 42-Day Follow-up Period.  The Investigator must 
make every effort to obtain information regarding the subject’s survival status before 
determining the subject is lost to follow up. Survival follow up can be performed via the 
telephone.  
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EDMS Doc. Number: 24487940 - 21868350
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ACE-536-MF-001 Amendment 4 Final: 19 Feb 2020
Long-term follow up may be conducted by record review (including public records, if available 
and allowed by local regulations) and/or telephone contact with the subject, family, or the 
subject’s treating physician.
6.6.
Unscheduled Visits 
An unscheduled visit in this protocol refers to any assessment or procedure that is completed 
outside of the designated time points and frequencies outlined in Section 5, Table 3.  Should it 
become necessary to repeat an evaluation (eg, laboratory tests or vital signs), the results of the 
repeat evaluation should be entered as an additional unscheduled visit in the eCRF.  
Refer to the eCRF completion guidelines for detailed instructions related to eCRF data entry.
6.7.
Pharmacokinetics 
Blood samples will be collected to analyze luspatercept concentrations in serum in all subjects as 
indicated in Section 5, Table 3. At each pharmacokinetic (PK) time point, approximately 3 mL 
of blood will be collected and serum prepared as described in the study reference guide. Blood 
samples for PK will be taken at the following visits during the study: 

Primary Phase of Treatment Period: C1D1 (must be collected before the first dose), 
C1D8, C1D15, C2D1, C4D1, C5D1, C5D8, C6D1, and C8D1 (collect samples only if the 
subject is still in the Primary Phase) 

Day 169 Disease Response Assessment

Extension Phase of Treatment Period (if applicable): Day 1 of every 4th Extension 
Phase treatment cycle for up to 1 year post the date of first dose of luspatercept 
The dose level and dosing time of luspatercept on the PK visit days should be recorded in eCRF.  
Detailed procedures of PK sample collection, processing, and shipping are provided in the study 
reference guide.
6.7.1.
Unscheduled Pharmacokinetic Visits
Pharmacokinetic (PK) sampling per Investigator’s or Sponsor’s discretion is allowed and should 
be recorded as an unscheduled visit.  
6.8.
Antidrug Antibody 
Blood samples will be collected for assessment of antidrug antibodies (ADA) against 
luspatercept in serum in all subjects.  The maximum ADA monitoring period will be 2 years 
from Cycle 1 Day 1 of the Treatment Period.  At each ADA time point, approximately 3 mL of 
blood will be collected and serum prepared as described in the study reference guide. However, 
during the first year of treatment, an additional blood draw may not be needed for the ADA test, 
as the ADA test may be conducted utilizing the PK samples obtained at the same visit.  Blood 
samples for ADA will be taken at the following visits during the study (also see Table 3): 

Primary Phase of Treatment Period: C1D1 (must be collected before the first dose), 
C2D1, C4D1, C6D1, and C8D1
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
Extension Phase of Treatment Period (if applicable): Day 1 of every 4th Extension 
Phase treatment cycle for up to 1 year post the date of first dose of luspatercept.  If the 
last available antiluspatercept antibody result is positive at the end of 1 year, subjects 
may be asked to return for ADA sample collection every 12 weeks for up to 2 years post 
the date of first dose of luspatercept or until the ADA level returns to baseline, whichever 
comes first.

End of Treatment Visit 

Posttreatment Follow-up Period: If the last available antiluspatercept antibody result is 
positive at the end of treatment, subjects may be asked to return for ADA sample 
collection every 12 weeks for up to 2 years post the date of first dose of luspatercept or 
until the ADA level returns to baseline, whichever comes first.
Antidrug antibodies (ADA) sampling per Investigator’s or Sponsor’s discretion is allowed and 
should be recorded as an unscheduled visit.
Detailed procedures of ADA sample collection, processing, and shipping are provided in the 
study reference guide.
 
 
 
 
 
 
6.10.
Subject Reported Outcomes or Quality of Life Measurements
Myeloproliferative neoplasm (MPN)-associated myelofibrosis-related symptoms (fatigue, night 
sweats, itchiness, abdominal discomfort, pain under the ribs on the left side, early satiety, and 
bone pain) will be recorded using the MPN-SAF TSS, which will be completed on a weekly 
basis and prior to luspatercept administration on Day 1 of dosing in the Primary Phase of the 
Treatment Period, in addition to the Day 169 Disease Response Assessment, and on Day 1 of 
every other treatment cycle prior to luspatercept administration thereafter during the Extension 
Phase of the Treatment Period, as well as the End of Treatment Visit.  
Fatigue-related symptoms and their impact on subjects’ functionality will be measured via the 
FACT-An, which will be completed on Day 1 during every other treatment cycle prior to 
luspatercept administration during the Primary Phase of the Treatment Period, in addition to the 
Day 169 Disease Response Assessment, and Day 1 of every other treatment cycle prior to 
luspatercept administration thereafter during the Extension Phase of the Treatment Period, as 
well as the End of Treatment Visit.
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Information on general quality of life (eg, mobility, self-care, usual activities, pain/discomfort, 
and anxiety/depression) will be assessed via the EQ-5D-5L, which will be completed on Day 1 
during every other treatment cycle prior to luspatercept administration during the Primary Phase 
of the Treatment Period, in addition to the Day 169 Disease Response Assessment, and Day 1 of 
every other treatment cycle prior to luspatercept administration thereafter during the Extension 
Phase of the Treatment Period, as well as the End of Treatment Visit.
6.11.
Screen Failures
For all subjects determined as screen failures, the following information is to be captured in the 
subject’s source documents and eCRF page(s): the date the informed consent form (ICF) was 
signed, demographics, the reason subject did not qualify for the study, and the Investigator’s 
signature for the eCRF pages.  The adverse events experienced by screen failure subjects will be 
collected from the date of signing consent to the day the subject is confirmed as a screen failure.  
Relevant information will also be recorded on the Screening Log.
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7.
DESCRIPTION OF STUDY TREATMENTS
7.1.
Description of Investigational Product(s)
Luspatercept will be provided by the Sponsor. Luspatercept for injection is formulated as a 
sterile, preservative-free, lyophilized cake/powder.  Luspatercept for injection is available in 25 
mg and 75 mg vials and when reconstituted, each consists of 50 mg/mL luspatercept in a 
 mM 
citrate buffer-based solution (
 mM citrate, pH 
% sucrose, 
% polysorbate 80).  
The recommended storage condition for luspatercept for injection (25 mg/vial and 75 mg/vial; 
lyophilized powder formulation) is 2°C to 8°C.  Reconstituted luspatercept in its original 
container closure system may be held for up to 10 hours at 2°C to 8°C, however it should be 
administered at room temperature. It is recommended that the reconstituted luspatercept for 
injection be used immediately. If not used immediately, the total in-use time of the reconstituted 
luspatercept for injection, from reconstitution to administration, must not exceed 10 hours.  
Samples of luspatercept drug product, held at the recommended storage condition, have been 
shown to be stable through the labeled shelf-life.
Subjects enrolled in Cohort 3 are receiving ruxolitinib as prescribed by their physician.  Celgene 
will not be supplying ruxolitinib for this study.  Instead, ruxolitinib will be obtained by the sites 
according to local clinical study agreement and in accordance with local guidelines.
7.2.
Treatment Administration and Schedule
Luspatercept will be administered on Day 1 of every 21-day cycle, at an initial dose level of 1.0 
mg/kg (*Note for Protocol Amendment 3: Additional subjects enrolling into Cohort 3B will 
begin luspatercept treatment at a starting dose of 1.33 mg/kg and can have their dose increased to 
a maximum dose of 1.75 mg/kg [with the total dose not to exceed 168 mg]).  Doses may be 
titrated up starting in Cycle 3 as described in Section 7.3.  Luspatercept will be administered as a 
subcutaneous injection to subjects by the study staff at the clinical site and administration will be 
documented in the subject’s source record.  Subjects must have their Hgb, WBC, blood 
myeloblast percentage, and blood pressure assessed prior to each luspatercept administration. 
Subcutaneous injections will be given in the upper arm, thigh, and/or abdomen. Calculated doses 
requiring reconstituted volume greater than 1.2 mL should be divided into separate, similar 
volume injections across 2 or 3 separate sites using the same anatomical location, but on opposite 
sides of the body (example left thigh and right thigh). The maximum volume per subcutaneous
injection should not exceed 1.2 mL. The injection sites can be rotated according to Investigator 
judgment, and the injections can be given in the following order as needed, for example: 1) right 
upper arm, 2) left upper arm, 3) right upper thigh, 4) left upper thigh.
7.3.
Dose Modifications: Dose Titration, Dose Reduction, and Dose Delay
Starting dose with dose increases and reductions are presented below for reference (refer to 
Table 4). The total dose administered should not exceed 168 mg.
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Table 4:
Starting Dose Level with Dose Reductions and Dose Titration
3rd Dose 
Reduction
(~25% 
reduction)
2nd Dose 
Reduction
(~25% 
reduction)
1st Dose 
Reduction
(~20% 
reduction)
Starting Dose 
Levela
1st Dose 
Titration 
Increase
2nd Dose 
Titration 
Increase
0.45 mg/kg
0.6 mg/kg
0.8 mg/kg
1.0 mg/kg
1.33 mg/kg
1.75 mg/kg
a Note for Protocol Amendment 3: Additional subjects enrolling into Cohort 3B will begin luspatercept treatment at 
a starting dose of 1.33 mg/kg and can have their dose increased to a maximum dose of 1.75 mg/kg (with the total 
dose not to exceed 168 mg).
7.3.1.
Dose Titration
Starting as soon as Cycle 3 Day 1 and assessed by the Investigator prior to every subsequent 
treatment cycle, subjects may have the dose level increased in a stepwise manner beyond the 
starting dose level of 1.0 mg/kg to 1.33 mg/kg, and up to a maximum of 1.75 mg/kg (but no 
more than 168 mg) during the Treatment Period.
*Note for Protocol Amendment 3: Additional subjects enrolling into Cohort 3B will begin 
luspatercept treatment at a starting dose of 1.33 mg/kg and can have their dose increased to a 
maximum dose of 1.75 mg/kg (with the total dose not to exceed 168 mg). 
If the subject has 2 of the most recent prior treatment cycles assessed at the same dose level and
if the subject has not met any protocol dose delay and/or reduction criteria in the 2 most prior 
treatment cycles, they may be eligible for a dose titration. The dose may be increased by 1 dose 
level if 1 or more of the following criteria are met:

For all cohorts: subject has ≥1 RBC transfusion event (for pretransfusion Hgb of ≤ 
9.5 g/dL) during the 2 most recent prior treatment cycles (~6 weeks)

For all cohorts:  Hemoglobin decrease of ≥ 1 g/dL is observed and this decrease is 
not preceded by an RBC transfusion (the hemoglobin decrease occurs ≥ 14 days after 
the last RBC transfusion)

For subjects in Cohorts 1 and 3A: Hemoglobin increase from baseline is < 1.5 
g/dL throughout the previous 2 cycles at the same dose level

For subjects in Cohorts 1 and 3A: Hemoglobin increase from baseline is ≥1.5 g/dL 
but not sustained for at least 2 consecutive study measurements during the previous 2
cycles at the same dose level 

For subjects in Cohorts 2 and 3B: Hgb value is not exceeding 1 g/dL increase from 
the baseline mean pretransfusion Hgb value, which will be calculated using the 
reported RBC transfusions that confirmed the eligibility of the subject
The dose level should be titrated individually for each subject.
7.3.2.
Dose Reduction and Dose Delay 
Dose delay and/or reduction or discontinuation may be required due to increased hemoglobin or 
adverse events. Table 5 below provides guidelines for dose modifications and dose delay.
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Table 5:
Dose Modification: Dose Delay, Dose Reduction, and Discontinuation 
Guidelines 
Event at the Day of Dosing
(Assessed prior to each luspatercept
administration)
Action
Any suspected related adverse event (AE) ≥ Grade 
3a,b 
Dose delayc until resolved to ≤ Grade 1 or 
baseline, and then reduce dose by 1 dose level
≥ 2 dose reductions suspected related AEa
Discontinue treatment
Change in hemoglobin (Hgb) ≥ 2 g/dL compared 
to predose Hgb of previous treatment cycle 
Reduce dose by 1 dose leveld if change in Hgb not 
influenced by red blood cell (RBC) transfusions
Predose Hgb ≥ 11.5 g/dL 
Dose delay until Hgb ≤ 11 g/dL 
Blood myeloblast percentagee
(based on either local or central lab hematology 
sample)
If the blood myeloblast percentage at the first day 
of a dosing cycle is ≥ 10% conduct retesting 
within a week before the next dosing cycle: 

If the retest has a myeloblast percentage that 
is still ≥ 10%, discontinue luspatercept 

If the retest has a myeloblast percentage 
< 10%, the subject may continue 
luspatercept treatment
Transformation to blast phase
(based on either local or central lab)
If there is transformation to blast phase confirmed 
by a bone marrow blast count of ≥ 20% or an 
increase in blood myeloblast percentage of ≥ 20% 
associated with an absolute blast count ≥ 1 x 109/L 
that lasts for at least 2 weeks, discontinue 
luspatercept.
Refer to Section 6.1
White blood count (WBC) is:

≥120 x 109/L or

≥ 3 x baseline and ≥ 30 x 109/Lf
(based on either local or central lab hematology 
sample)
Dose delayc with weekly WBC monitoring until 
WBC is:

< 120 x 109/L or

< 3 x baseline or < 30 x 109/L 
If WBC continues to be elevated for 3 consecutive 
determinations, discontinue luspatercept 
treatment.  
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Table 5:
Dose Modification: Dose Delay, Dose Reduction, and Discontinuation 
Guidelines (Continued)
Event at the Day of Dosing
(Assessed prior to each luspatercept
administration)
Action
Leukopenia, Neutropenia and/or 
Thrombocytopenia
A shift (worsening) by ≥2 gradesg leukopenia, 
neutropenia or thrombocytopenia to ≥ Grade 3 during 
treatment with luspatercept not clearly and solely 
related to an extraneous case such as advancing 
MPN-associated myelofibrosis or an infectious 
event.
Worsening of Anemia:
For Cohorts 2 and 3B: A ≥ 50% increase from 
baseline in transfusion burden in combination with 
an unexplained shift from baseline (worsening) of ≥ 
2 gradesg leukopenia, neutropenia or 
thrombocytopenia.
For Cohorts 1 and 3A: A decrease of > 2 g/dL Hgb 
from baseline [uninfluenced by transfusion] or 
becomes transfusion dependent in combination with 
an unexplained shift from baseline (worsening) of ≥ 
2 gradesg leukopenia, neutropenia or 
thrombocytopenia.
Dose delayc and repeat WBC, neutrophils and 
platelet counts weekly for two weeks

If WBC, neutrophils and platelet counts 
are resolved to ≤ Grade 1, baseline, or 
shifts by at least one toxicity grade 
(improvement) and if cytopenia is not 
regarded as related to luspatercept and 
the myeloblast percentage is < 10% 
(follow the myeloblast percentage rule 
above), then discuss the dose level for 
continuation of therapy with the medical 
monitor. 

If WBC, neutrophils and platelet counts 
are not resolved to ≤ Grade 1, baseline or 
does not shift by at least one toxicity 
grade (improvement) and an alternative 
cause cannot be identified, then consider 
additional bone marrow assessments and 
discuss next steps with the medical 
monitor.
a Possibly, probably or definitely related to luspatercept.
b Includes systolic blood pressure ≥ 160 mmHg and diastolic blood pressure ≥ 100 mmHg.
c If dose delay is > 12 consecutive weeks, treatment should be discontinued.
d Predose Hgb value not being influenced by red blood cell (RBC) transfusion (ie, hemoglobin [Hgb] result > 14 
days after last RBC transfusion); Hgb should be rechecked weekly during dose delay.
e The Investigator may contact the Medical Monitor and forward appropriate supporting documents for review and 
discussion prior to making decision regarding treatment discontinuation.
f Corrected WBC should be used to establish the baseline white blood count (WBC).  Baseline = highest WBC 
between Screening WBC and Cycle 1 Day 1 (C1D1).
g Thrombocytopenia, leukopenia, and neutropenia toxicity grades as defined by CTCAE criteria.
7.4.
Overdose
Overdose, as defined for this protocol, refers to luspatercept dosing only.  On a per dose basis, an
overdose is defined as the following amount over the protocol-specified dose of luspatercept 
assigned to a given subject, regardless of any associated adverse events or sequelae:  
Subcutaneous 10% over the protocol-specified dose
On a schedule or frequency basis, an overdose is defined as anything more frequent than the 
protocol required schedule or frequency.  Complete data about drug administration, including 
any overdose, regardless of whether the overdose was accidental or intentional, should be 
reported in the eCRF.  See Section 10.1 for the reporting of adverse events associated with 
overdose.
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7.5.
Method of Treatment Assignment 
The cohort assignment will occur at the end of the Screening Period, once all the required 
screening procedures have been completed and all required data have been submitted to the 
Sponsor or its authorized representative.  Upon receiving acknowledgment of subject’s eligibility
review from the Sponsor or its authorized representative, the subject can be assigned treatment 
using an IRT built for this study. 
Designated research personnel at each investigational site will be assigned unique, password-
protected user accounts which give them the authorization to utilize the IRT to enroll subjects.  
For drug assignment, dose reduction or titrations, site staff must contact the IRT to record the 
new dose level and obtain the new study treatment assignment.
7.6.
Packaging and Labeling
The label(s) for luspatercept will include Sponsor name, address and telephone number, the 
protocol number, luspatercept name, dosage form and strength (where applicable), amount of 
luspatercept per container, lot number, expiry date (where applicable), medication 
identification/kit number, dosing instructions, storage conditions, and required caution 
statements and/or regulatory statements as applicable. Additional information may be included 
on the label as applicable per local regulations.
7.7.
Investigational Product Accountability and Disposal 
Accountability for luspatercept that is administered during the course of the study is the 
responsibility of the Investigator or designee.  Investigational clinical supplies must be received 
by a designated person at the clinical site and kept in a secure and temperature-controlled 
location.  The investigational site must maintain accurate records demonstrating dates and 
amounts of luspatercept received, to whom it was administered (subject-by-subject accounting), 
and accounts of any luspatercept accidentally or deliberately destroyed or returned.  Accurate 
recording of all luspatercept administration will be made in the appropriate section of the 
subject’s eCRF and source documents.  Unless otherwise notified, all vials of luspatercept, both 
used and unused, must be saved for drug accountability.  The used vials may be discarded, per 
the institution’s standard practice, after drug accountability has been completed by the monitor.  
The Investigator must return all unused vials of luspatercept to the Sponsor at the end of the 
study, or luspatercept may be destroyed at the clinical site with the permission of the Sponsor.  
For either scenario, the outcome must be documented on the drug accountability log.  The 
Sponsor will provide direction for the outcome of all unused vials.
Celgene (or designee) will review with the Investigator and relevant site personnel the process 
for investigational product return, disposal, and/or destruction including responsibilities for the 
site versus Celgene (or designee).
7.8.
Investigational Product Compliance
Luspatercept will be administered as a subcutaneous injection at the clinical site by the study 
staff.  Monitoring for subject compliance with the treatment regimen is therefore unnecessary.
Accurate recording of all luspatercept administration will be made in the appropriate section of 
the subject’s eCRF and source documents.
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The Investigator or designee is responsible for accounting for all luspatercept that is 
administered during the course of the study.
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8.
CONCOMITANT MEDICATIONS AND PROCEDURES
Over the course of this study, additional medications may be required to manage aspects of the 
disease state of the subjects, including side effects from trial treatments or disease progression. 
Supportive care, such as anti-emetic medications, may be administered at the discretion of the 
Investigator. 
All prior/concomitant treatments used from 28 days prior to the enrollment date until 42 days 
after the last dose of luspatercept must be reported on the eCRF. Additionally, any 
prior/concomitant treatments with a potential effect on the hematopoietic system should be 
captured from 112 days prior to the enrollment date until 42 days after the last dose of 
luspatercept and must be reported on the eCRF.  
All prior procedures within the 28 days prior to the enrollment date will be recorded on the 
appropriate eCRF(s).
Prior granulocyte colony-stimulating factor (G-CSF)/ granulocyte macrophage colony-stimulating 
factor (GM-CSF) and ICT should be recorded on the appropriate eCRF(s) regardless of treatment 
discontinuation date.
Prior anticancer treatments should be recorded on the appropriate eCRF(s) regardless of 
treatment discontinuation/procedure date.
If a subject requires treatment with any new medications that are specifically excluded in 
Section 8.2, the subject will be discontinued from treatment and should complete the End of 
Treatment Visit and enter the Posttreatment Follow-up Period. The Investigator should consult 
the medical monitor regarding any questions about whether a new medication or dosage of 
existing medication would require the subject to discontinue from the study. 
For information regarding other drugs that may interact with luspatercept and affect its 
metabolism, pharmacokinetics, or excretion, please see the Investigator’s Brochure and/or local 
package insert.
8.1.
Permitted Concomitant Medications and Procedures
For subjects in Cohort 2 and Cohort 3B, concurrent treatment for anemia with blood transfusions 
is recommended when Hgb is ≤9.0 g/dL or at the discretion of the Investigator if Hgb is ≥9.0 
g/dL and associated with symptom(s) of anemia (eg, hemodynamic or pulmonary compromise 
requiring treatment) or comorbidity justifying a threshold of ≥9.0 g/dL Hgb.
For any RBC transfusions received during the study, the Hgb value just prior to transfusion
should be collected, along with several other parameters (ie, number of units transfused, volume 
transfused, date of transfusion).
Granulocyte colony stimulating factors (ie, G-CSF, GM-CSF) are allowed only in cases of 
neutropenic fever or as clinically indicated per product label.
Thrombopoietin and platelet transfusions are permitted.  
Treatment with systemic corticosteroids is permitted for nonhematological conditions providing 
the subject is receiving a stable or decreasing dose for ≥84 days immediately prior to enrollment 
and is receiving a constant dose equivalent to ≤10 mg prednisone during the study.
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Administration of attenuated vaccines (eg, influenza vaccine) is allowed if clinically indicated 
per Investigator discretion.
Subjects who are using iron chelation therapies at the time of enrollment should be on a stable 
dose during the study and is recommended to be used per product label.
8.2.
Prohibited Concomitant Medications and Procedures
The following concomitant medications are specifically excluded during the course of the study:

Cytotoxic, chemotherapeutic, targeted, or investigational agents/therapies

Azacitidine, decitabine, or other hypomethylating agents

Lenalidomide, thalidomide, and other immunomodulatory compounds

Erythropoietin stimulating agents (ESAs) and other RBC hematopoietic growth factors 
(eg, IL-3)

Hydroxyurea or other alkylating agents 

Androgens (unless given to treat hypogonadism)

Oral retinoids (topical retinoids are permitted)

Arsenic trioxide

Interferon

Anagrelide
The following procedures are specifically excluded during the course of the study:

Splenectomy

Radiotherapy
For subjects specifically in Cohorts 1 and 2, concomitant treatment with ruxolitinib is prohibited.
Subjects in Cohort 1 and Cohort 3A are not permitted to receive RBC transfusions during the 
Treatment Period.  Should an RBC transfusion be indicated to manage anemia, subjects in these 
cohorts might not be available for the efficacy evaluable population.
8.3.
Required Concomitant Medications and Procedures
Not applicable.  
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9.
STATISTICAL CONSIDERATIONS
9.1.
Overview
This is a Phase 2, multicenter, open-label study to evaluate the efficacy and safety of luspatercept
in subjects with MPN-associated myelofibrosis and anemia with and without RBC-transfusion 
dependence.
The design of the study, including the proposed targeted subject population, study endpoints, and 
statistical plan, is discussed below.
9.2.
Study Population Definitions
Subjects will be enrolled to provide approximately 100 ITT subjects in this study, denoted by the 
following cohorts:  
Cohort 1 (anemia only):
Approximately 20 subjects, but no less than 14 efficacy evaluable subjects, with MPN-
associated myelofibrosis who are RBC-transfusion independent (no RBC transfusions within 
at least 84 days immediately up to the C1D1 date) with anemia will be enrolled in Cohort 1 
and receive luspatercept at a starting dose level of 1.0 mg/kg (subcutaneous injection on Day 
1 of a 21-day treatment cycle) for up to 8 cycles (or up through Day 168 in the event of dose 
delays).  Should subjects meet the clinical benefit definition, they may continue treatment for 
approximately 2 years or more from the C1D1 date following the Day 169 Disease Response 
Assessment.  
Cohort 2 (RBC-transfusion dependent):
Approximately 20 subjects with MPN-associated myelofibrosis and an average RBC-
transfusion burden of 2 to 4 RBC units/28 days (calculated from the 84-day period 
immediately up to the C1D1 date) will be enrolled in Cohort 2 and receive luspatercept at a 
starting dose level of 1.0 mg/kg (subcutaneous injection on Day 1 of a 21-day treatment 
cycle) for up to 8 cycles (or up through Day 168 in the event of dose delays).  Should 
subjects meet the clinical benefit definition, they may continue treatment for approximately 2 
years or more, from the C1D1 date following the Day 169 Disease Response Assessment.  
Cohort 3 (subjects on ruxolitinib as part of their standard-of-care therapy):
Approximately 60 subjects will be enrolled in Cohort 3 who must be on a stable dose of 
ruxolitinib for at least 112 days (16 weeks) immediately up to the enrollment date. Effective 
from Protocol Amendment 3, the additional subjects enrolled into Cohort 3B must also have 
a minimum prior treatment with ruxolitinib per their local standard-of-care for at least 280 
days (40 weeks) without interruptions exceeding 2 consecutive weeks leading up to the date 
of enrollment.  These subjects will receive luspatercept at a starting dose level of 1.0 mg/kg 
(subcutaneous injection on Day 1 of a 21-day treatment cycle) for up to 8 cycles (or up 
through Day 168 in the event of dose delays) *Note for Protocol Amendment 3: Additional 
subjects enrolling into Cohort 3B will begin luspatercept treatment at a starting dose of 1.33 
mg/kg and can have their dose increased to a maximum dose of 1.75 mg/kg (with the total 
dose not to exceed 168 mg).  Should subjects meet the clinical response definition, they may 
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continue treatment for approximately 2 years or more, following the Day 169 Disease 
Response Assessment.
Study populations to be analyzed are defined as follows:
Intent-to-treat (ITT) Population: 
The intent-to-treat (ITT) population will consist of all enrolled subjects regardless of whether or 
not the subject received luspatercept.  Efficacy analyses will be conducted primarily on the ITT 
population.  
Efficacy Evaluable (EE) Population:
A subject who meets all the inclusion/exclusion criteria will be considered “efficacy evaluable” 
upon receiving ≥ 3 cycles of luspatercept and remain in the study for ≥ 21 days following the 
third dose of luspatercept.  Subjects who attain Hgb values > 13 g/dL in < 3 cycles will also be 
considered efficacy evaluable.  Subjects not considered “efficacy evaluable” are in general those 
that receive < 3 cycles of luspatercept in which luspatercept is held or discontinued or who 
receive < 3 cycles due to a treatment-emergent adverse event (TEAE) or discontinued treatment 
for any other reason.
Subjects will become nonefficacy evaluable in certain cases (eg, prohibited concomitant 
medication/s was/were used during the study).  Subjects specifically in Cohort 3 become 
nonefficacy evaluable in certain cases (eg, the ruxolitinib dose was modified during the study).  
The study steering committee will review the allocation of all subjects to the EE population.  
Efficacy analyses will be conducted based on the ITT and EE populations.  
Safety Population: 
The Safety Population will consist of all subjects who were enrolled and received at least 1 dose 
of luspatercept. 
Statistical methods to handle missing data will be described in the statistical analysis plan (SAP).
The SAP will describe any predefined rules for including/excluding any subjects with data from 
any analyses (eg, time windows, visit by visit analysis, endpoint analysis, protocol violation).  
9.3.
Sample Size and Power Considerations
The Sponsor estimates that out of 20 enrolled subjects in Cohort 1, at least 14 will become 
efficacy evaluable.  
For Cohort 1, the probability of observing no responses among 14 subjects is less than 0.05 if the 
response probability is greater than 20%. If no responses are observed in the first 14 evaluable 
subjects, the trial is stopped because it can be concluded that the response rate for the primary 
endpoint is less than 20% in Cohort 1.  
For Cohort 2, the probability of observing no responses among 14 subjects is less than 0.05 if the 
response probability is greater than 20%.  If no responses are observed in the first 14 evaluable 
subjects, enrollment in this cohort will be stopped because it can be concluded that the response 
rate for the primary endpoint is less than 20% in Cohort 2.
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The sample size of Cohort 3 has been increased to approximately 60 ITT subjects. A total of 14 
subjects in Cohort 3A would be sufficient to ensure the probability of observing no responses is 
less than 0.05 if the true response probability were greater than 20%, while 46 subjects in Cohort 
3B would provide for 80% power to detect a 15% increase in response rate for luspatercept over 
a null response rate of 17%. This assumes a one-sided z test of a binomial proportion (with a 5% 
significance level). 
9.4.
Background and Demographic Characteristics
Subjects’ age, height, weight, and baseline characteristics will be summarized using descriptive 
statistics, while gender, race, and other categorical variables will be provided using frequency 
tabulations by dose cohort.  Prior transfusion history will be summarized.  Medical history data 
will be summarized using frequency tabulations by the Medical Dictionary for Regulatory 
Activities (MedDRA) system organ class and preferred term.  Myeloproliferative neoplasm 
(MPN)-associated myelofibrosis diagnoses as well as RBC transfusion dependence will be 
summarized using frequency tabulations.
9.5.
Subject Disposition
Subject disposition (analysis population allocation, entered, discontinued, along with primary 
reason for discontinuation) will be summarized using frequency and percent for both treatment 
and follow-up phases.  A summary of subjects enrolled by site will be provided.  Protocol 
deviations will be summarized using frequency tabulations.
9.6.
Efficacy Analysis
Efficacy analyses will be primarily conducted in the ITT population, and confirmatory analyses
will be conducted in the EE population.  Statistical analyses will be primarily descriptive in 
nature since the goal of the study is to establish efficacy and safety of luspatercept for further 
investigation.  The results will be presented by cohort that subject is assigned to.  Subjects in 
Cohorts 3A and 3B will be summarized separately.  
9.6.1.
Primary Efficacy Analysis 
The primary efficacy endpoint is the proportion of subjects that achieved anemia response as 
defined below: 
Cohorts 1 (anemia only) and 3A: 
Proportion of subjects achieving ≥1.5 g/dL hemoglobin increase from baseline over any 
consecutive 84-day period without an RBC transfusion from Day 1 up through and including 
Day 168. This 84-day period will begin as soon as the ≥1.5 g/dL hemoglobin increase is 
detected.  There must be ≥ 3 determinations of ≥1.5 g/dL hemoglobin increase from baseline
in this interval with no value showing a < 1.5 g/dL hemoglobin increase from baseline and
no 2 measurements are ≥ 42 days apart.
Cohorts 2 (RBC-transfusion dependent) and 3B: 
Proportion of subjects who become RBC-transfusion free over any consecutive 84-day 
period from Day 1 up through and including Day 168.  This 84-day period will begin from 
the date of the prior RBC transfusion that is given for a Hgb value ≤9.5 g/dL.
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Examples of any consecutive 84-day period are from Day 1 to 84, Day 2 to 85, Day 3 to 86, etc. 
Response rate will be calculated using the number of responders divided by number of subjects 
in the ITT population (responders plus nonresponders).
Anemia response rate, together with a 95% confidence interval, will be calculated for each 
cohort. 
9.6.2.
Secondary Efficacy Analyses 
Time to anemia response will be summarized only for subjects who achieved anemia response.
It is defined as time from first dose to first onset of anemia response, calculated from Day 1 
through and including Day 168. 
Duration of anemia response will be summarized only for subjects who achieved anemia 
response. It is defined as maximum duration of modified anemia response, calculated from Day 
1 through end of treatment.
Frequency of RBC transfusions will be assessed for Cohort 2 subjects and RBC-transfusion 
dependent subjects in Cohort 3B.  It is defined as the mean number of RBC units transfused per 
subject per 28 days. It will be calculated from Day 1 through and including Day 168 and Day 1 
through end of treatment. 
Frequency of RBC-transfusion dependence will be assessed for Cohort 2 subjects and RBC-
transfusion dependent subjects in Cohort 3B. It is defined as the proportion of subjects who 
reduce their transfusion burden by ≥ 50% from baseline over any consecutive 84-day period. It 
will be calculated from Day 1 through and including Day 168 and Day 1 through end of 
treatment. 
Symptoms response improvement will be assessed using the proportion of subjects who 
achieve ≥50% reduction in fatigue symptom as measured by the MPN-SAF TSS, calculated from 
Day 1 through and including Day 168 and Day 1 through end of treatment.  The proportion of 
subjects who achieve ≥50% reduction in total symptom score (TSS) will also calculated.
Health-related quality of life (HRQoL) will be assessed via the mean changes in domain scores 
over the study compared to baseline using the FACT-An and EQ-5D-5L, calculated from Day 1 
through and including Day 168 and Day 1 through end of treatment.  Various schemes will be 
assessed for missing data imputation if needed.  
Changes in hemoglobin will be assessed for Cohorts 1 and 3A subjects over the study compared 
to baseline in the absence of RBC transfusions, calculated from Day 1 through and including 
Day 168 and Day 1 through end of treatment.  
Mean hemoglobin increase of ≥ 1.5 g/dL from baseline over any consecutive 84-day period 
without an RBC transfusion will be assessed for Cohorts 1 and 3A subjects, calculated from Day 
1 through and including Day 168 and Day 1 through end of treatment.  Duration of anemia 
response may be estimated using Kaplan-Meier methods. Point estimates and 95% confidence 
intervals will be provided where appropriate. Additional details of the censoring rules will be 
specified in the SAP. 
Other efficacy endpoints will be primarily summarized by descriptive statistics. There will be no 
inferential comparison between treatment cohorts. 
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9.7.
Safety Analysis
All safety analyses will be performed on the safety population.  Full details will be included in 
the SAP. Planned data presentations and analyses include the following:

Adverse events will be coded using MedDRA.  Adverse event listings will include the 
verbatim term and the MedDRA preferred term.  Treatment-emergent adverse events will 
be summarized by system organ class and preferred term.  Treatment-emergent adverse 
events leading to death or to discontinuation from treatment, TEAEs classified as 
National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events 
(CTCAE) (version 4.03) all grades or grade 3/4 TEAEs, related to investigational 
product, and serious TEAEs will be summarized separately.

Clinical laboratory results will be summarized descriptively by cohort.  Clinically 
significant hematologic and nonhematologic laboratory abnormalities will be listed and 
summarized according to the NCI CTCAE (version 4.03).  Cross tabulations will be 
provided to summarize frequencies of abnormalities.

Physical examination data and vital sign measurements, including body weight, will be 
listed for each subject at each visit.  Descriptive statistics for vital signs, both observed 
values and changes from baseline, will be summarized by cohort.
Graphical displays will be provided where useful to assist in the interpretation of results.
9.8.
Timing of Analyses 
9.8.1.
Interim Analysis 
No formal interim analysis is planned for the study.  Once the last subject completes or 
discontinues the Primary Phase of the Treatment Period, top-line results on efficacy and safety 
endpoints will be generated.  
9.8.2.
Final Analysis 
The final analysis will be performed when all subjects have completed or discontinued the 
Treatment Period.  Additional follow-up analyses will be performed when subjects complete the 
Long-term Follow-up Period.
9.9.
Other Topics
9.9.1.
Pharmacokinetic Analysis 
Population PK analysis will be performed for luspatercept using nonlinear mixed effect 
modeling. Concentration data obtained from this study and other studies may be combined to 
develop a population PK model that describes the PK exposure data and the associated 
variability.  Subject-specific factors (demographics, baseline characteristics, markers for organ 
function, antiluspatercept antibodies, etc.) will be explored as covariates for their potential to 
influence luspatercept PK parameters.  Empiric individual Bayesian estimates of PK parameters 
will be generated using the final population PK model. With these individual parameter 
estimates, appropriate measures of luspatercept exposure (area under the curve [AUC], 
maximum plasma concentration of drug [Cmax], or other exposure metrics of interest) will be 
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computed for each subject. The relationship between serum luspatercept exposure and selected 
efficacy endpoints and AEs of interest may be explored as appropriate.
Furthermore, frequency of ADA and effects on efficacy, safety, or PK parameters will also be 
assessed. 
 
 
 
 
9.9.3.
Steering Committee 
A SC will be established by charter for this study.  The SC will be comprised of study 
Investigators, Sponsor representatives, and may include additional ad hoc members as 
appropriate.  The SC will have the opportunity to review efficacy and safety data on an ongoing 
basis. The SC will serve in an advisory capacity to the Sponsor.  The SC may advise and 
recommend to the Sponsor on the following (but not limited to) points:

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.
The SC will review all available safety and efficacy data after:

approximately 3 subjects in Cohort 3 complete 2 cycles of therapy; 

approximately 6 efficacy-evaluable subjects complete at least 5 cycles of therapy; and 

approximately 14 efficacy-evaluable subjects complete at least 5 cycles of therapy in 
Cohort 1.
During this time, enrollment will continue without delay in all 3 cohorts. 
If a minimum level of response is not seen in Cohort 1 (at least 1 per protocol responder out of 
the first 14 efficacy evaluable subjects in Cohort 1), the SC may recommend ending the study 
early due to lack of efficacy.  
The SC responsibilities, authorities, and procedures will be detailed in the SC charter, which will 
be endorsed by the SC prior to the first data review meeting.
Additional details, including operational considerations, for the SC will be detailed in a separate 
SC charter. 
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10.
ADVERSE EVENTS
10.1.
Monitoring, Recording and Reporting of Adverse Events
An AE is any noxious, unintended, or untoward medical occurrence that may appear or worsen 
in a subject during the course of a study. It may be a new intercurrent illness, a worsening 
concomitant illness, an injury, or any concomitant impairment of the subject’s health, including 
laboratory test values (as specified by the criteria in Section 10.3), regardless of etiology. Any 
worsening (ie, any clinically significant adverse change in the frequency or intensity of a pre-
existing condition) should be considered an AE.  A diagnosis or syndrome should be recorded on 
the AE page of the eCRF rather than the individual signs or symptoms of the diagnosis or 
syndrome. 
Abuse, withdrawal, sensitivity or toxicity to an investigational product should be reported as an 
AE. Overdose, accidental or intentional, whether or not it is associated with an AE should be 
reported on the overdose eCRF (See Section 7.2 for the definition of overdose). Any sequela of 
an accidental or intentional overdose of an investigational product should be reported as an AE 
on the AE eCRF. If the sequela of an overdose is an SAE, then the sequela must be reported on 
an SAE report form and on the AE eCRF. The overdose resulting in the SAE should be 
identified as the cause of the event on the SAE report form and eCRF but should not be reported 
as an SAE itself.
In the event of overdose, the subject should be monitored as appropriate and should receive 
supportive measures as necessary.  There is no known specific antidote for luspatercept
overdose. Actual treatment should depend on the severity of the clinical situation and the 
judgment and experience of the treating physician.
All subjects will be monitored for AEs during the study.  Assessments may include monitoring 
of any or all of the following parameters: the subject’s clinical symptoms, laboratory, 
pathological, radiological or surgical findings, physical examination findings, or findings from 
other tests and/or procedures.
All AEs (including serious adverse events [SAEs]), regardless of causal relationship to 
luspatercept, will be recorded by the Investigator from the time the subject signs informed 
consent until 42 days after the last dose of luspatercept.  After the 42-Day Follow-up Period, 
only those serious adverse events (SAEs) made known to the Investigator that are suspected of 
being related to luspatercept will be recorded by the Investigator.
Adverse events (AEs) and SAEs will be recorded on the AE page of the eCRF 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.
10.2.
Evaluation of Adverse Events
A qualified Investigator will evaluate all adverse events as to: 
10.2.1.
Seriousness 
An SAE is any AE occurring at any dose that:
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
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.
Important medical events are defined as those occurrences that may not be immediately life-
threatening or result in death, hospitalization, or disability, but may jeopardize the subject or 
require medical or surgical intervention to prevent one of the other outcomes listed above.  
Medical and scientific judgment should be exercised in deciding whether such an AE should be 
considered serious.
Events not considered to be SAEs are hospitalizations for:

a standard procedure for protocol therapy administration.  However, hospitalization or 
prolonged hospitalization for a complication of therapy administration will be 
reported as an SAE. 

routine treatment or monitoring of the studied indication not associated with any 
deterioration in condition.

the administration of blood or platelet transfusion as routine treatment of studied 
indication.  However, hospitalization or prolonged hospitalization for a complication 
of such transfusion remains a reportable SAE.

a procedure for protocol/disease-related investigations (eg, surgery, scans, endoscopy, 
sampling for laboratory tests, bone marrow sampling).  However, hospitalization or 
prolonged hospitalization for a complication of such procedures remains a reportable 
SAE.

hospitalization or prolongation of hospitalization for technical, practical, or social 
reasons, in absence of an AE.

a procedure that is planned (ie, planned prior to start of treatment on study); must be 
documented in the source document and the eCRF.  Hospitalization or prolonged 
hospitalization for a complication remains a reportable SAE.

an elective treatment of or an elective procedure for a pre-existing condition, 
unrelated to the studied indication, that has not worsened from baseline. 

emergency outpatient treatment or observation that does not result in admission, 
unless fulfilling other seriousness criteria above.
If an AE is considered serious, both the AE page/screen of the eCRF and the SAE Report Form 
must be completed.
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For each SAE, the Investigator will provide information on severity, start and stop dates, 
relationship to the luspatercept, action taken regarding the luspatercept, and outcome.
10.2.2.
Severity/Intensity
For both AEs and SAEs, the Investigator must assess the severity/intensity of the event. 
The severity/intensity of AEs will be graded based upon the subject’s symptoms according to the 
current active minor version of the Common Terminology Criteria for Adverse Events (CTCAE, 
version 4.03);
https://evs.nci.nih.gov/ftp1/CTCAE/About.html
Adverse events (AEs) that are not defined in the CTCAE should be evaluated for 
severity/intensity according to the following scale:

Grade 1 = Mild – transient or mild discomfort; no limitation in activity; no medical 
intervention/therapy required

Grade 2 = Moderate – mild to moderate limitation in activity, some assistance may be 
needed; no or minimal medical intervention/therapy required

Grade 3 = Severe – marked limitation in activity, some assistance usually required; 
medical intervention/therapy required, hospitalization is possible

Grade 4 = Life-threatening – extreme limitation in activity, significant assistance 
required; significant medical intervention/therapy required, hospitalization or hospice 
care probable

Grade 5 = Death - the event results in death
The term “severe” is often used to describe the intensity of a specific event (as in mild, moderate 
or severe myocardial infarction); the event itself, however, may be of relatively minor medical 
significance (such as severe headache).  This criterion is not the same as “serious” which is 
based on subject/event outcome or action criteria associated with events that pose a threat to a 
subject’s life or functioning.  
Seriousness, not severity, serves as a guide for defining regulatory obligations.
10.2.3.
Causality
The Investigator must determine the relationship between the administration of luspatercept and 
the occurrence of an AE/SAE as Not Suspected or Suspected as defined below:
Not suspected:
a causal relationship of the adverse event to luspatercept
administration is unlikely or remote, or other medications, 
therapeutic interventions, or underlying conditions provide a 
sufficient explanation for the observed event.
Suspected:
there is a reasonable possibility that the administration of 
luspatercept caused the adverse event.  ‘Reasonable possibility’ 
means there is evidence to suggest a causal relationship between 
the luspatercept and the adverse event.
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Causality should be assessed and provided for every AE/SAE based on currently available 
information.  Causality is to be reassessed and provided as additional information becomes 
available.
If an event is assessed as suspected of being related to a comparator, ancillary or additional 
luspatercept that has not been manufactured or provided by Celgene, please provide the name of 
the manufacturer when reporting the event.
10.2.4.
Duration
For both AEs and SAEs, the Investigator will provide a record of the start and stop dates of the 
event.
10.2.5.
Action Taken
The Investigator will report the action taken with luspatercept as a result of an AE or SAE, as 
applicable (eg, discontinuation, interruption, or dose reduction of luspatercept, as appropriate) 
and report if concomitant and/or additional treatments were given for the event. 
10.2.6.
Outcome
The Investigator will report the outcome of the event for both AEs and SAEs.
All SAEs that have not resolved upon discontinuation of the subject’s participation in the study 
must be followed until recovered (returned to baseline), recovered with sequelae, or death (due to 
the SAE).
10.3.
Adverse Events of Special Interest
The occurrence of a new malignancy or premalignant lesion will be monitored as an event of 
special interest and should be included as part of the assessment of adverse events throughout the 
course of the study. Investigators are to report the development of any new malignancy or 
premalignant lesion as a serious adverse event, regardless of causal relationship to IP, occurring 
at any time for the duration of the study, from the time of signing the ICF up to and including at 
least 5 years following the date of first dose of IP or 3 years post last dose of IP of the 
Posttreatment Follow-up Period, whichever occurs later.
Events of new malignancy and premalignant lesions (excluding benign tumors or benign 
neoplasia) are to be reported within 24 hours of the Investigator’s knowledge of the event by fax, 
or other appropriate method, using the SAE Report Form, and must be considered an “Important 
Medical Event” even if no other serious criteria apply; these events must also be documented in 
the appropriate page(s) of the eCRF and subject’s source documents. Documentation of the 
diagnosed malignancy must be provided at the time of reporting as a serious adverse event (eg, 
any confirmatory histology or cytology results, x-rays, computed tomography [CT] scans, etc.).
Malignancies or cancerous tumors are lesions capable of invading into adjacent tissues and may 
be capable of spreading to distant tissues.  A benign tumor has none of those properties.
Malignancy or cancer is characterized by anaplasia, invasiveness, and metastasis.  For MPN-
associated myelofibrosis studies, these also include transformation to blast phase, 
myeloproliferation (eg, clinically significant increases in blasts), etc.
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Premalignant or precancerous lesions refer to a state of disordered morphology of cells that is 
associated with an increased risk of cancer.  If left untreated, these conditions may lead to 
cancer.  Such conditions are usually either dysplasia or benign neoplasia (and the dividing line 
between those is sometimes blurry).  Sometimes the term "precancer" is used to describe 
carcinoma in situ, which is a noninvasive cancer that has not progressed to an aggressive, 
invasive stage.  Not all carcinoma in situ will progress to invasive disease.
Premalignant lesions are morphologically atypical tissue which appears abnormal under 
microscopic examination and in which cancer is more likely to occur than in its apparently 
normal counterpart.
10.4.
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 luspatercept dose, or any other 
therapeutic intervention; or

is judged to be of significant clinical importance, eg, one that indicates a new disease 
process and/or organ toxicity, or is an exacerbation or worsening of an existing 
condition.
Regardless of severity grade, only laboratory abnormalities that fulfill a seriousness criterion 
need to be documented as a serious adverse event.
If a laboratory abnormality is one component of a diagnosis or syndrome, then only the diagnosis 
or syndrome should be recorded on the AE page/screen of the eCRF.  If the abnormality was not 
a part of a diagnosis or syndrome, then the laboratory abnormality should be recorded as the AE. 
If possible, the laboratory abnormality should be recorded as a medical term and not simply as an 
abnormal laboratory result (eg, record thrombocytopenia rather than decreased platelets).
10.5.
Pregnancy
All pregnancies or suspected pregnancies occurring in either a female subject of childbearing 
potential or partner of childbearing potential of a male subject are immediately reportable events.  
10.5.1.
Females of Childbearing Potential:
Pregnancies and suspected pregnancies (including elevated β-hCG or positive pregnancy test in a 
female subject of childbearing potential regardless of disease state) occurring while the subject is 
on luspatercept, or within 12 weeks of the subject’s last dose of luspatercept, are considered 
immediately reportable events.  Luspatercept is to be discontinued immediately. The pregnancy, 
suspected pregnancy, or positive pregnancy test must be reported to Celgene Drug Safety 
immediately by email, phone or facsimile, or other appropriate method, using the Pregnancy 
Initial Report Form, or approved equivalent form.  
The female subject may be referred to an obstetrician-gynecologist or another appropriate 
healthcare professional for further evaluation.
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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 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 luspatercept should also be reported 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.
10.5.2.
Male Subjects
If a female partner of a male subject taking luspatercept becomes pregnant, the male subject 
taking luspatercept should notify the Investigator, and the pregnant female partner should be 
advised to call their healthcare provider immediately.  
Males will be advised to use a latex condom during any sexual contact with FCBP prior to study 
entry and continue for 12 weeks following the last dose of luspatercept, even if he has undergone 
a successful vasectomy.
10.6.
Reporting of Serious Adverse Events
Any AE that meets any criterion for an SAE requires the completion of an SAE Report Form in 
addition to being recorded on the AE page/screen of the eCRF.  All SAEs must be reported to 
Celgene Drug Safety and Medical Monitor within 24 hours of the Investigator’s knowledge of 
the event by facsimile, or other appropriate method (eg, via email), 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 are accurate and consistent.  
This requirement applies to all SAEs (regardless of relationship to luspatercept) that occur during 
the study (from the time the subject signs informed consent until 42 days after the last dose of 
luspatercept) or any SAE made known to the Investigator at any time thereafter that are 
suspected of being related to luspatercept.  Serious adverse events occurring prior to treatment 
(after signing the ICF) will be captured.
The SAE report should provide a detailed description of the SAE and include a concise summary 
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 should 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 Institutional 
Review Board/Ethics Committee (IRB/EC) of the SAE and providing them with all relevant 
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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.
In addition, any report of transformation to blast phase or AML, regardless of causality, will be 
reported as an expedited safety report to the regulatory authorities, if requested.
10.6.1.
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.
10.7.
Expedited Reporting of Adverse Events
For the purpose of regulatory reporting, Celgene Drug Safety will determine the expectedness of 
events suspected of being related to luspatercept based on the IB.
In the United States, all suspected unexpected serious adverse reactions (SUSARs) 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, SUSARs in accordance with Directive 2001/20/EC and the Detailed 
Guidance on collection, verification and presentation of adverse reaction reports arising from 
clinical trials on 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 luspatercept 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 
these new serious and unexpected AE(s) or significant risks to subjects.
The Investigator must keep copies of all pertinent safety information on file including 
correspondence with Celgene and the IRB/EC.  (See Section 14.3 for record retention 
information).
Celgene Drug Safety Contact Information:
For Celgene Drug Safety contact information, please refer to the Serious Adverse Event Report 
Form Completion Guidelines or to the Pregnancy Report Form Completion Guidelines.
10.8.
Monitoring of Toxicity and Study Stopping Rules
Adverse events occurring in the study are monitored continuously by Celgene. 
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When more than three such adverse events of a particular type (preferred term) are reported this 
will be addressed by the Celgene Safety Management Team and will be brought to the attention 
of the Study Steering Committee.
Excessive toxicity in the context of this study is defined as a rate of treatment-emergent Grade 3 
or above serious adverse events assessed by investigator or Celgene as related to luspatercept of 
20% or higher. 
If the posterior probability of the toxicity rate exceeding 20% is greater than 0.8, then further 
subject enrollment will be put on hold and after assessment of the findings by the Celgene Safety 
Management Team and the Study Steering Committee study treatment for all ongoing subjects 
receiving luspatercept might be stopped early. 
For the subject on ongoing treatment and additional enrollment of subjects into Cohort 3B the 
following stopping rule will apply, accounting for the subjects already enrolled in the study. This 
assumes a relatively weak prior distribution of Beta (1/3, 1/3) for toxicity rate, which will allow 
the accruing data on toxicities to dominate. This prior is also ‘neutral’ in the sense that the 
maximum likelihood estimate of toxicity rate is approximately at the posterior median (Kerman, 
2011).
Number of Subjects
Number of Subjects with Toxicities Required 
to Stop Study
1-75
Not applicable
76-79
19
80-84
20
85-88
21
89-93
22
94-98
23
99-102
24
103-107
25
108-111
26
112-116
27
117-120
28
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11.
DISCONTINUATIONS
11.1.
Treatment Discontinuation
Subjects will have an End of Treatment (EOT) Visit at the time of luspatercept discontinuation
(refer to Section 6.4 for more information).  All subjects who received at least one dose of 
luspatercept will be followed for at least 3 years post last dose of luspatercept.
The following events are considered sufficient reasons for discontinuing a subject from the 
investigational product(s):

Adverse Event

Withdrawal by subject

Death

Lost to follow up

Pregnancy

Protocol violation/deviation

Study terminated by Sponsor 

Disease progression of MPN-associated myelofibrosis according to IWG-MRT
criteria, defined as:
o
Appearance of a new splenomegaly that is palpable at least 5 cm below the left 
costal margin (LCM);
o
A ≥100% increase in palpable distance, below LCM, for baseline splenomegaly 
of 5 to 10 cm;
o
A 50% increase in palpable distance, below LCM, for baseline splenomegaly of >
10 cm; 
o
Transformation to blast phase confirmed by a bone marrow blast count of ≥20%
or a blood myeloblast percentage of ≥20% associated with a blast count of ≥1 x
109/L that lasts for at least 2 weeks.  

≥ 2 dose reductions suspected related AE 

Dose delay lasting > 12 consecutive weeks

Requiring a medication/procedure on the prohibited medication/procedure list (refer 
to Section 8.2 for more information

Other (to be specified on the eCRF and in the protocol)
o
Including treatment discontinuation guidance related to dose modifications (refer 
to Section 7, Table 5)
o
Clinical benefit criteria (refer to Section 6.2.2 for more information) 
The reason for discontinuation of treatment should be recorded in the eCRF and in the source 
documents.
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The decision to discontinue a subject from treatment remains the responsibility of the treating 
physician, which will not be delayed or refused by the Sponsor.  However, prior to discontinuing 
a subject, the Investigator may contact the Medical Monitor and forward appropriate supporting 
documents for review and discussion.
All subjects discontinued from luspatercept for any reason will have EOT evaluations at the time 
of discontinuation, outlined in Section 6.4.  Subsequently, subjects would then move into the 
Posttreatment Follow-up Period, consisting of a 42-Day Follow-up Period and Long-term 
Follow-up Period (refer to Section 6.5).
11.2.
Study Discontinuation
Subjects who discontinue from treatment for any reason will be followed via telephone contact 
by the site for collection of data on survival, cause(s) of death, transformation to blast phase, and
posttreatment therapies for MPN-associated myelofibrosis during the 42-Day Follow-up Period.  
During the Long-term Follow-up Period time points, collection of data on posttreatment 
therapies for MPN-associated myelofibrosis, survival, cause(s) of death, and transformation to 
blast phase will occur every 3 months after the 42-Day Follow-up Period for at least 3 years after 
the last dose of luspatercept or until death, lost to follow up, or withdrawal of consent from the 
study.
Every attempt should be made to contact subjects during follow up unless subjects discontinue
from the study. Every attempt should be made to collect all data on discontinued subjects.
The following events are considered sufficient reasons for discontinuing a subject from the 
study:

Screen failure

Adverse events 

Withdrawal by subject

Death

Lost to follow up

Protocol violation/deviation

Study terminated by Sponsor 

Other (to be specified on the eCRF)
The reason for study discontinuation should be recorded in the eCRF and in the source 
documents.
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12.
EMERGENCY PROCEDURES
12.1.
Emergency Contact
In emergency situations, the Investigator should contact the responsible Clinical Research 
Physician/Medical Monitor or designee by telephone at the number(s) listed on the Emergency 
Contact Information page of the protocol (after title page).  Following the phone discussion with 
the Clinical Research Physician/Medical Monitor, a courtesy email can be sent to the study 
Medical Monitor Mailbox to alert the full study team and for action on any additional follow-up 
items.  
In the unlikely event that the Clinical Research Physician/Medical Monitor or designee cannot be 
reached, please contact the global Emergency Call Center by telephone at the number listed on 
the Emergency Contact Information page of the protocol (after title page). This global 
Emergency Call Center is available 24 hours a day and 7 days a week. The representatives are 
responsible for obtaining your call-back information and contacting the on-call Celgene/contract 
research organization Medical Monitor, who will then contact you promptly.
Note: The back-up 24-hour global emergency contact call center should only be used if you are 
not able to reach the Clinical Research Physician(s) or Medical Monitor or designee for 
emergency calls. 
12.2.
Emergency Identification of Investigational Products
This is an open-label study; therefore, luspatercept will be identified on the package labeling.
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13.
REGULATORY CONSIDERATIONS
13.1.
Good Clinical Practice
The procedures set out in this study protocol pertaining to the conduct, evaluation, and 
documentation of this study are designed to ensure that Celgene, its authorized representative, 
and Investigator abide by Good Clinical Practice (GCP), as described in International Council for
Harmonisation (ICH) Guideline E6 and in accordance with the general ethical principles outlined 
in the Declaration of Helsinki. The study will receive approval from an IRB/EC prior to 
commencement. The Investigator will conduct all aspects of this study in accordance with 
applicable national, state, and local laws of the pertinent regulatory authorities.
13.2.
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, 
including obligations of confidentiality of Celgene information. The Investigator should 
maintain a list of Sub-investigators and other appropriately qualified persons to whom he or she 
has delegated significant study-related duties.
The Investigator is responsible for keeping a record of all subjects who sign an informed consent 
form (ICF) and are screened for entry into the study.  Subjects who fail screening must have the 
reason(s) recorded in the subject’s source documents.
The Investigator, or a designated member of the Investigator’s staff, must be available during 
monitoring visits to review data, resolve queries and allow direct access to subject records (eg, 
medical records, office charts, hospital charts, and study-related charts) for source data 
verification.  The Investigator must ensure timely and accurate completion of eCRFs and queries.
The information contained in the protocol and amendments (with the exception of the 
information provided by Celgene on public registry websites) is considered Celgene confidential 
information.  Only information that is previously disclosed by Celgene on a public registry 
website may be freely disclosed by the Investigator or its institution, or as outlined in the Clinical 
Trial Agreement.  Celgene protocol, amendment and IB information is not to be made publicly 
available (for example on the Investigator’s or their institution’s website) without express written 
approval from Celgene.  Information proposed for posting on the Investigator’s or their 
institution’s website must be submitted to Celgene for review and approval, providing at least 5 
business days for review.
At the time results of this study are made available to the public, Celgene will provide 
Investigators with a summary of the results that is written for the lay person. The Investigator is 
responsible for sharing these results with the subject and/or their caregiver as agreed by the 
subject.
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13.3.
Subject Information and Informed Consent
The Investigator must obtain informed consent of a subject and/or a subject’s legal representative 
prior to any study related procedures.
Documentation that informed consent occurred prior to the study subject’s entry into the study 
and of the informed consent process should be recorded in the study subject’s source documents 
including the date.  The original ICF signed and dated by the study subject and by the person 
consenting the study subject prior to the study subject’s entry into the study, must be maintained 
in the Investigator’s study files and a copy given to the study subject.  In addition, if a protocol is 
amended and it impacts on the content of the informed consent, the ICF must be revised.  Study 
subjects participating in the study when the amended protocol is implemented must be re-
consented with the revised version of the ICF.  The revised ICF signed and dated by the study 
subject and by the person consenting the study subject must be maintained in the Investigator’s 
study files and a copy given to the study subject.
13.4.
Confidentiality
Celgene affirms the subject's right to protection against invasion of privacy and to be in 
compliance with ICH and other local regulations (whichever is most stringent). Celgene requires 
the Investigator to permit Celgene's representatives and, when necessary, representatives from 
regulatory authorities, to review and/or copy any medical records relevant to the study in 
accordance with local laws.
Should direct access to medical records require a waiver or authorization separate from the 
subject’s signed ICF, it is the responsibility of the Investigator to obtain such permission in 
writing from the appropriate individual.
13.5.
Protocol Amendments
Any amendment to this protocol must be initiated only by Celgene and approved by the Celgene 
Clinical Research Physician/Medical Monitor.  Amendments will be submitted to the IRB/EC for 
written approval.  Written approval must be obtained before implementation of the amended 
version occurs.  The written signed approval from the IRB/EC should specifically reference the 
Investigator name, protocol number, study title and amendment number(s) that is applicable. 
Amendments that are administrative in nature do not require IRB/IEC approval but will be 
submitted to the IRB/IEC for information purposes.
13.6.
Institutional Review Board/Independent Ethics Committee Review 
and Approval
Before the start of the study, the study protocol, ICF, and any other appropriate documents will 
be submitted to the IRB/EC with a cover letter or a form listing the documents submitted, their 
dates of issue, and the site (or region or area of jurisdiction, as applicable) for which approval is 
sought. If applicable, the documents will also be submitted to the authorities in accordance with 
local legal requirements.
Luspatercept 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 
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by Celgene or its authorized representative. This documentation must also include a list of the 
members of the IRB/EC and their occupation and qualifications. If the IRB/EC will not disclose 
the names, occupations and qualifications of the committee members, it should be asked to issue 
a statement confirming that the composition of the committee is in accordance with GCP. For 
example, the IRB General Assurance Number may be accepted as a substitute for this list. 
Formal approval by the IRB/EC should mention the protocol title, number, amendment number 
(if applicable), study site (or region or area of jurisdiction, as applicable), and any other 
documents reviewed. It must mention the date on which the decision was made and must be 
officially signed by a committee member. Before the first subject is enrolled in the study, all 
ethical and legal requirements must be met.
The IRB/EC and, if applicable, the authorities, must be informed of all subsequent protocol 
amendments in accordance with local legal requirements. Amendments must be evaluated to 
determine whether formal approval must be sought and whether the ICF should also be revised.
The Investigator must keep a record of all communication with the IRB/EC and, if applicable, 
between a Coordinating Investigator and the IRB/EC. This statement also applies to any 
communication between the Investigator (or Coordinating Investigator, if applicable) and 
regulatory authorities.
Any advertisements used to recruit subjects for the study must be reviewed by Celgene and the 
IRB/EC prior to use.  
13.7.
Ongoing Information for Institutional Review Board/ Ethics 
Committee
If required by legislation or the IRB/EC, the Investigator must submit to the IRB/EC:

Information on serious or unexpected adverse events as soon as possible; 

Periodic reports on the progress of the study;

Deviations from the protocol or anything that may involve added risk to subjects.
13.8.
Termination of the Study
Celgene reserves the right to terminate this study prematurely at any time for reasonable medical 
or administrative reasons. Any premature discontinuation will be appropriately documented 
according to local requirements (eg, IRB/EC, regulatory authorities, etc.).
The Sponsor may consider closing this trial when data supporting key endpoints and objectives 
of the study have been analyzed.  In the case where there are subjects still being administered 
luspatercept, and it is the opinion of the Investigator(s) that these subjects continue to receive 
benefit from treatment, the Sponsor may choose to initiate a roll-over or extension study under a 
separate protocol, if applicable, to allow these subjects continued access to luspatercept 
following their participation in the ACE-536-MF-001 study.
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;
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
GCP noncompliance;

Inaccurate or incomplete data collection;

Falsification of records;

Failure to adhere to the study protocol.
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14.
DATA HANDLING AND RECORDKEEPING 
14.1.
Data/Documents
The Investigator must ensure that the records and documents pertaining to the conduct of the 
study and the distribution of the investigational product are complete, accurate, filed and 
retained.  Examples of source documents include: hospital records; clinic and office charts; 
laboratory notes; memoranda; subject’s diaries or evaluation checklists; subject questionnaires; 
dispensing records; recorded data from automated instruments; copies or transcriptions certified 
after verification as being accurate copies; microfiche; x-ray film and reports; and records kept at 
the pharmacy, and the laboratories, as well as copies of eCRFs or CD-ROM.
14.2.
Data Management
Data will be collected via eCRF and entered into the clinical database per Celgene standard 
operating procedures (SOPs). This data will be electronically verified through the 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 as necessary.  Resolutions 
to these issues will be reflected in the database.  An audit trail within the system will track all 
changes made to the data.
14.3.
Record Retention
Essential documents must be retained by the Investigator according to the period of time outlined 
in the clinical trial agreement. The Investigator must retain these documents for the time period 
described above or according to local laws or requirements, whichever is longer. Essential 
documents include, but are not limited to, the following:

Signed ICFs for all subjects;

Subject identification code list, screening log (if applicable), and enrollment log;

Record of all communications between the Investigator and the IRB/EC;

Composition of the IRB/EC;

Record of all communications between the Investigator, Celgene, and their authorized 
representative(s);

List of Sub-investigators and other appropriately qualified persons to whom the 
Investigator has delegated significant study-related duties, together with their roles in 
the study, curriculum vitae, and their signatures;

Copies of eCRFs and of documentation of corrections for all subjects;

Luspatercept accountability records;

Record of any body fluids or tissue samples retained;

All other source documents (subject records, hospital records, laboratory records, 
etc.); 
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
All other documents as listed in Section 8 of the ICH consolidated guideline on GCP 
(Essential Documents for the Conduct of a Clinical Trial).
The Investigator must notify Celgene if he/she wishes to assign the essential documents to 
someone else, remove them to another location or is unable to retain them for a specified period.  
The Investigator must obtain approval in writing from Celgene prior to destruction of any 
records. If the Investigator is unable to meet this obligation, the Investigator must ask Celgene 
for permission to make alternative arrangements. Details of these arrangements should be 
documented. 
All study documents should be made available if required by relevant health authorities. 
Investigator or institution should take measures to prevent accidental or premature destruction of 
these documents.
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15.
QUALITY CONTROL AND QUALITY ASSURANCE
All aspects of the study will be carefully monitored by Celgene or its authorized representative 
for compliance with applicable government regulations with respect to current GCP and SOPs.
15.1.
Study Monitoring and Source Data Verification
Celgene ensures that appropriate monitoring procedures are performed before, during and after 
the study.  All aspects of the study are reviewed with the Investigator and the staff at a study 
initiation visit and/or at an Investigators’ Meeting.  Prior to enrolling subjects into the study, a 
Celgene representative will review the protocol, eCRFs, procedures for obtaining informed 
consent, record keeping, and reporting of AEs/SAEs with the Investigator.  Monitoring will 
include on-site visits with the Investigator and his/her staff as well as any appropriate 
communications by mail, email, fax, or telephone.  During monitoring visits, the facilities, 
investigational product storage area, eCRFs, subject’s source documents, and all other study 
documentation will be inspected/reviewed by the Celgene representative in accordance with the 
Study Monitoring Plan.
Accuracy will be checked by performing source data verification that is a direct comparison of 
the entries made onto the eCRFs against the appropriate source documentation.  Any resulting 
discrepancies will be reviewed with the Investigator and/or his/her staff.  Any necessary 
corrections will be made directly to the eCRFs or via queries by the Investigator and/or his/her 
staff. Monitoring procedures require that informed consents, adherence to inclusion/exclusion 
criteria and documentation of SAEs and their proper recording be verified.  Additional 
monitoring activities may be outlined in a study-specific monitoring plan.
15.2.
Audits and Inspections
In addition to the routine monitoring procedures, a Good Clinical Practice Quality Assurance 
unit exists within Celgene.  Representatives of this unit will conduct audits of clinical research 
activities in accordance with Celgene SOPs to evaluate compliance with Good Clinical Practice 
guidelines and regulations.
The Investigator is required to permit direct access to the facilities where the study took place, 
source documents, eCRFs and applicable supporting records of study subject participation for 
audits and inspections by IRB/ECs, regulatory authorities (eg, 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.
15.3.
Product Quality Complaint
A Product Quality Complaint (PQC) is any written, electronic, or oral communication that 
alleges deficiencies related to the identity, quality, durability, reliability, safety, effectiveness, 
purity, or performance of any drug product manufactured by or on behalf of Celgene Corporation 
after it is released for distribution.  PQCs may reduce the usability of the product for its intended 
function or affect performance of the product and therefore pose a significant risk to the subject.  
Examples of PQCs include (but are not limited to): mixed product, mislabeling, lack of effect, 
seal/packaging breach, product missing/short/overage, contamination, suspected falsified, 
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tampered, diverted or stolen material, and general product/packaging damage. If you become 
aware of a suspected PQC, you are obligated to report the issue immediately.  You can do so by 
emailing 
 or by contacting the Celgene Customer Care Center 
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16.
PUBLICATIONS
As described in Section 13.2, all protocol- and amendment-related information, with the 
exception of the information provided by Celgene on public registry websites, is considered 
Celgene confidential information and is not to be used in any publications.  Celgene protocol-
related information proposed for use in a publication must be submitted to Celgene for review 
and approval, and should not be utilized in a publication without express written approval from 
Celgene, or as described in the Clinical Trial Agreement.
Celgene will ensure Celgene-sponsored studies are considered for publication in the scientific 
literature in a peer-reviewed journal, irrespective of the results.  At a minimum, this applies to 
results from all Phase 3 clinical studies, and any other study results of significant medical 
importance.  This also includes results relating to investigational medicines whose development 
programs have been discontinued.
Study results may also be presented at one or more medical congresses, and may be used for 
scientific exchange and teaching purposes.  Additionally, this study and its results may be 
submitted for inclusion in all appropriate health authority study registries, as well as publication 
on health authority study registry websites, as required by local health authority regulations.
Eligibility for external authorship, as well as selection of first authorship, will be based on 
several considerations, including, but not limited to, contribution to protocol development, study 
recruitment, data quality, participation in data analysis, participation in study steering committee 
(when applicable) and contribution to abstract, presentation and/or publication development.
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17.
REFERENCES
 
 
  
Arber D, Orazi A, Hasserjian R, Thiele J, Borowitz M, Le Beau M, et al. The 2016 revision to 
the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 
2016;127(20):2391-405.  
Barosi G, Liberato LN, Guarnone R. Serum erythropoietin in patients with myelofibrosis with 
myeloid metaplasia. Br J Haematol. 1993;83:365-9.  
Barosi G, Magrini U, Gale RP.  Does Auto-Immunity Contribute to Anemia in 
Myeloproliferative Neoplasms (MPN)-Associated Myelofibrosis? Leuk Res. 2010;34(9):1119-
20.
 
 
Bose P, Daver N, Jabbour EJ, Pike A, Newberry KJ, Zhou L, et al. Phase-2 study of sotatercept 
(ACE-011) in myeloproliferative neoplasm-associated myelofibrosis and anemia. Blood. 
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Branda R, Amsden T, Jacob H. Randomized study of nandrolone therapy for anemias due to 
bone marrow failure. Arch Intern Med. 1977;137:65-9.
Brubaker L, Brière J, Laszlo J, Kraut E, Landaw S, Peterson P, et. al. Treatment of anemia in 
myeloproliferative disorders: a randomized study of fluoxymesterone v transfusions only. Arch 
Intern Med. 1982;142:1533-7.
Cappellini MD, Viprakasit V, Taher A, Georgiev P, Kuo KHM, Coates TD, et al. The Believe 
Trial: results of a Phase 3, randomized, double-blind, placebo-controlled study of luspatercept in 
adult beta-thalassemia patients who require regular red blood cell (RBC) transfusions. Blood, 
2018;132(Suppl 1):163.
  
  
Cervantes F, Alvarez-Larran A, Hernandez-Boluda JC, Sureda A, Torrebadell M, Montserrat E. 
Erythropoietin treatment of the anaemia of myelofibrosis with myeloid metaplasia: results in 20 
patients and review of the literature. Br J Haematol. 2004;127:399-403.
Cervantes F, Alvarez-Larran A, Domingo A, Arellano-Rodrigo E, Montserrat E. Efficacy and 
tolerability of danazol as a treatment for the anaemia of myelofibrosis with myeloid metaplasia: 
long-term results in 30 patients. Br J Haematol. 2005;129:771–5.
Cervantes F, Alvarez-Larran A, Hernandez-Boluda JC, Sureda A, Granell M, Vallansot R, et al. 
Darbepoetin-alpha for the anaemia of myelofibrosis with myeloid metaplasia. Br J Haematol.  
2006;134:184–6.
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Cervantes F, Dupriez B, Pereira A, Passamonti F, Reilly J, Morra E, et al. New prognostic 
scoring system for primary myelofibrosis based on a study of the International Working Group 
for Myelofibrosis Research and Treatment. Blood. 2009;113:2895-901.
Cervantes F, Isola I, Alvarez-Larran A, Hernandez-Boluda JC, Correa JG, Pereira A. Danazol 
therapy for the anemia of myelofibrosis: assessment of efficacy with current criteria of response 
and long-term results. Ann Hematol. 2015;94:1791-6.  
Dupriez B, Morel P, Demory JL, Lai JL, Simon M, Plantier I, et al. Prognostic factors in 
agnogenic myeloid metaplasia: a report on 195 cases with a new scoring system. Blood. 
1996;88:1013-8.
Dussiot M, Maciel T, Fricot A, Chartier C, Negre O, Veiga J, et al. An activin receptor IIA 
ligand trap corrects ineffective erythropoiesis in β-thalassemia. Nat Med. 2014;20(4):398-407.
Elena C, Passamonti F, Rumi E, Malcovati L, Arcaini L, Boveri E, et al. Red blood cell 
transfusion-dependency implies a poor survival in primary myelofibrosis irrespective of IPSS 
and DIPPS. Haematologica. 2011;96(1):167-70.
Fenaux P, Platzbecker U, Mufti G, Garcia-Manero G, Buckstein R, Santini V, et al. The Medalist 
Trial: results of a Phase 3, randomized, double-blind, placebo-controlled study of luspatercept to 
treat anemia in patients with very low-, low-, or intermediate-risk myelodysplastic syndromes 
(MDS) with ring sideroblasts (RS) who require red blood cell (RBC) transfusions. Blood, 
2018;132(Suppl 1):1.
Huang J, Tefferi A. Erythropoiesis stimulating agents have limited therapeutic activity in 
transfusion-dependent patients with primary myelofibrosis regardless of serum erythropoietin 
level. Eur J Haematol. 2009;83(2):154-5.  
Kerman J. Neutral noninformative and informative conjugate beta and gamma prior 
distributions. Electronic Journal of Statistics. 2011;5:1450-70.
  
Lévy V, Bourgarit A, Delmer A, Legrand O, Baudard M, Rio B, Zittoun R. Treatment of 
agnogenic myeloid metaplasia with danazol: a report of four cases. Am J Hematol. 1996;53:239-
41.
Massague J. TGF-β signal transduction. Annu Rev Biochem. 1998;67:753-91.  
Moulard O, Mehta J, Fryzek J, Olivares R, Iqbal U, Mesa R. Epidemiology of myelofibrosis, 
essential thrombocythemia, and polycythemia vera in the European Union. Eur J Haematol. 
2013;92:289-97.
Odenike O, Tefferi A. Conventional and new treatment options for myelofibrosis with myeloid
metaplasia. Semin Oncol. 2005;32:422-31.  
Oken M, Creech R, Tormey D, Horton J, Davis TE, McFadden E, et al. Toxicity and response 
criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 1982;5(6):649-55.
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Passamonti F, Cervantes F, Vannucchi A, Morra E, Rumi E, Pereira A, et al. A dynamic 
prognostic model to predict survival in primary myelofibrosis: a study by the IWG-MRT 
(International Working Group for Myeloproliferative Neoplasms Research and Treatment).
Blood. 2010;115:1703-8.  
Piga A, Perrotta S, Melpignano A, Borgna-Pignatti C, Gamberini R, Voskaridou E, et al. 
Luspatercept (ACE-536) increases hemoglobin and decreases transfusion burden and liver iron 
concentration in adults with beta-thalassemia: preliminary results from a Phase 2 study 
[abstract]. Presented at: The 58th Annual Meeting of the American Society of Hematology (ASH) 
and Exposition: 2016; San Diego, CA; USA. Abstract 851.
Platzbecker U, Germing U, Götze K, Kiewe P, Wolff T, Mayer K, et al. Luspatercept increases 
hemoglobin and reduces transfusion burden in patients with low-intermediate risk 
myelodysplastic syndromes (MDS): long-term results from Phase 2 PACE-MDS study. Blood. 
2016;128(22), 3168.
Quintas-Cardama A, Kantarjian H, Pierce S, Cortes J, Verstovsek S. Prognostic model to identify 
patients with myelofibrosis at the highest risk of transformation to acute myeloid leukemia. Clin 
Lymphoma Myeloma Leuk. 2013;13(3):315-8.  
Rodriguez JN, Martino ML, Dieguez JC, Prados D.  rHuEpo for the treatment of anemia in 
myelofibrosis with myeloid metaplasia. Experience in 6 patients and meta-analytical approach. 
Haematologica. 1998;83:616–21.
Schlenk RF, Stegelmann F, Reiter A, Jost E, Gattermann N, Hebart H, et al. Pomalidomide in 
myeloproliferative neoplasm-associated myelofibrosis. Leukemia. Advance online publication 
29 November 2016;1-7.  
Shantzer L, Berger K, Pu J. Primary myelofibrosis and its targeted therapy. Ann Hematol. 
2016;96(4):531-5.  
Suragani R, Cadena S, Cawley S, Sako D, Mitchell D, Li R, et al. Transforming growth factor-β
superfamily ligand trap ACE-536 corrects anemia by promoting late-stage erythropoiesis. Nat 
Med. 2014;20(4):408-14.  
Tefferi A, Huang J, Schwager S, Li CY, Wu W, Pardanani A, et al. Validation and comparison 
of contemporary prognostic models in primary myelofibrosis: analysis based on 334 patients 
from a single institution. Cancer. 2007;109:2083-8.
Tefferi A, Skoda R, Vardiman JW. Myeloproliferative neoplasms: contemporary diagnosis using 
histology and genetics. Nat Rev Clin Oncol. 2009;6:627-37.  
Tefferi A, Cervantes F, Mesa R, Passamonti F, Verstovsek S, Vannucchi A, et al. Revised 
response criteria for myelofibrosis: International Working Group-Myeloproliferative Neoplasms 
Research and Treatment (IWG-MRT) and European LeukemiaNet (ELN) consensus report.
Blood. 2013;122(8):1395-8.
Tefferi A, Al-Ali HK, Barosi G, Devos T, Gisslinger H, Jiang Q, et al. A randomized study of 
pomalidomide vs placebo in persons with myeloproliferative neoplasm-associated myelofibrosis 
and RBC-transfusion-dependence. Leukemia. 2017;31(4):896-902. 
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Tsiara SN, Chaidos A, Bourantas LK, Kapsali HD, Bourantas KL. Recombinant human 
erythropoietin for the treatment of anaemia in patients with chronic idiopathic myelofibrosis.  
Acta Haematol. 2007;117:156-61.
 
 
  
 
  
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18.
APPENDICES
Appendix A: Table of Abbreviations
Abbreviation or 
Specialist Term
Explanation
ActRIIB
Activin receptor type IIB
ADA
Antidrug antibodies
AE
Adverse event
ALT
Alanine transaminase (SGPT)
AST
Aspartate aminotransferase (SGOT)
AUC
Area under the curve
β-hCG
β-subunit of human chorionic gonadotropin
BMP6, BMP9
Bone morphogenetic protein 6, bone morphogenetic protein 9
CALR
Calreticulin 
CRF
Case report form
CT
Computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
ECG
Electrocardiogram
EEA
European Economic Area
EMA
European Medicines Agency
FACT-An
Functional Assessment of Cancer Therapy – Anemia 
FCBP
Female of childbearing potential
FDA
Food and Drug Administration
GDF11
Growth differentiation factor 11
GCP
Good Clinical Practice
G-CSF
Granulocyte colony-stimulating factor
GM-CSF
Granulocyte macrophage colony-stimulating factor 
HepB
Hepatitis B
HepC
Hepatitis C
Hgb
Hemoglobin
HI-E
Hematologic improvement – erythroid response 
HIV
Human immunodeficiency virus
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Abbreviation or 
Specialist Term
Explanation
HRQoL
Health-related quality of life
IB
Investigator’s Brochure
ICF
Informed consent form
ICH
International Council for Harmonisation
ICT
Iron chelation therapy
Ig
Immunoglobulin
IL
Interleukin
IRB
Institutional Review Board
IRT
Integrated Response Technology
ITT
Intent-to-treat
IWG
International Working Group
IWG-MRT
International Working Group – Myeloproliferative Neoplasms Research 
and Treatment 
JAK
Janus kinase
JAK2
Janus kinase 2 gene 
LCM
Left costal margin
LTFU
Long-term follow-up
MDRD
Modification of diet in renal disease 
MDS
Myelodysplastic syndrome
MedDRA
Medical Dictionary for Regulatory Activities
MPL
Thrombopoietin receptor 
MPN
Myeloproliferative neoplasm 
MPN-SAF TSS
Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom 
Score 
NCI
National Cancer Institute
NTD
Non-transfusion dependent
Post-ET MF
Post-essential thrombocythemia myelofibrosis
Post-PV MF
Post-polycythemia vera myelofibrosis
PV
Polycythemia vera
RBC
Red blood cell 
RBC-TI
Red blood cell – transfusion independence 
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Abbreviation or 
Specialist Term
Explanation
RNA 
Ribonucleic acid 
SAE
Serious adverse event
SAP
Statistical analysis plan
SC
Steering committee
SGOT
Serum glutamic oxaloacetic transaminase 
SGPT
Serum glutamic pyruvic transaminase
SOP
Standard operating procedure
SUSAR
Suspected unexpected serious adverse reaction
TD
Transfusion-dependent
TGF-β
Transforming growth factor-beta
TSS
Total symptom score 
ULN
Upper limit of normal
WBC
White blood count
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Appendix B: Eastern Cooperative Oncology Group (ECOG) Performance 
Status Scale
The ECOG scale (Oken, 1982) is used to assess a subject’s quality of life in an evaluation by a 
health professional of the daily activities and how the activities are affected by the disease of the 
subject.  
Eastern Cooperative Oncology Group (ECOG) Performance Status
Grade
ECOG
0
Fully active, able to carry on all pre-disease performance without restriction.
1
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or 
sedentary nature, eg, light house work, office work.
2
Ambulatory and capable of all selfcare but unable to carry out any work activities.  Up and about 
more than 50% of waking hours.
3
Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours.
4
Completely disabled.  Cannot carry on any selfcare.  Totally confined to bed or chair.
5
Dead.
Source:  Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity and response criteria of the 
Eastern Cooperative Oncology Group. Am J. Clin Oncol 1982; 5(6):649-55.
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Appendix C: National Cancer Institute (NCI) Common Terminology Criteria 
for Adverse Events (CTCAE), Version 4.03
Currently active minor version of NCI CTCAE, version 4.03:
https://evs.nci.nih.gov/ftp1/CTCAE/About.html
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Celgene Signing Page
This is a representation of an electronic record that was signed electronically in Livelink.
This page is the manifestation of the electronic signature(s) used in compliance with
the organizations electronic signature policies and procedures.
UserName: 
Title:  
Date: Sunday, 23 February 2020, 04:03 PM   Eastern Daylight Time
Meaning: Approved, no changes necessary.
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Luspatercept (ACE-536)
Protocol ACE-536-MF-001
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ACE-536-MF-001 Amendment 4 Final: 19 Feb 2020
1.
JUSTIFICATION FOR AMENDMENT
The following change was made to the protocol as subjects on luspatercept therapy continue to 
demonstrate clinical benefit while on study treatment in the absence of any significant safety 
signals.  To enable long-term access to luspatercept therapy (provided subjects continue to 
demonstrate clinical benefit as assessed by the Investigator and do not meet any protocol 
treatment discontinuation criteria), the Extension Phase has been extended beyond 2 years.
Significant changes included in this amendment are summarized below:

Prolongation of Extension Phase of the Treatment PeriodThe primary purpose of 
this protocol amendment is to amend the 2-year study treatment limit for subjects in 
the Extension Phase of the Treatment Period to extend beyond 2 years for those that
continue to receive benefit according to investigator assessment (eg, ≥50% reduction
of transfusion burden from baseline).Revised sections: Protocol Summary, Section
3.1, Section 3.2, Section 6.2.2, Section 6.2.3, and Section 9.2 The amendment also 
includes several other minor clarifications and corrections:Correction of 
Column Header and diagram text for Figure 2 in Section 3.1: wording added to 
indicate Treatment Period may extend past 2 years from C1D1 date. Clarification 
made to Section 9.2: text that mentioned that subjects who are not efficacy evaluable 
will be scored as nonresponders was removed. Clarification made to Section 10: 
Removed and consolidated Section 10.6 “Other Malignancies/Premalignancies” with
Section 10.3 “Adverse Events of Special Interest” as these sections contained 
duplicate information pertaining to “Other Malignancies/Premalignancies.”Added 
Section 15.3: provided contact information for product quality complaints for drug 
products manufactured by Celgene CorporationOther additional administrative 
changes (ie, spelling, grammatical error corrections, etc.) were also made throughout 
the document.
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Luspatercept (ACE-536)
Summary of Changes ACE-536-MF-001
Celgene Corporation
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ACE-536-MF-001 Amendment 3 Final: 01 Aug 2019
1.
JUSTIFICATION FOR AMENDMENT
Significant changes included in the amendment are summarized below.  The following changes 
were made to provide a more accurate estimate of the luspatercept treatment effect to enable 
effective planning of a future potential Phase 3 study.  

Expansion of Cohort 3 enrollment

Expand total enrollment of Cohort 3B by approximately 27 subjects for an 
approximate total of 46 subjects.  This would result in an approximate total of 60 
subjects in Cohort 3 and an approximate total study enrollment of 100 subjects.  

Revised sections: Protocol Summary, Section 3.1, Section 4.1, Section 9.2, 
Section 9.3

Modifying Cohorts 2 and 3B inclusion criterion

Update inclusion criterion to enable subjects with a transfusion burden defined as 
4 to 12 RBC units/84 days, with no interval > 56 days between RBC transfusions
to collect additional data on subjects with a lower transfusion burden.  

Revised section: Section 1.4.2, Section 4.2

Statistical considerations supporting Cohort 3 expansion

Sample size and power calculations have been incorporated to justify expansion 
of Cohort 3B. 

Revised section: Protocol Summary, Section 9.3

Addition of secondary endpoint to assess mean hemoglobin increase 

Update to protocol to include an additional secondary endpoint to analyze the 
mean hemoglobin increase of ≥ 1.5 g/dL from baseline over any consecutive 84-
day period without an RBC transfusion that will be assessed for Cohort 1 and 3A 
subjects, calculated from Day 1 through and including Day 168 and Day 1 
through end of treatment. 
 

Revised sections: Protocol Summary, Section 2 (Tables 1 and 2), Section 9.6.2
Additional significant changes made to the protocol are described below. 
 
 
  
Furthermore, language has been incorporated that reflects implementation of an approved roll-
over study that subjects in the parent protocol may transition over to if eligible.  

Modifying dose titration criteria

For subjects in any cohort who may start to demonstrate a loss of response as 
defined as a Hgb decrease of ≥ 1 g/dL (not influenced by an RBC transfusion), the 
dose level may be increased by 1 dose level. 
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Luspatercept (ACE-536)
Summary of Changes ACE-536-MF-001
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ACE-536-MF-001 Amendment 3 Final: 01 Aug 2019

For subjects in Cohorts 2 and 3B whose Hgb is not exceeding 1 g/dL increase 
from the baseline mean pretransfusion Hgb value (calculated using the reported 
RBC transfusions that confirmed the eligibility of the subject), the dose level may 
be increased by 1 dose level   

Revised section: Section 7.3.1 

Adapting clinical benefit criteria to allow subjects to continue in the Extension 
Phase 

Added additional wording that would allow subjects to continue receiving 
luspatercept therapy if, in the assessment of the Investigator, the subject is 
benefiting from treatment not necessarily reflected by the protocol’s clinical 
benefit criteria (eg, clinically significant reduction of the transfusion burden or 
clinically significant improvement of a subject’s symptom burden) and that these 
cases would be discussed with the Medical Monitor.

Revised sections: Section 3.1, Section 6.2.2

Addition of language supporting the ACE-536-LTFU-001 roll-over study

As the ACE-536-LTFU-001 roll-over study has been implemented, language has 
been added that when applicable, any subject remaining on the ACE-536-MF-001 
study may be consented and transition over to the new roll-over study to continue 
to receive access to luspatercept and/or complete posttreatment follow up 
requirements.   

Revised section: Figure 2, Section 3.3 
Another significant change made to the protocol includes a starting dose of 1.33 mg/kg and can
dose titrate up to a maximum dose of 1.75 mg/kg, with a total dose not to exceed 168 mg) for the 
additional Cohort 3B subjects that are enrolled.
 
 
 
 
 
 
 
 
 

New starting dose level of 1.33 mg/kg 

Additional language has been provided that denotes subjects enrolling into Cohort 
3B due to Protocol Amendment 3 will start a luspatercept dose of 1.33 mg/kg and 
can have their dose increased to a maximum dose of 1.75 mg/kg (with the total 
dose not to exceed 168 mg).  

Revised sections: Protocol Summary, 
, Section 3.1, Section 7.2, 
Section 7.3, Section 7.3.1, Section 9.2
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Summary of Changes ACE-536-MF-001
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ACE-536-MF-001 Amendment 3 Final: 01 Aug 2019
The following changes were made in response to a regulatory agency request received from the 
FDA for IND 112,562 on 04 Jun 2019.  

Amended Exclusion Criterion #3 for ruxolitinib dosing in Cohort 3
‒
In addition to the original Exclusion Criterion #3 requiring subjects to be on a 
stable daily dose of ruxolitinib for at least 112 days (16 weeks), Exclusion 
criterion #3 was amended to signify that Cohort 3 subjects are also required to 
have at least 280 days (40 weeks) of ruxolitinib dosing without interruptions 
exceeding 2 weeks consecutively leading up to the date of enrollment also.
‒
Revised sections: Protocol Summary, Section 3.1, Section 4.3, Section 9.2

Added Section 10.9 Monitoring of Toxicity and Study Stopping Rules
This amendment also includes additional minor clarifications and corrections:  

Inclusion of updated luspatercept Phase 3 results to Section 1.3.2 and Section 17: 
data from the Phase 3 MEDALIST and BELIEVE studies have been incorporated along 
with their applicable references. 

Clarification of capturing RBC transfusion information in Table 3, Section 6.1, 
6.2.1, Section 6.2.2, Section 6.2.3, Section 6.4, and Section 6.5.1: when applicable, 
additional language has been incorporated to ensure all subjects (regardless if local 
procedures are in place) will receive a transfusion diary to collect pertinent information 
regarding transfusions given outside the study site.  Furthermore, appropriate source 
documentation for historical transfusions or transfusions given while subject is on study 
must be available for source document verification. 

Modification and clarification of the length of study duration in the Protocol 
Summary section: enrollment timelines reflecting Cohort 3 expansion have been 
implemented in the overall study duration timelines, as well as clarifying expected time 
on study for an individual subject and the expected total study duration.

Updated references in Section 17: several references were updated/modified with more 
recent publication information available; one reference was removed due to the 
referenced text being deleted from the protocol.  

Other additional administrative changes (ie, spelling, grammatical error corrections, etc.) 
were also made throughout the document.
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Luspatercept (ACE-536)
Summary of Changes ACE-536-MF-001
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3
ACE-536-MF-001 Amendment 2 Final: 18 Dec 2018
1.
JUSTIFICATION FOR AMENDMENT
Significant changes included in the amendment are summarized below.
 
 
 additional criteria for dose adjustments has been introduced: 
-
Dose delay for worsening by ≥ 2 grades for leukopenia, neutropenia, or 
thrombocytopenia to ≥ Grade 3 that is not clearly and solely related to an extraneous case 
such as advancing myeloproliferative neoplasm-associated myelofibrosis or an infectious 
event
-
Dose delay for worsening of anemia in presence of unexplained shift (worsening) from 
baseline of ≥ 2 grades for leukopenia, neutropenia, or thrombocytopenia
Revised section: Section 7.3.2 (Table 5)
This amendment also includes additional minor clarifications and corrections:  

 
 
 
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Luspatercept (ACE-536)
Summary of Changes ACE-536-MF-001
Celgene Corporation
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3
ACE-536-MF-001 Amendment 1 Final: 21 Mar 2018
1.
JUSTIFICATION FOR AMENDMENT
Significant changes included in the amendment following the recommendation from the study’s 
Steering Committee from a 12 Jan 2018 meeting are summarized below.
 
  

Addition of exclusion criterion for a white blood count threshold 
o
Update to the protocol to exclude subjects in screening with a white blood count 
> 100 x 109/L.  
o
Revised section: Section 4.3

Addition of exclusion criterion for a platelet count threshold 
o
Update to the protocol to exclude subjects in screening with a platelet count 
> 1000 x 109/L.
o
Revised section: Section 4.3
Additional significant changes agreed upon by the Steering Committee Chair on 31 Jan 2018 
included in the amendment are described below.  
 
 

Addition of exclusion criterion for subjects on anticoagulant therapy who are not 
under appropriate control or not on a stable dose of anticoagulant therapy for ≥ 8 
weeks up to the enrollment date
o
Update to the protocol to exclude subjects on anticoagulant therapy who may not 
be under appropriate control or subjects not on a stable dose of anticoagulant 
therapy for ≥ 8 weeks up to the enrollment date.
o
Revised section: Section 4.3

Addition of exclusion criterion for subjects on anagrelide within 28 days 
immediately up to the enrollment date
o
Update to the protocol to exclude subjects on anagrelide within 28 days prior to 
the enrollment date. 
o
Revised sections: Section 4.3, Section 8.2

Addition of exclusion criterion for subjects with a major bleeding event in the last 6
months prior to enrollment
o
Update to the protocol to exclude subjects with a major bleeding event (defined as 
symptomatic bleeding in a critical area or organ and/or bleeding causing a fall in 
hemoglobin of ≥ 2 g/dL or leading to transfusion of ≥ 2 units of packed red cells) 
within the last 6 months prior to enrollment.   
o
Revised section: Section 4.3
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EDMS Doc. Number: 22595378 - 22596095
Luspatercept (ACE-536)
Summary of Changes ACE-536-MF-001
Celgene Corporation
Confidential and Proprietary
4
ACE-536-MF-001 Amendment 1 Final: 21 Mar 2018
Additional significant changes that were included in the amendment:

Addition of secondary endpoint to capture changes in hemoglobin over the study 
compared to baseline in the absence of red blood cell (RBC) transfusions
o
Update to the protocol to include an additional secondary endpoint to analyze in 
Cohorts 1 and 3A subjects the changes in hemoglobin over the course of the study 
compared to baseline in the absence of RBC transfusions starting from Day 1 
through and including Day 168 and Day 1 through end of treatment.
o
Revised sections: Protocol Summary, Section 2 (Table 2), Section 9.6.2

Addition of minimum number of days between hemoglobin assessments as outlined 
within Inclusion Criterion 3A
o
Update to the protocol to include a minimum number of 14 days between 
hemoglobin assessments within the 84-day period immediately up to the Cycle 1
Day 1 date when evaluating the hemoglobin baseline to ensure that subjects with 
persistent anemia are enrolled. 
o
Revised section: Section 4.2

Modified protocol criteria related to dose modification (dose delay, dose reductions, 
and discontinuation) measures to account for elevated white blood counts at the day 
of dosing 
o
Update to the protocol to include additional white blood count parameters at the 
day of dosing to guide dosing decisions.  In addition to the ≥ 3 x baseline and 
≥30 x 109/L white blood count parameters, a white blood count of ≥ 120 x 109/L 
would also result in a dose delay to account for subjects with an elevated white 
blood count at baseline.  
o
Revised section: Section 7.3.2 (Table 5)
This amendment also includes several other minor clarifications and corrections:  

Administrative change in the Celgene Therapeutic Area Head signature: required 
signature has been updated from 
 to 
.  

Administrative change to Section 1.3.2: number of patients and affiliated percentages 
have been provided for the response rates for the luspatercept Phase 2 clinical studies.

Administrative change to Section 4.2: most recent local bone marrow biopsy report 
should confirm diagnosis of myeloproliferative neoplasm-associated myelofibrosis 
according to the World Health Organization 2016 criteria (Arber, 2016).

 
 

Clarification regarding implementation of MPN-SAF TSS questionnaire: as the 
MPN-SAF TSS questionnaire has been confirmed over the MPN-SAF v4, language in the 
protocol has been updated to reflect this. 
Approved
2.0
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Approved
1.0
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EDMS Doc. Number: 22595378 - 22596095
Luspatercept (ACE-536)
Summary of Changes ACE-536-MF-001
Celgene Corporation
Confidential and Proprietary
5
ACE-536-MF-001 Amendment 1 Final: 21 Mar 2018

Removal of posttransfusion hemoglobin collection: as we are no longer collecting this 
information for the study, all references to posttransfusion hemoglobin collection in the 
protocol have been removed.  

Clarification to assessments required prior to luspatercept administration: white 
blood counts and blood myeloblast percentage, in addition to hemoglobin and blood 
pressure, must be assessed prior to luspatercept dosing.  This change has been reflected in 
the protocol.  

Clarification to secondary endpoint (frequency of RBC transfusions): time duration 
has been updated from 4 weeks to 28 days to remain consistent with eligibility average of 
RBC transfusions.

Other additional administrative changes (ie, spelling, grammatical error corrections, etc.) 
were also made throughout the document.
Approved
2.0
v
Approved
1.0
v