Clinical trial NCT00931606
Conditions: Chemotherapy Induced Anemia
Keywords: anemia metastatic breast cancer
Sponsor: Merck Sharp & Dohme LLC
Start date: 2009-06-01; Completion date: 2010-11-18
Enrollment: 30 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the percentage of participants in each sotatercept dose regimen who achieve a hematopoietic response during the treatment period including up to 2 months after the last dose of sotatercept treatment of chemotherapy-induced anemia (CIA) in participants with metastatic breast cancer. Hematopoietic response was defined as an increase in hemoglobin concentration of ≥ 1 g/dL relative to baseline for 28 consecutive days during the treatment period including up to 2 months after the last dose of sotatercept in the absence of red blood cell (RBC) transfusion or treatment with an erythropoiesis-stimulating agent (ESA).

Detailed description:

Arms: arm 1: Participants will receive sotatercept 0.1 mg/kg subcutaneously every 28 days up to 4 doses. arm 2: Participants will receive sotatercept 0.3 mg/kg subcutaneously every 28 days up to 4 doses. arm 3: Participants will receive sotatercept 0.5 mg/kg subcutaneously every 28 days up to 4 doses. arm 4: Participants will receive placebo subcutaneously every 28 days up to 4 doses.
Interventions: intervention 1: Sotatercept intervention 2: Placebo
Intervention descriptions: intervention 1: up to 4 subcutaneous doses of sotatercept given once every 28 days intervention 2: up to 4 subcutaneous doses of placebo given once every 28 days

Protocol documents:
Prot_000.pdf: 
Official Protocol Title:
NCT number:
NCT00931606
Document Date:
A Phase 2, Double-Blind, Randomized,
Placebo-Controlled Study of ACE-011 for the
Treatment of Chemotherapy Induced Anemia in
Patients with Metastatic Breast Cancer
13-Mar-2009


   CLINICAL STUDY PROTOCOL 
A Phase 2, Double-Blind, Randomized, Placebo-Controlled 
Study of ACE-011 for the Treatment of Chemotherapy Induced 
Anemia in Patients with Metastatic Breast Cancer 
STUDY DRUG:
ACE-011 
PROTOCOL NUMBER: 
 
A011-08 
SPONSOR: 
      Acceleron Pharma, Inc. 
            128 Sidney Street 
            Cambridge, MA 02139  
MEDICAL MONITOR: 
 PPD Inc. 
PROTOCOL DATE: 
 13 March 2009 
Confidentiality Statement 
This confidential information in this document is provided to you as an investigator or consultant for review by you, your staff, 
and the applicable institutional Review Board/Independent Ethics Committee.  Your acceptance of this document constitutes 
agreement that you will not disclose the information contained herein to others without written authorization from the Sponsor. 
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PROCEDURES IN CASE OF EMERGENCY 
 
Table 1: 
Emergency Contact Information 
Role in Study 
Name 
Address and Telephone number 
PPD Medical Monitor 
PPD Inc. 
1800 Perimeter Park Drive,  Suite 275 
Morrisville, NC 27560-7200 USA 
Clinical Trial Manager 
Acceleron Pharma, Inc. 
128 Sidney Street  
Cambridge, MA 02139 USA  
 
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2. 
PROTOCOL SYNOPSIS 
Name of Sponsor/Company:  Acceleron Pharma, Inc. 
 
 
 
 
                          128 Sidney Street 
 
 
 
 
                          Cambridge, MA 02139 
Name of Investigational Product: ACE-011 
Name of Active Ingredient:   
ACE-011 is a fully human fusion protein consisting of the extracellular domain (ECD) of the 
activin receptor IIA (ActRIIA) linked to the human IgG1 Fc domain.  
Mechanism of Action: ACE-011 is a disulfide-linked, glycosylated, dimeric protein. ACE-011 
competes with the activin receptor IIA that binds a number of TGF-β superfamily ligands 
including activin, myostatin (growth differentiation factor [GDF]-8), and GDF-11. 
Title of Study:  A Phase 2, Double-blind, Randomized, Placebo-Controlled Study of ACE-011 
for the Treatment of Chemotherapy Induced Anemia in Patients with Metastatic Breast 
Cancer. 
Study center(s): approximately 25-35 centers  
Phase of development: 2 
Objectives 
Primary:  
1. To evaluate the proportion of patients in each ACE-011 dose regimen who achieve a 
hematopoietic response during the treatment period including up to 2 months after the 
last dose of ACE-011 treatment of chemotherapy induced anemia in patients with 
metastatic breast cancer. 
Secondary: 
1. To evaluate the safety and tolerability of ACE-011 for the treatment of chemotherapy 
induced anemia in patients with metastatic breast cancer.  
2. To evaluate the percentage of patients who achieve an increase in hemoglobin of ≥ 1 
g/dL,  ≥ 2 g/dL and/or hemoglobin concentration ≥ 11 g/dL for 28 consecutive days 
during the treatment period including up to 2 months after the last dose of ACE-011 in 
the absence of any RBC transfusions and/or ESAs.   
3. To estimate the duration of the hematopoietic response associated with each ACE-011 
dose regimen. 
4. To estimate the time to the hematopoietic response associated with each ACE-011 dose 
regimen. 
5. To estimate the proportion of patients receiving red blood cell (RBC) transfusions 
and/or ESAs within each cycle of ACE-011 with each dose regimen. 
 
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6. To estimate the effect of each ACE-011 dose regimen on progression free survival 
(PFS) and objective response rate (ORR). 
Exploratory objectives: 
1. To estimate the effect of each ACE-011 dose regimen on serum bone biomarkers (OC, 
BSAP, PINP, CTX, TRACP-5b), urine bone biomarker (uNTX), bone mineral density 
(DXA scans of lumbar spine and hip) and incidence of skeletal related events (SREs). 
2. To evaluate the quality of life during the study in relation to the treatment of 
chemotherapy induced anemia in patients with metastatic breast cancer during the 
study. 
Methodology: This is a Phase 2, double-blind, randomized, placebo controlled study to 
evaluate the efficacy, safety, and tolerability of ACE-011 for the treatment of chemotherapy 
induced anemia in patients with metastatic breast cancer. Patients will be randomized to one of 
three treatment arms or placebo: 
 
1. ACE-011 0.1 mg/kg subcutaneously (SC) every 28 days for up to 4 doses. 
2. ACE-011 0.3 mg/kg SC every 28 days for up to 4 doses.  
3. ACE-011 0.5 mg/kg SC every 28 days for up to 4 doses. 
4. Placebo SC every 28 days for up to 4 doses. 
 
  
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Number of patients (planned): 105 patients 
Diagnosis and main criteria for inclusion 
 
Inclusion Criteria: 
1. Women > 18 years of age. 
2. Histologically confirmed diagnosis of breast cancer documented by cytology or biopsy. 
3. Evidence of metastatic breast cancer with a minimum of one measurable lesion or non 
measurable lesion per RECIST criteria (Appendix 1). 
4. Receiving a multicycle myelosuppressive chemotherapy regimen including one of the 
following: anthracycline, taxane, gemcitabine or vinorelbine. 
5. Planned treatment with the same myelosuppressive chemotherapy regimen for a minimum 
of 9 weeks after Day 1 of ACE-011/placebo administration.  
6. Hemoglobin value between ≥ 6.5 to < 11.0 g/dL (≥ 65 to < 110 g/L).  
7. ≥ 30 days must have elapsed (from Day 1) since previous treatment with erythropoiesis-
stimulating agent (including concurrent treatment with IV iron) for chemotherapy induced 
anemia.  
8. ≥ 7 days have elapsed (from Day 1) since the last RBC blood transfusion and receipt of ≤ 2 
units of blood in the past 30 days.  
9. ECOG Performance status of 0 – 2 (Appendix 2). 
10. Adequate renal (creatinine ≤ 1.5 x ULN or creatinine clearance ≥ 40 mL/min) and hepatic 
function (bilirubin < 1.5 x ULN; AST/ALT < 2.5 x ULN). 
11. Females of childbearing potential  participating in the study are to use adequate birth 
control measures (i.e. oral contraceptives or two forms of barrier method birth control) 
during study participation. Females of childbearing potential must have a negative serum 
pregnancy test within 3 days to ACE-011/placebo administration (Day 1). A female of 
childbearing potential is a sexually mature woman who has not undergone a hysterectomy 
or who has not been postmenopausal for at least 24 consecutive months (i.e. who has had 
menses at some time in the preceding 24 months). 
12. Life expectancy of ≥ 6 months. 
13. Is willing to adhere to the study visit schedule, understand and comply with all protocol 
requirements. 
14. Understand and sign a written informed consent. 
 
 
 
 
 
 
 
 
 
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Exclusion Criteria: 
1. At the time of screening patients who have any grade > 3 toxicity (as per NCI CTCAE 
v3.0 (Appendix 3)) (except for the following disease related toxicities:  hematological 
events- anemia, thrombocytopenia or neutropenia or non hematological events- nausea, 
vomiting, fatigue, or muscle or bone/joint pain).  
2. Prior radiation therapy to > 20% of the whole skeleton. Use of palliative radiation if the 
area being treated is <15% of body surface area with no pelvic radiation or no more than 
10% of the bone marrow reserve is radiated is permitted during patient participation in the 
study, at the discretion of the investigator. 
3. Have received more than 5 prior chemotherapy treatment regimens for metastatic breast 
cancer.  
4. Concurrent use of bevacizumab with the chemotherapy regimen during study participation. 
5. Clinically significant pulmonary, endocrine, neurologic, gastrointestinal, hepatic or 
genitourinary disease unrelated to underlying hematologic disorder.  
6. Patients with heart failure as classified by the New York Heart Association (NYHA) 
classification of 3 or higher (Appendix 4). 
7. History of thrombosis, deep vein thrombosis (DVT), pulmonary emboli, or embolic stroke. 
8. Untreated CNS metastases (exception: CNS metastases treated with whole brain 
radiotherapy > 6 months prior to randomization). 
9. Diagnosis of a myeloid malignancy or known history of myelodysplasia.  
10. History of second malignancy within 5 years (except excised and cured basal cell 
carcinoma, squamous cell carcinoma of the skin or cervical carcinoma in situ).  
11. Patients with a recent history (within 14 days of Day 1) of administration of systemic (IV 
or oral) antibiotics. Patients should be free of infection at least 14 days after the last dose 
of systemic antibiotic treatment (from Day 1). 
12. Uncontrolled hypertension. If hypertension is considered clinically stable, systolic blood 
pressure (BP) must be < 150 mmHg and diastolic BP must be < 100 mmHg.  
13. Known history of hepatitis C antibody (HCV), hepatitis B surface antigen (HBsAg and HB 
core Ab), or human immunodeficiency virus (HIV) antibody.   
14. Deficiency in iron (serum ferritin < 100 ng/mL (< 224.7 pmol/L)), vitamin B12, or folate. 
15. History of anemia as a result of inherited hemoglobinopathy such as sickle cell anemia or 
thalassemia.  
16. History of autoimmune or hereditary hemolysis or gastrointestinal bleeding. 
17. Patient received treatment with another investigational drug or device within 1 month prior 
to Day 1, or if the half life of the previous product is known, within 5 times the half life 
prior to dosing, whichever may be longer.  
18. Pregnant or lactating females. 
19. History of severe allergic or anaphylactic reactions or hypersensitivity to recombinant 
proteins or excipients in the investigational product.    
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Investigational product, dosage and mode of administration:  
ACE-011/placebo will be administered as a SC injection, approximately every 28 days, on 
days 1, 29, 57, and 85 of the treatment period.  Each patient will be randomized to one of three 
treatment arms or placebo: 
 
 
 
 
 
 
 
 
 
ACE-011/placebo dose modification rules are based on hemoglobin values and blood pressure 
measurements during each treatment cycle. ACE-011/placebo dose interruption and dose 
reduction rules will be implemented for those patients with hemoglobin of ≥ 11 g/dL, an 
increase of ≥ 2 g/dL/ 28 days, or hypertension ≥ Grade 2 within each cycle (see Figure 1). 
Dose  
Number of  Patients 
0.1 mg/kg 
30 
0.3 mg/kg 
30 
0.5 mg/kg 
30 
Placebo 
15 
Total patients enrolled: 105 
Duration of study: Patients will be followed for a minimum of 7 months following their last 
dose of study drug. Study participation for each patient is approximately 10.5 months (14 day 
screening period, 3 month treatment period with a 2 month treatment follow up period, and a 5 
month post treatment follow-up period). The start date of the chemotherapy regimen used in 
this protocol to treat metastatic breast cancer will be recorded. If a patient begins a new 
chemotherapy regimen during the study, the patient will discontinue further ACE-011/placebo 
treatment and be followed for survival only. If a patient has a positive anti-drug antibody result 
at the Day 281/Termination visit, they may be asked to return to the clinical site for additional 
monthly repeat anti-drug antibody testing for up to 12 months.  The study is complete when 
the last patient enrolled has completed the last protocol required follow up visit. 
Criteria for evaluation 
Efficacy: The primary endpoint is to establish the proportion of patients who have a 
hematopoietic response of an increase in hemoglobin of ≥ 0.5 g/dL above the study baseline 
value for 28 consecutive days during the treatment period including up to 2 months after the 
last dose of ACE-011, in the absence of any RBC transfusions and/or ESAs.   
The proportion of patients with an increase in hemoglobin of ≥ 1g/dL, ≥ 2 g/dL and/or 
hemoglobin concentration ≥ 11 g/dL for 28 consecutive days during the treatment period up to 
2 months after the last dose of ACE-011 in the absence of any RBC transfusions and/or ESAs 
will be evaluated as a secondary efficacy endpoint. 
The hematopoietic endpoints will be determined by the monitoring of hematologic laboratory 
values, RBC transfusion and/or ESAs administration. The evaluation of response will be from 
the first dose of ACE-011 through 2 months after the last dose (for each patient).  Additional 
endpoints will be evaluated with the assessment of disease progression by CT/MRI and bone 
scan and bone mineral density by DXA scans.  Bone biomarkers will be evaluated in all 
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patients and incidence of SREs will be recorded, as applicable. SREs are defined as pathologic 
fracture, radiation therapy to bone, surgery to bone, or spinal cord compression. 
Safety: Throughout the study, safety will be evaluated by the sponsor, medical monitor and 
principal investigator.  Additionally, the DMC will review safety parameters for patients 
enrolled in the study. All patients will be assessed for safety by monitoring adverse events, 
clinical laboratory tests, and assessment of quality of life, vital signs and physical 
examinations on an ongoing basis.  ECGs will also be performed during screening, prior to 
dosing on the first and second cycle, Day 15, and Day 113 (28 days after the last dose of ACE-
011) and at Day 281/Termination visit to monitor safety.  Blood pressure and lab values will 
be assessed at each study visit; weekly for the first two treatment (dosing) periods and 
approximately every one to two weeks for subsequent treatment (dosing) periods.  
Pharmacokinetics: The blood samples will be collected at selected study sites from 
approximately one-third of patients for the evaluation of serum concentrations of ACE-011.  
Pre-dose PK samples will be collected on Day 1.  See Appendix 5 for PK sampling schedule. 
Statistical methods  
Sample size determination: With an anticipated dropout rate of 20%, a sample size of 30 
patients per dose level is planned to achieve at least 80% power with 2 sided significance level 
of 0.05 to differentiate targeted response rate of p1=0.45 from null hypothesis p0=0.20. An 
additional 15 patients will be enrolled into the placebo group for safety comparison. A total of 
105 patients will be randomized to three ACE-011 dose groups or placebo with a ratio of 
2:2:2:1. 
Efficacy analysis: The primary endpoint is the proportion of patients who have a 
hematopoietic response of an increase in hemoglobin of ≥ 0.5 g/dL for 28 consecutive days 
during the treatment period including up to 2 months after the last dose of ACE-011, in the 
absence of any RBC transfusions and/or ESAs. The proportion of responders will be 
determined together with 95% confidence interval.  
For binary endpoints, the proportion of responders and 95% confidence interval will be 
calculated. For time to event endpoints, the Kaplan-Meier method will be used to estimate the 
survival curve and median time to event.  Due to the nature of the study, no multiplicity 
adjustment will be made for efficacy analysis. 
Safety analysis: Data from all patients who receive at least one dose of ACE-011/placebo will 
be included in the safety analyses. To assess clinical safety, adverse events, vital sign 
measurements and clinical laboratory information will be summarized. Adverse events and 
laboratory results will also be summarized by severity grade (NCI CTCAE v3.0). Changes 
from baseline clinical laboratory values and vital signs will be summarized over time. 
Descriptive statistics and shift tables will be generated as appropriate.  
 
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3.
TABLE OF CONTENTS, LIST OF TABLES AND LIST OF
FIGURES
TABLE OF CONTENTS 
1.
TITLE PAGE................................................................................................................1 
2.
PROTOCOL SYNOPSIS .............................................................................................4 
3.
TABLE OF CONTENTS, LIST OF TABLES AND LIST OF FIGURES................12 
4.
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................18 
5.
INTRODUCTION......................................................................................................21
5.1. 
Indication and Rationale.............................................................................................21 
5.2. 
Description of ACE-011.............................................................................................21 
5.3. 
Activin Biology ..........................................................................................................22 
5.3.1. 
Pharmacology Studies ................................................................................................22 
5.3.2. 
Toxicology..................................................................................................................24 
5.4. 
Summary of Clinical Experience................................................................................25 
5.4.1. 
A011-01: A Phase 1a Study in Healthy Postmenopausal Women .............................25 
5.4.2. 
A011-02: A Phase 1b Study in Healthy Postmenopausal Women.............................26 
5.4.3. 
A011-04: A Phase 2a Study in Patients with Osteolytic Lesions of Multiple 
Myeloma.....................................................................................................................29 
5.5. 
Potential Risks for Human Use...................................................................................31 
6.
TRIAL OBJECTIVES AND PURPOSE....................................................................33 
6.1. 
Primary objective........................................................................................................33 
6.2. 
Secondary objectives ..................................................................................................33 
6.3. 
Exploratory objectives................................................................................................33 
7.
INVESTIGATIONAL PLAN.....................................................................................34 
7.1. 
Overall Study Design and Plan...................................................................................34 
8.
SELECTION AND WITHDRAWL OF PATIENTS.................................................38 
8.1. 
Number of Patients .....................................................................................................38 
8.2. 
Entry Criteria ..............................................................................................................38 
8.2.1. 
Patient Inclusion Criteria............................................................................................38 
8.2.2. 
Patient Exclusion Criteria...........................................................................................39 
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8.3. 
Patient Withdrawal Criteria........................................................................................40 
9.
TREATMENT OF PATIENTS..................................................................................41 
9.1. 
Concomitant Medications...........................................................................................41 
9.1.1. 
General Concomitant Medication Usage....................................................................41 
9.1.2. 
Concomitant treatment for anemia .............................................................................41 
9.1.2.1. 
Iron supplementation ..................................................................................................41 
9.1.2.2. 
Erythropoiesis-stimulating agents (ESAs)..................................................................41 
9.1.2.3. 
RBC Transfusions.......................................................................................................41 
9.2. 
Chemotherapy.............................................................................................................42 
9.3. 
Treatment Compliance................................................................................................42 
9.4. 
Randomization............................................................................................................42 
9.4.1. 
Blinding ......................................................................................................................42 
9.4.2. 
Unblinding..................................................................................................................42 
9.5. 
Treatments Administered............................................................................................43 
9.5.1. 
Selection of Doses in the Study..................................................................................43 
9.5.2. 
Selection and Timing of Dosing for Each Patient ......................................................43 
9.5.2.1. 
ACE-011 Dose Modification Rules............................................................................43 
10.
STUDY PROCEDURES AND SCHEDULE ............................................................46 
10.1.1. 
Written Informed consent...........................................................................................46 
10.1.2. 
Screening (Within 14 days of dosing) ........................................................................46 
10.1.3. 
Initial Dosing: Day 1 ..................................................................................................47 
10.1.4. 
ACE-011/placebo administration : Days 29, 57, and 85 (± 3 days)...........................48 
10.1.5. 
Additional visits during Treatment Period: Days 8, 15, 22, 36 (± 1 day), 43,  
64 and 71 (± 2 days) ...................................................................................................49 
10.1.6. 
Treatment Period Follow-up visits : Days 113 and 141 (± 7 days)............................50 
10.1.7. 
Post Treatment Period Follow-up visits : Days 169, 197, 225, and 253 (± 7 
days)............................................................................................................................51 
10.1.8. 
Termination Visit:  Day 281 (± 7 days)......................................................................51 
10.2. 
Discontinuation of study.............................................................................................52 
11. 
INVESTIGATIONAL PRODUCT MATERIALS AND MANAGEMENT.............53 
11.1. 
Reference Product.......................................................................................................53 
11.2. 
Investigational Product Packaging and Labeling .......................................................53 
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11.3. 
Investigational Product Storage..................................................................................53 
11.4. 
Investigational Product Preparation............................................................................53 
11.5. 
Administration............................................................................................................53 
11.6. 
Drug Accountability ...................................................................................................53 
11.7. 
Investigational Product Handling and Disposal .........................................................54 
12. 
ASSESSMENT OF EFFICACY ................................................................................55 
13. 
ASSESSMENT OF SAFETY.....................................................................................56 
13.1. 
Safety Parameters .......................................................................................................56 
13.1.1. 
Adverse Events...........................................................................................................56 
13.1.2. 
Clinical Laboratory Tests ...........................................................................................56 
13.1.3. 
Other Safety Assessments...........................................................................................57 
13.2. 
Pharmacokinetics........................................................................................................57 
14. 
ADVERSE EVENT....................................................................................................58 
14.1. 
Adverse Event Classification......................................................................................59 
14.2. 
Recording Adverse Events .........................................................................................59 
14.3. 
Reporting Adverse Events..........................................................................................60 
14.4. 
Emergency Sponsor Contact.......................................................................................61 
15. 
STATISTICS..............................................................................................................62 
15.1. 
Determination of Sample Size....................................................................................62 
15.2. 
Analysis Populations ..................................................................................................62 
15.3. 
Background and Demographic Characteristics ..........................................................62 
15.3.1. 
Patient Disposition......................................................................................................62 
15.3.2. 
ACE-011.....................................................................................................................63 
15.3.3. 
Concomitant Therapy .................................................................................................63 
15.4. 
Efficacy Evaluation ....................................................................................................63 
15.4.1. 
Primary Efficacy Analysis..........................................................................................63 
15.4.2. 
Secondary Efficacy Analyses .....................................................................................64 
15.5. 
Safety Evaluation........................................................................................................64 
15.6. 
Pharmacokinetic Evaluation.......................................................................................65 
15.6.1. 
Anti-drug Antibody Data............................................................................................65 
15.7. 
Interim Analysis..........................................................................................................65 
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15.8. 
Deviation from Original Analysis Plan ......................................................................65 
16. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................66 
16.1. 
Study Monitoring........................................................................................................66 
16.2. 
Audits and Inspections................................................................................................66 
17. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................67 
17.1. 
Data Quality Control and Quality Assurance.............................................................67 
17.1.1. 
Investigator responsibility ..........................................................................................67 
17.1.2. 
Protocol modifications................................................................................................67 
17.2. 
Financing and Insurance.............................................................................................67 
17.3. 
Confidentiality............................................................................................................67 
17.4. 
Publication Policy.......................................................................................................67 
17.5. 
Protocol Amendments ................................................................................................68 
18. 
ETHICS ......................................................................................................................69 
18.1. 
Institutional Review Board or Independent Ethics Committee ..................................69 
18.2. 
Ethical Conduct of the Study......................................................................................69 
18.3. 
Written Informed Consent..........................................................................................69 
18.3.1. 
Informed Consent .......................................................................................................69 
18.3.2. 
Patient Data Protection ...............................................................................................69 
19. 
DATA HANDLING AND RECORDKEEPING.......................................................70 
19.1. 
Case Report Form Completion...................................................................................70 
19.2. 
Retention of Records ..................................................................................................70 
20. 
REFERENCES ...........................................................................................................71 
21. 
APPENDICES............................................................................................................73 
 
  
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LIST OF TABLES 
Table 1: 
Emergency Contact Information...................................................................................3 
Table 2: 
Abbreviations and specialist terms .............................................................................18 
Table 3:      A011-02: A Phase 1b Study in Healthy Postmenopausal Women: Hemoglobin  
 Evaluation................................................................................................................... 27 
Table 4: 
A011-02: Incidence of Most Common Adverse Events.............................................28 
Table 5:      A011-02: A Phase 1b Study in Healthy Postmenopausal Women: BMD..................29 
Table 6: 
Study Design...............................................................................................................34 
Table 7: 
Schedule of Events .....................................................................................................36 
Table 8:      ACE-011/Placebo Dose Reduction Levels.................................................................45 
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LIST OF FIGURES 
Figure 1: ACE-011/Placebo Dose Modification Rules .....................................................44 
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4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
The following abbreviations and specialist terms are used in this study protocol. 
Table 2: 
Abbreviations and specialist terms  
Term 
Definition 
ACTH 
Adrenocorticotropic hormone 
ActRIIA 
Activin receptor IIA  
AE 
Adverse event 
ALT 
Alanine aminotransferase  
AST 
Aspartate aminotransferase  
AUC 
Area under the plasma concentration - time curve 
AUC(0-last) 
AUC from time 0 to time of last quantifiable sample  
AUC(0-∞) 
AUC extrapolated to infinity  
BMD 
Bone mineral density 
BP 
Blood pressure 
BSAP 
Bone specific alkaline phosphatase 
BUN 
Blood urea nitrogen 
CBC 
Complete Blood Count 
CFR 
Code of Federal Regulations (US) 
CH 
Constant domain 
CI 
Confidence interval 
CIA 
Chemotherapy induced anemia 
CL 
Clearance 
CL/F 
Total clearance 
Cmax 
Maximum observed concentration  
CNS 
Central nervous system 
CO2 
Carbon dioxide 
CRF 
Case report form 
CRO 
Clinical research organization 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTX 
Serum C-terminal type I collagen telopeptide 
DLT 
Dose-limiting toxicity 
DXA 
Dual-energy x-ray absorptiometry 
DMC 
Data Monitoring Committee 
DVT 
Deep vein thrombosis 
ECD 
Extracellular domain 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EDF 
Erythroid differentiation factor  
ESA 
Erythropoiesis-stimulating agents 
F 
Bioavailability (absolute) 
FACT 
Functional Assessment of Chronic Illness 
FDA 
Food and Drug Administration  
FSH 
Follicle-stimulating hormone 
GCP 
Good Clinical Practices 
GH 
Growth hormone 
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Term 
Definition 
HBV 
Hepatitis B virus 
Hct 
Hematocrit 
HCV 
Hepatitis C virus 
Hgb 
Hemoglobin 
HIV 
Human immunodeficiency virus 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug 
IP 
Intraperitoneal 
IRB 
Institutional Review Board 
IV 
Intravenous 
IVRS 
Interactive Voice Response System 
Kd 
Binding coefficient 
λz 
Elimination rate constant 
LDH 
Lactate dehydrogenase 
LH 
Luteinizing hormone 
MCH 
Mean corpuscular hemoglobin 
MCHC 
Mean corpuscular hemoglobin concentration 
MCV 
Mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MITT 
Modified Intent to Treat (population) 
MRI 
Magnetic resonance imaging 
NOAEL 
No adverse events level  
NYHA 
New York Heart Association 
OC 
Osteocalcin 
ORR 
Objective response rate 
OVX 
Ovariectomized 
PD 
Progressive disease 
PFS 
Progression free survival 
PHI 
Protected health information 
PINP 
Serum intact procollagen type I N terminal propeptide 
PK 
Pharmacokinetic 
PP 
Per-protocol (population) 
PT 
Prothrombin time 
PTH 
Parathyroid hormone 
PTT 
Partial thromboplastin time 
RAP-011 
Murine version of ACE-011, ActRIIA mFc 
RBC 
Red blood cell (count) 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SC 
Subcutaneous 
SERM 
Selective estrogen receptor modulator 
SHAM 
Sham-operated 
SPEP 
Serum protein electrophoresis 
SRE 
Skeletal-related event 
T1/2 
Elimination half-life  
TIBC 
Total iron binding capacity 
Tmax 
Time to Cmax 
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Term 
Definition 
TRACP-5b 
Serum tartrate-resistant acid phosphatase isoform-5b 
ULN 
Upper limit of normal 
Vz/F 
Volume of distribution 
WBC 
White blood cell (count) 
 
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5. 
INTRODUCTION 
5.1. 
Indication and Rationale 
This study is designed to evaluate the efficacy, safety, and tolerability of ACE-011 for the 
treatment of chemotherapy induced anemia in patients with metastatic breast cancer. 
Treatment of patients with metastatic breast cancer with myelosuppressive chemotherapy is 
frequently associated with anemia. Chemotherapy induced anemia (CIA) is a significant problem 
for patients with cancer, causing fatigue and reduced quality of life (1).  Patients with CIA are 
currently treated with blood transfusion and/or erythropoiesis-stimulating agents (2). However, 
with these treatment options CIA is still an area of unmet medical need. Erythropoiesis-
stimulating agents (ESAs) can successfully mitigate transfusion need in a proportion of these 
patients, but concerns have emerged regarding apparent negative effects on survival and/or tumor 
progression in certain patient populations. The murine surrogate to ACE-011, RAP-011, has been 
tested as a single agent in breast cancer cell lines MDA-MB-231 and MCF-7 and no effect on 
enhanced proliferation of these cell lines has been observed in vitro. Therefore, treatment with 
ACE-011 may provide a distinct benefit/risk profile to patients with chemotherapy induced 
anemia.  
In both a Phase 1 single dose and multiple dose study of ACE-011 in postmenopausal women, 
increases in hemoglobin and hematocrit were observed following ACE-011 treatment and 
remained elevated over the course of study.  The observed hemoglobin and hematocrit effects of 
ACE-011 were dose and time dependent.  Please refer to the Investigator Brochure for further 
information.  
Based on the effect of ACE-011 on hematopoiesis and consistent biological phenomena observed 
in both non clinical and clinical studies, it is hypothesized that the blockade of ActRIIA receptor 
signaling impedes the terminal differentiation step in erythropoiesis to allow additional rounds of 
cell replication before cells enter the final differentiation phase. The result is a substantial 
increase in mature erythrocytes released into the circulation.  Since this proposed mechanism is 
different to that of known ESAs, ACE-011 may provide a different clinical profile in the 
treatment of CIA.  
This study will provide information on the pharmacodynamics (PD) properties regarding the 
ability of ACE-011 to increase hemoglobin in patients with CIA. 
5.2. 
Description of ACE-011 
ACE-011 (ActRIIA-IgG1) is a fully human fusion protein consisting of the extracellular domain 
(ECD) of activin receptor IIA (ActRIIA) linked to the human IgG1 Fc domain, which includes 
the heavy chain hinge and constant domains, CH2 and CH3.  ACE-011 avidly binds to activin A 
with a binding coefficient (Kd) approximately 8.9 pM and prevents its binding to endogenous 
receptors, thereby inhibiting biological effects of activin.   
 
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5.3. 
Activin Biology 
Activin A was initially identified as a gonadal differentiation factor involved in modulating 
follicle stimulating hormone (FSH) secretion from the pituitary (3). Subsequently, the pleiotropic 
nature of activin A has become more apparent (4).   There is a growing body of data suggesting a 
role for activin A in bone remodeling, specifically as a negative regulator of bone growth (5).  
Before the two molecules were shown to be identical (6), activin A was also described as 
erythroid differentiation factor (EDF), effecting red blood cells in the later stages of maturation 
(7).  The mechanism(s) by which activin A influences erythropoiesis remain under investigation 
and, in fact, there are data from studies in vitro and in animals that support erythropoiesis-
stimulatory (8,9) and -inhibitory effects (10).   
At the cellular level, activin A binds initially to the high-affinity Type II receptor (ActRIIA).  The 
ligand-bound ActRIIA then recruits the low-affinity Type I receptor (ActRIA or ALK-4).  The 
receptor heterocomplex, through its cytoplasmic protein kinase activity, then activates the Smad 
signal cascade to eventually influence nuclear transcriptional factors (11, 12).  The competitive 
binding of activin A in the blood by the ACE-011 soluble fusion protein can result in inhibition 
of ActRIIA receptor signaling pathway by impeding biological processes attributed to activin A.  
Activin has also been attributed to erythroid differentiation and has been reported to have 
proerythrocytic effects and to induce terminal differentiation of RBCs.  Inhibition of activin may 
lead to increases in proliferation of the erythroid lineage.  Based on its pharmacologic effects, 
ACE-011 (ActRIIA-IgG1) is being developed for the treatment of bone loss associated with 
various disease states (e.g., osteoporosis and treatment of osteolytic lesions in patients with 
multiple myeloma), and treatment of anemia associated with a variety of disorders, such as 
chemotherapy induced anemia. 
The extracellular domain sequence of ActRIIA is completely conserved among numerous species 
including mouse, rat, cynomolgus monkey and humans, thus ACE-011 is active in these animals.  
However, in order to reduce the potential immunogenicity of the fully human molecule, ACE-
011, in mice and to maximize the opportunity to maintain exposures in chronic models, a murine 
surrogate molecule was constructed by exchanging the human immunoglobulin Fc sequence 
portion of ACE-011 with its murine IgG2a homolog.  The resultant construct is referred to as 
RAP-011 (ActRIIA-mIgG2aFc).   
5.3.1. 
Pharmacology Studies 
RAP-011 was evaluated in a broad range of animal pharmacology studies to assess the effects of 
inhibition of activin A on the biological processes attributed to that regulatory protein.  RAP-011 
has been shown to have significant effects on the red cell compartment.  RAP-011 treatment of 
mice at 10, 30 and 50 mg/kg by intraperitoneal injection (IP) twice per week for 3 months 
resulted in a 16-26% increase in red blood cell (RBC) counts compared to control animals.  Rats 
treated with RAP-011 at 0.3, 3 and 30 mg/kg once per week for 3 months showed RBC count 
increases of 6-15% over control animals.  Finally, in cynomolgus monkeys treated with 10, 30 or  
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50 mg/kg of ACE-011 twice per month for 3 months there was a 21- 24% increase in RBC counts 
compared to controls animals.  In this study, the RBC count increase was apparent as early as 2 
weeks following the initial dose of ACE-011.   
While the mechanism(s) underlying the stimulation effect of ACE-011 on erythropoiesis are not 
yet fully understood, it is hypothesized that a blockade of ActRIIA receptor signaling impedes the 
terminal differentiation step in erythropoiesis to allow additional rounds of erythroid cell 
replication before cells enter the terminal differentiation phase.  The result is a substantial 
increase in mature erythrocytes released into circulation.   
RAP-011 administered at 10 mg/kg to mice three days prior to administration of paclitaxel at 30 
mg/kg was sufficient to prevent decreases in red blood cell parameters seen three days later.  
Mice receiving paclitaxel alone had decreased hematocrit from 43% to 38% three days later.  
RAP-011 administered 3 days prior to paclitaxel injection was sufficient to keep the hematocrit 
above 42% at three days and up to two weeks after paclitaxel administration.  Therefore 
prophylactic treatment with RAP-011 was able to prevent paclitaxel induced anemia in mice. 
RAP-011 has also been shown to significantly increase bone mineral density and strength in 
normal animals and in a variety of animal models of bone loss (13, 14, 15).  In a murine 
ovariectomy (OVX)-induced model of osteopenia, RAP-011 (10 mg/kg IV, twice per week x 12 
weeks) increased trabecular BMD > 25% in 6-12 weeks compared to the phosphate buffered 
saline (PBS)-treated controls (p<0.002).  RAP-011 treatment was able to reverse the accelerated 
bone loss associated with ovariectomy.  As expected sham-operated (SHAM) mice (i.e., intact 
ovaries) started the study with a greater trabecular BMD than OVX mice.  PBS-treated SHAM 
mice showed a 10% decrease in trabecular BMD after 12 weeks of treatment compared to 
baseline, while SHAM-RAP-011 mice had a 32% increase in trabecular BMD over the same 
period.  These data demonstrate that RAP-011 is able to increase trabecular BMD in both the 
normal state and in a model of established bone loss.  The femurs of both the RAP-011 treated 
OVX and SHAM mice showed statistically significant increases in all measured parameters of 
bone strength (i.e., maximum load, stiffness, energy, ultimate strength, and elastic modulus).  In 
summary, treatment with RAP-011 produced bone of superior quality consistent with an anabolic 
agent. 
RAP-011 was evaluated in a mouse model of skeletal metastasis using luciferase-tagged, human 
MDA-MB-231 breast cancer cells (estrogen receptor negative).  Mice were pretreated for 2 
weeks with RAP-011 (10 mg/kg, biweekly, SC) prior to intracardiac injection of tumor cells.  
Treatment with RAP-011 was continued for an additional 5 weeks following tumor implantation. 
A parallel study was conducted to examine the effect of RAP-011 treatment, as described above, 
on survival of MDA-MB-231 bearing mice. 
The data demonstrate that RAP-011 treatment acts to inhibit MDA-MB-231 metastasis to bone 
and may also play a role in inhibiting tumor growth in soft tissue.  Furthermore, in the presence 
of tumor cells, RAP-011 is able to prevent lytic disease through an anabolic mechanism of bone 
formation.  Lastly, inhibition of tumor growth and metastasis with RAP-011 leads to a greater 
than 25% survival benefit in this model.  
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The efficacy of RAP-011 was examined in an orthotopic model of breast cancer using luciferase-
tagged human MCF-7 breast cancer cells (estrogen receptor positive). Mice were pretreated for 2 
weeks with RAP-011 (10 mg/kg, biweekly, SC) prior to the implantation of tumor cells into the 
mammary fat pad of female nude mice. Treatment with RAP-011 was continued for an additional 
7 weeks following tumor implantation at which time mice were sacrificed and assessed for tumor 
burden. RAP-011 effectively lowered the tumor burden in mice as detected by bio-luminescence. 
In addition, a 60% reduction in tumor weight was observed in the RAP-011 treated mice.  
The ability of RAP-011 to repair osteolytic lesions caused by metastatic disease was investigated 
in mice.  In this model athymic nude mice received an intratibial injection of MDA-MB-231-Luc 
cells to mimic bone metastasis.  Mice were treated with a chemotherapy regimen of paclitaxel (20 
mg/kg, IP, every three days) starting seven days after tumor injection and continuing for the 
duration of the study.  On study day 42 mice with a detectable tumor burden by bioluminescent 
imaging were divided into two groups and began treatment with RAP-011 (10 mg/kg, SC, 
biweekly) or vehicle.  Prior to dosing, μCT scans of the tumor bearing tibia were conducted to 
identify osteolytic lesions.  RAP-011 treatment continued for four weeks (to study day 70) and a 
final μCT scan of the tibia was performed.  On study day 70 osteolytic lesions remained the same 
or had progressed further when compared to study day 42 in the vehicle treated mice.  While 
some mice showed progression of osteolytic lesions (most likely related to tumor burden) on 
study day 70, a majority of mice treated with RAP-011 demonstrated repair of the osteolytic 
lesions seen on study day 42.  Therefore treatment with RAP-011 has the ability to repair 
osteolytic lesions caused by tumors and after cytoxic chemotherapy with paclitaxel. 
5.3.2. 
Toxicology 
ACE-011 has been evaluated for toxicological effects in two species, Sprague-Dawley rats and 
cynomolgus monkeys.  The dose levels ranged from 0.3 to 30 mg/kg in rats and from 1 to 50 
mg/kg in monkeys.  These dose ranges were designed to support Phase 1a single-dose levels of 
0.01 to 3.0 mg/kg IV and Phase 1b multiple doses of 0.1 to 2 mg/kg (monthly, SC).  Weekly 
dosing in animals was designed to provide continuous, but fluctuating serum concentrations of 
ACE-011, which would be mimicked by a one-month dosing interval in humans. 
Initial studies utilized IV dosing to identify target organs while longer-term studies (3 months in 
rats; 3 and 6 months in monkeys) utilized SC dosing to mimic the intended dosing regimen for 
patients.  The expected pharmacologic effect, increased red blood cells (RBCs), hemoglobin 
(Hb), hematocrit (HCT) and reticulocytes, was observed in all studies, presumably based on the 
ability of ACE-011 to inhibit activin.  A second expected pharmacologic effect of ACE-011, 
based on inhibition of activin, was the reversible reduction in sperm production and testicular 
tubular damage in rats.  Since male cynomolgus monkeys were sexually immature in these 
studies, it was not possible to monitor this effect in this species. 
Effects on the adrenal gland were only seen in rats and were more pronounced in female rats. 
This toxicological observation may not be relevant for predicting effects in humans since adrenal 
toxicity was not seen in cynomolgus monkeys.  Dose-limiting toxicity and no observable adverse 
effect levels (NOAELs) were primarily based on renal toxicity in both rats and monkeys.  There  
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was some indication that kidney toxicity was an indirect effect, based on the formation of 
antibody/antigen complexes, but since these studies were not designed to investigate 
toxicological mechanisms, a definitive cause of renal impairment and renal damage was not 
determined.  Development of antibodies to ACE-011 was noted in all of these studies, which is 
an expected immune reaction in rats and monkeys dosed with a human protein.  
The no observable adverse effect level (NOAELs) from the 3 month SC studies was 3 and 30 
mg/kg in rats and monkeys, respectively. Because the kidney findings were observed at all dose 
levels, the NOAEL from the 6 month monkey study is < 10 mg/kg.  
5.4. 
Summary of Clinical Experience 
5.4.1. 
A011-01: A Phase 1a Study in Healthy Postmenopausal Women  
ACE-011 was first studied in a randomized, Phase 1a, single dose, dose escalation study in 
healthy, post-menopausal females (16).  ACE-011 was diluted in normal saline administered as 
an IV infusion (over approximately 1 hour) or as a SC injection on Day 1.  Dose levels were 0.01, 
0.03, 0.1, 0.3, 1.0, and 3.0 mg/kg IV and 0.03 and 0.1 mg/kg SC.  A total of 48 subjects were 
enrolled; 5 active and 1 placebo at each of the IV and SC dose levels.  All subjects were followed 
for 4 months following a single dose administration. 
The pharmacokinetics of ACE-011 was linear for all IV and SC doses.  Across IV doses ranging 
from 0.1 through 3.0 mg/kg, the mean clearance (CL) ranged from 0.092 to 0.128 mL/h/kg, the 
volume of distribution ranged from 73.7 to 110 mL/kg, and the mean T1/2 ranged from 23.7 to 
31.8 days, with no apparent dependence on dose.  After SC administration of 0.03 and 0.1 mg/kg, 
ACE-011 was completely absorbed, and the mean T1/2 was approximately 30 days, with no 
apparent dependence on dose.   
The most commonly occurring treatment-emergent adverse events (AEs; i.e., those occurring in 
more than 1 subject in any treatment group) were headache, infusion site reaction, injection site 
hemorrhage, and toothache.  The majority of the injection site reactions and injection site 
hemorrhages were in the first IV cohort and were related to infiltration of the IV site.  The 
majority of treatment-emergent AEs were mild in severity and were judged to be unrelated to 
ACE-011.  No deaths, serious AEs (SAEs), or AEs leading to discontinuation were reported.  
Changes in red blood cells (RBCs), hemoglobin, reticulocytes, liver function tests, glucose, uric 
acid, amylase and lipase occurred in some subjects; however, none of these laboratory results 
were reported as adverse events.  Mild, transient elevations in pancreas enzymes, liver enzymes, 
or glucose were reported as AEs in five patients.  There were no clinically significant changes 
from baseline in vital signs, physical examination, endocrine function, or electrocardiogram 
(ECG) data.  Preservation of adrenal cortical function was monitored through evaluation of serum 
electrolytes (sodium and potassium levels) and through cortisol response to adrenocorticotropic 
hormone (ACTH) stimulation.  No clinically significant findings were observed at doses up to 3.0 
mg/kg IV, and ACE-011 was well tolerated in healthy, post-menopausal female volunteers in 
single dose levels up to 0.1 mg/kg SC and 3.0 mg/kg IV, the highest dose levels tested in this 
study. 
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5.4.2. 
A011-02: A Phase 1b Study in Healthy Postmenopausal Women  
ACE-011 was studied in a Phase 1b, single-center, randomized, double-blind, placebo-controlled, 
multi-dose, dose-escalating study to evaluate the safety, tolerability and pharmacodynamics of 
ACE-011 in healthy postmenopausal women.  Four cohorts of 10 subjects each were planned at 
the following dose levels: 0.1, 0.3, 1.0, and 2.0 mg/kg administered subcutaneously.  Within each 
cohort, subjects were to be randomized to either active or placebo treatment in an 8:2 ratio. 
Subjects were to receive one SC injection of ACE-011 or placebo every 28 days for a total of 4 
doses. All subjects were to be followed for 12 weeks after the last dose. 
The treatment phase of the study was terminated early after a dose-limiting pharmacodynamic 
effect was observed.  While on study, one subject in the 1.0 mg/kg cohort experienced a Serious 
Adverse Event (SAE) of progressive and persistent hypertension that was attributed to a rapid 
and significant rise in hemoglobin and hematocrit levels.  Due to symptoms of headaches, nausea, 
eye pain, dizziness and vomiting approximately 1 week following the second dose, the subject 
was hospitalized for monitoring and evaluation of her hypertension.  The head MRI, fundoscopy, 
and ECG performed were reported as normal and headache symptoms resolved following 
therapeutic phlebotomy. The SAE resolved and the subject was discharged from the hospital the 
following day.  The hypertension was monitored closely and managed initially with 
antihypertensive medication.  The hypertension resolved by the end of the study without need of 
any antihypertensive medication. The subject received aspirin prophylactically until the end of 
the study and continued taking ibuprofen as needed for headaches.  Further details can be found 
in the Investigator Brochure.  
Based on the magnitude of the hematopoietic response, the Sponsor suspended dose escalation to 
the 2.0 mg/kg dose level and further dosing in all cohorts as a result of this dose-limiting 
pharmacodynamic effect at the 1.0 mg/kg dose level.  In total, 31 subjects were enrolled and 
treated.  Dose levels of ACE-011 administered included 0.1, 0.3, and 1.0 mg/kg (Cohorts 1, 2, 
and 3 respectively).  All subjects randomized to active treatment in Cohort 1 received all 4 
planned doses of ACE-011.  Due to early discontinuation of study drug, subjects randomized to 
active treatment in Cohort 2 received 3 doses of ACE-011, and subjects randomized to active 
treatment in Cohort 3 received 2 doses of ACE-011.  Subjects randomized to placebo treatment 
received between 1 and 4 doses of study treatment.   
In the analysis of the unblinded data, after the administration of the first dose, a dose and time 
dependent increase in hemoglobin values was observed (see Table 3 below): 
 
 
 
 
 
 
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Table 3:     A011-02: A Phase 1b Study in Healthy Postmenopausal Women: Hemoglobin  
 
 
 
Evaluation 
    
*The number of placebo subjects with data decreases over time as a result of the early discontinuation of the study (i.e., there were placebo 
subjects in each dosing cohort).  There were seven placebo subjects with data at baseline, Days 8, 15, and 36; six subjects with data at Days 29, 
43, 57, and 85; five subjects with data on Days 71 and 113; four subjects with data on Day 64; three subjects with data on Day 141; two subjects 
with data on Day 99; and one subject with data on Days 92 and 169. 
** Number of doses administered per treatment group: 0.1 mg/kg 4 doses; 0.3 mg/kg 3 doses; 1.0 mg/kg 2 doses.  Data beyond this study day are 
considered follow-up results. 
***n=1 
No severe or life-threatening events were reported. The incidence of the most common treatment-
emergent AEs (i.e., occurring in more than one subject in any treatment group) is presented 
below (see Table 4). The most notable AEs were those related to increases in hematologic 
laboratory measures in the 1.0 mg/kg dose group: hematocrit, hemoglobin, and RBC count.  AEs 
of increased hemoglobin and/or hematocrit were reported for seven of the eight subjects in this 
dose group.  These events were reported as mild or moderate elevations; all were considered 
probably related to study drug treatment. Three of the subjects in the 1.0 mg/kg group with 
elevated hemoglobin levels underwent phlebotomies and all hemoglobin elevations were resolved 
by the end of the follow-up period. No erythroid lineage AEs were reported in the 0.1 or 0.3 
mg/kg treatment groups.   
 
Mean Change from Baseline (g/dL) 
Evaluation Time Point 
Placebo 
 
N=7* 
ACE-011 
0.1 mg/kg 
N=8 
ACE-011 
0.3 mg/kg 
N=8 
ACE-011 
1.0 mg/kg 
N=8 
Baseline Mean, pre-Dose 1 
13.20 
13.11 
13.30 
12.71 
Day 8 
0.17 
0.68 
0.85 
1.21 
Day 15 
-0.27 
0.43 
0.44 
1.75 
Day 29 
0.27 
0.61 
1.21 
    2.68** 
Day 36 
0.56 
0.64 
1.89 
2.96 
Day 43 
-0.02 
0.89 
1.21 
2.85 
Day 57 
0.27 
1.28 
    1.64** 
2.09 
Day 64 
0.53 
1.11 
2.49 
2.21 
Day 71 
-0.10 
1.34 
2.09 
1.66 
Day 85 
0.38 
    1.18** 
2.55 
1.86 
Day 92 
      0.00*** 
1.04 
      1.60*** 
      3.80*** 
Day 99 
-0.20 
1.21 
      3.20*** 
      1.28*** 
Day 113 
-0.02 
1.30 
1.29 
1.04 
Day 141 
 0.30 
0.95 
0.34 
2.30 
Day 169 
       0.20*** 
0.06 
 
      2.00*** 
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Headache was reported frequently in all treatment groups with no apparent dose response trend, 
though the reports in the higher dose groups were more often considered possibly related to 
treatment.  Most headaches were reported as mild (one headache was reported as moderate).  
Paresthesia and dizziness were reported more frequently in the ACE-011 groups, though the 
events were generally not considered drug related.  Other frequently reported events (e.g. fatigue, 
upper respiratory infection) did not appear to increase with dose and were generally mild.  
 
Table 4:  A011-02: Incidence of Most Common Adverse Events  
Dose Group 
System Organ Class and Preferred Term 
Placebo 
N=7 
n (%) 
0.1 mg/kg 
N=8 
n (%) 
0.3 mg/kg 
N=8 
n (%) 
1.0 mg/kg 
N=8 
n (%) 
GASTROINTESTINAL DISORDERS 
     Diarrhea 
0 (0.0%) 
2 (25.0%) 
0 (0.0%) 
0 (0.0%) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
     Asthenia 
0 (0.0%) 
1 (12.5%) 
2 (25.0%) 
0 (0.0%) 
     Fatigue 
2 (28.6%) 
0 (0.0%) 
1 (12.5%) 
2 (25.0%) 
INFECTIONS AND INFESTATIONS 
     Viral upper respiratory tract infection 
0 (0.0%) 
4 (50.0%) 
0 (0.0%) 
0 (0.0%) 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
     Limb injury 
0 (0.0%) 
1 (12.5%) 
0 (0.0%) 
2 (25.0%) 
INVESTIGATIONS 
     Hematocrit increased 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
6 (75.0%) 
     Hemoglobin increased 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
7 (87.5%) 
     Red blood cell count increased 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
3 (37.5%) 
METABOLISM AND NUTRITION DISORDERS 
     Decreased Appetite 
1 (14.3%) 
0 (0.0%) 
2 (25.0%) 
0 (0.0%) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
     Arthralgia 
2 (28.6%) 
0 (0.0%) 
2 (25.0%) 
0 (0.0%) 
     Muscle spasms 
0 (0.0%) 
1 (12.5%) 
0 (0.0%) 
2 (25.0%) 
NERVOUS SYSTEM DISORDERS 
     Dizziness 
0 (0.0%) 
0 (0.0%) 
2 (25.0%) 
2 (25.0%) 
     Headache 
2 (28.6%) 
4 (50.0%) 
3 (37.5%) 
2 (25.0%) 
     Paresthesia 
1 (14.3%) 
0 (0.0%) 
0 (0.0%) 
3 (37.5%) 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
     Oropharyngeal pain 
2 (28.6%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
VASCULAR DISORDERS 
     Hot flush 
0 (0.0%) 
2 (25.0%) 
0 (0.0%) 
1 (12.5%) 
Note: Table presents AEs reported in more than one subject in any treatment group. 
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Hemoglobin levels for all subjects with elevations had returned to within normal limits by the end 
of the study.   
Adrenal cortical function was monitored through evaluation of serum electrolytes (sodium and 
potassium levels) and through cortisol response to adrenocorticotropic hormone (ACTH) 
stimulation. All ACTH simulation test results were normal. 
PK results confirmed that the PK of ACE-011 is linear following the first SC doses of all three 
dose levels tested, 0.1, 0.3, and 1.0 mg/kg. The terminal half life (T1/2) of ACE-011 following the 
last dose in all three dose groups was identical, with mean T1/2 being approximately 23 days. The 
mean CL/F ranged from 3.05 to 3.90 mL/d/kg, the mean Vz/F ranged from 97.47 to 103.03 
mL/kg, and the mean T1/2 ranged from 20.92 to 23.34 days in all 3 dose levels, with no apparent 
dependence on dose.  
Bone mineral density was assessed by dual-energy X-ray absorptiometry (DXA).  Mean change 
and mean percent change in BMD results from baseline to study end are summarized in the table 
below.  A dose-dependent increase in the BMD of the total hip from baseline to end of study was 
observed, with a significant and rapid increase of 2.4% in the 1.0 mg/kg dose group, compared to 
a 0.7% decrease in the placebo group.  BMD results for lumbar spine showed slight increases of 
0.4% to 1.0% from baseline to study end in all active treatment groups, compared with a 0.5% 
decrease in the placebo group (see Table 5 below): 
Table 5:     A011-02: A Phase 1b Study in Healthy Postmenopausal Women: BMD 
 
5.4.3. 
A011-04: A Phase 2a Study in Patients with Osteolytic Lesions of Multiple 
Myeloma  
Study A011-04 is an ongoing, non-IND, Phase 2a, multi-center, randomized, multiple-dose study 
to evaluate the safety, tolerability and efficacy of ACE-011 in patients with osteolytic lesions of 
multiple myeloma.  Safety evaluations include adverse events (AEs), clinical laboratory tests, 
standard 12-lead electrocardiogram (ECG), vital signs, Eastern Cooperative Oncology Group  
Treatment Group 
Placebo 
 
N=7 
ACE-011 
0.1 mg/kg 
N=8 
ACE-011 
0.3 mg/kg 
N=8 
ACE-011 
1.0 mg/kg 
N=8 
 
Mean 
Change 
Mean Percent 
Change 
Mean 
Change 
Mean Percent 
Change 
Mean 
Change 
Mean Percent 
Change 
Mean 
Change 
Mean Percent 
Change 
Lumbar Spine 
(g/cm2) 
-0.0020 
-0.5% 
0.0099 
0.7% 
0.0082 
1.0% 
0.0051 
0.4% 
Total Hip 
(g/cm2) 
-0.0062 
-0.7% 
0.0050 
0.6% 
0.0075 
0.9% 
0.0220 
2.4% 
Number of doses administered and day of last dose per treatment group: 0.1 mg/kg 4 doses (Day 85); 0.3 mg/kg 3 doses (Day 57); 1.0 mg/kg 2 
doses (Day 29).  Data beyond this study day are considered follow-up results. 
 
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(ECOG) performance status and physical examinations.  Additionally, the study includes the 
assessment of biochemical markers of bone formation and resorption, skeletal related events 
(SREs), bone mineral density (BMD) by duel-energy x-ray absorptiometry (DXA) and bone pain 
by visual analog scale (VAS).  
In this study, patients are randomized in a 4:1 ratio to one of three dose levels of ACE-011 (0.1, 
0.3 and 0.5 mg/kg) or placebo, to be administered to patients every 28 days by subcutaneous 
injection, for up to four doses over a 3-month period.  The test article is being evaluated in 
combination with the anti-myeloma therapy of melphalan (4 mg/m2 on days 1-7), prednisolone 
(40 mg/m2 on days 1-7) and thalidomide (100 mg per day) (MPT).  The sites, Sponsor and 
Sponsor representatives are blinded to treatment assignment.    
As of 10 March 2009, 30 patients have been randomized, enrollment is complete and treatment is 
ongoing.  Fifteen patients have received multiple doses of their assigned treatment; 7 patients 
have received 4 doses, 3 patients have received 3 doses and 5 patients have received 2 doses.  Of 
the remaining 15 patients, 12 patients have received their first dose of ACE-011 or placebo and 3 
patients have not yet received their first dose.  There have been no ACE-011 related serious 
adverse events (SAEs) reported.  Per the monitored preliminary data on 18 patients presented to 
the Independent Data Monitoring Committee (DMC) on 9 February 2009, there were 8 Grade 
3/severe AEs reported in 4 patients, including neutropenia, platelet count decreased, pain in 
extremity, back pain and anemia.  All Grade 3 AEs were determined to be not related to ACE-
011 and the Grade 3 hematologic adverse events were considered either probably or definitely 
related to the MPT treatment.   
Following preliminary analysis of the blinded central laboratory data, increases in hemoglobin 
values were observed within 28 days after administration of the first dose of ACE-011/placebo.  
Per data available, 11 out of 30 patients had > 1 g/dL increase in hemoglobin within the first 28 
days on the study, 4 patients achieved a > 2 g/dL increase within their first 28 days on study, 
while 8 patients achieved a > 2 g/dL increase in hemoglobin through Day 85.      
Including all visits as of 10 March 2009 through Day 85, 9 out of 30 patients had a dose 
interruption due to a hemoglobin value of > 13 g/dL according to the dose modification rules 
defined in the protocol and 1 of the 9 patients, who had a history of hypertension, also had a dose 
interruption due to Grade 2 hypertension.  Three of the 9 patients that required a dose interruption 
due to a hemoglobin value of > 13 g/dL, as per protocol, had hemoglobin levels above 13 g/dL 
prior to their first dose.  Taken together, these data, suggest a beneficial pharmacodynamic effect 
of ACE-011 on erythropoiesis in a patient population with cancer chemotherapy induced anemia.  
No patients have had a dose reduction in ACE-011/placebo treatment or discontinued treatment.   
One SAE of prolonged hospitalization due to pneumonia, that was considered not related to 
ACE-011, was reported in a
enrolled in the study.  On 
, four 
days after the first dose of ACE-011/placebo and the initial doses of melphalan, prednisolone and 
thalidomide (MPT), the patient presented with elevated temperatures up to 39º C, cough and 
fatigue.  Chest x-ray performed on 
 revealed a pneumonic infiltration in the lower  
 
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lobe of the left lung.  On 
 hospitalization of the patient was prolonged due to the 
event.  The patient was treated with moxifloxacin, doripenem, meropenem and fluconazole.   
On 
 the pneumonic infiltration resolved, as confirmed by chest x-ray.  This SAE 
resolved upon discharge of the patient from the hospital on 
  
The investigator considered the event of pneumonia not related to ACE-011 and possibly related 
to MPT.  The Sponsor agreed with the Investigator’s assessment of causality.  Pneumonia is 
considered a labeled event per the current package insert for thalidomide.  The SAE was 
considered serious, related and expected with respect to thalidomide and unrelated to ACE-011. 
The A011-04 study has completed enrollment, while treatment, follow-up and data monitoring 
are ongoing.   
5.5. 
Potential Risks for Human Use 
The 1-month safety study in rats suggested that ACE-011 may affect sperm count and motility in 
a dose-dependent manner, although these findings appeared to be reversible upon drug 
discontinuation.  These reproductive effects are likely a result of the expected biological activity 
of activin inhibition.   
The 1-month safety study in rats also suggested that ACE-011 induces adrenocortical necrosis in 
rats.  At present, the mechanism by which ACE-011 has induced this lesion in rats and the basis 
for its apparent species specificity are unknown; the finding has not been observed in mice or 
cynomolgus monkeys at similar dose levels.  Adrenal cortical function was monitored in human 
subjects receiving ACE-011 by the evaluation of serum electrolytes including sodium and 
potassium levels and by the evaluation of cortisol response to ACTH stimulation in both the 
Phase 1a single dose and Phase 1b multiple dose healthy volunteer clinical studies.  These 
parameters were evaluated up to doses of 3.0 mg/kg IV and 1.0 mg/kg SC, and no clinically 
significant perturbations in adrenal function were observed.     
Laboratory findings from the Phase 1a single dose study showed elevations in hematology 
results, pancreas and liver enzymes, and uric acid.  The most commonly seen treatment-emergent 
adverse events in this study were headache, infusion site reaction, injection site hemorrhage, and 
toothache.  
Based on data from the Phase 1b study, the most notable AEs were increases in hematologic 
laboratory measures in the 1.0 mg/kg dose group: hematocrit, hemoglobin, and RBC count.  AEs 
of increased hemoglobin and/or hematocrit were reported for seven of the eight subjects in this 
dose group.  These events were reported as mild or moderate elevations; all were considered 
probably related to study drug treatment.  No erythroid lineage AEs were reported in the 0.1 or 
0.3 mg/kg treatment groups.  Hematologic parameters will be monitored carefully in this study.   
Headache was reported frequently in all treatment groups with no apparent dose response trend, 
though the reports in the higher dose groups were more often considered possibly related to 
treatment.  Most headaches were reported as mild (one headache was reported as moderate).  
Paresthesia and dizziness were reported more frequently in the ACE-011 groups, though the  
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events were generally not considered drug related.  Other frequently reported events (e.g. fatigue, 
upper respiratory infection) did not appear to increase with dose and were generally mild. 
In the Phase 1b multiple-dose healthy volunteer study, some subjects treated with ACE-011 
showed elevations in blood pressure.  One subject who had received two doses of ACE-011 at the 
1.0 mg/kg dose level had a serious adverse event.  The patient was hospitalized for further 
evaluation of increases in blood pressure and symptoms that may have been caused by the 
increase in blood pressure.  The symptoms that the subject experienced included headache, 
dizziness, nausea, vomiting, and elevated hematology values (increases in the number of red 
blood cells).  This serious adverse event was judged to be probably related to the study drug and 
resolved following discharge from hospital the following day. Throughout the course of the 
follow up period hematologic parameters were monitored frequently until the hemoglobin and 
hematocrit levels returned to within normal limits. Further details are outlined in the Investigator 
Brochure.  
As with all biologics there is the potential for anti-drug antibodies that can be associated with 
increased drug clearance and hypersensitivity reactions.  An immune response to ACE-011 has 
been seen in monkeys that received the drug for 1 month and longer.  Some of those animals 
developed kidney inflammation possibly related to that immune response.  Anti-drug antibody 
formation will be assessed in this study to examine the immunogenicity of ACE-011, and to 
monitor reversibility of any AEs over time.   
Please refer to the Investigator Brochure for more information. 
 
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6. 
TRIAL OBJECTIVES AND PURPOSE 
6.1. 
Primary objective  
1. To evaluate the proportion of patients in each ACE-011 dose regimen who achieve a 
hematopoietic response during the treatment period including up to 2 months after the last 
dose of ACE-011 treatment of chemotherapy induced anemia in patients with metastatic 
breast cancer. 
6.2. 
Secondary objectives 
1. To evaluate the safety and tolerability of ACE-011 for the treatment of chemotherapy 
induced anemia in patients with metastatic breast cancer.  
2. To estimate the duration of the hematopoietic response associated with each ACE-011 
dose regimen. 
3. To estimate the time to the hematopoietic response associated with each ACE-011 dose 
regimen. 
4. To estimate the proportion of patients receiving red blood cell (RBC) transfusions and/or 
ESAs within each cycle of ACE-011 with each dose regimen. 
5. To evaluate the percentage of patients who achieve an increase in hemoglobin of ≥ 1 g/dl, 
≥ 2 g/dL and/or hemoglobin concentration ≥ 11 g/dL for a consecutive 28 day period 
during the treatment period including up to 2 months after the last dose of ACE-011 in the 
absence of any RBC transfusions and/or ESAs.   
6. To estimate the effect of each ACE-011 dose regimen on progression free survival (PFS) 
and objective response rate (ORR). 
6.3. 
Exploratory objectives  
1. To estimate the effect of each ACE-011 dose regimen on serum bone biomarkers (OC, 
BSAP, PINP, CTX, TRACP-5b), urine bone biomarker (uNTX), bone mineral density 
(DXA scans of lumbar spine and hip) and incidence of skeletal related events (SREs). 
2. To evaluate the quality of life during the study in relation to the treatment of 
chemotherapy induced anemia in patients with metastatic breast cancer during the study. 
.  
 
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7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design and Plan 
This is a Phase 2, double-blind, randomized, placebo-controlled study to evaluate the efficacy, 
safety, and tolerability of ACE-011 for the treatment of chemotherapy induced anemia in patients 
with metastatic breast cancer. A total of 105 patients will be enrolled. 
The Data Monitoring Committee (DMC) is responsible for reviewing the safety. The DMC will 
be comprised of a minimum of 3 members.  The DMC will meet regularly during the study to 
review serious adverse events (SAEs), adverse events (AEs), laboratory results, and vital signs. 
Safety data will be reviewed throughout the study by the DMC, Medical Monitor and the 
Investigator. DMC responsibilities, membership, meeting frequencies and procedures will be 
outlined in the DMC charter.  
Patients will be evaluated for study inclusion/exclusion criteria by the Investigator. Patients who 
meet the study entry criteria will be enrolled within 14 days of the screening visit. Central lab 
values will be utilized for the evaluation of patient eligibility and in the evaluation of patient 
safety throughout the study. Local lab values for hemoglobin and hematocrit will be collected and 
reported from screening through the Day 281/Termination visit.  Three cohorts of 30 patients 
each are planned at the following doses of ACE-011: 0.1 mg/kg, 0.3 mg/kg and 0.5 mg/kg. 15 
patients will be enrolled into the placebo cohort (as shown in Table 6). 
Table 6: 
Study design   
 
 
 
  
 
 
 
 
Each eligible patient will be randomized to one of the four cohorts to receive a dose administered 
as a subcutaneous injection every 28 days for up to 4 doses. Dosing will be administered on days 
1, 29, 57, and 85. Concurrent treatment with a myelosuppressive chemotherapy regimen for 
metastatic breast cancer will also be administered per standard of care at the site. Patients will be 
stratified according to administration of either single agent weekly chemotherapy or less frequent 
chemotherapy regimens.  
Blood samples will be collected at selected study sites from approximately one-third of patients 
for the evaluation of serum concentrations of ACE-011.  Pre-dose PK samples will be collected 
on Day 1.  See Appendix 5 for PK sampling schedule. 
 
Dose  
Number of  Patients 
0.1 mg/kg 
30 
0.3 mg/kg 
30 
0.5 mg/kg 
30 
Placebo 
15 
Total patients enrolled: 105 
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Patients will be assessed for safety by monitoring adverse events, clinical laboratory tests, 
assessment of quality of life (FACT- Fatigue (17)), vital signs and physical examinations on an 
ongoing basis.  ECGs will be performed during screening, prior to dosing on the first and second 
cycle, Day 15, and Day 113 (28 days after the last dose of ACE-011) and at Day 281/ 
Termination visit to monitor safety.  Blood pressure and lab values will be assessed at each study 
visit during the treatment period; weekly for the first two cycles and approximately every two 
weeks for subsequent cycles.  
Local laboratory hemoglobin values and blood pressure values will be evaluated prior to dosing 
per the dose modification criteria, as applicable.  
Patients will be followed for a minimum of 7 months following their last dose of ACE-011. Study 
participation for each patient is approximately 10.5 months (14 day screening period, 3 month 
treatment period with a 2 month treatment follow up period, and a 5 month post treatment follow-
up period). If a patient discontinues the study due to progression of disease (metastatic breast 
cancer) and/or begins another chemotherapy regimen, the patient will complete the Day 
281/Termination visit procedures and be followed for survival only (a minimum 7 months from 
the last dose of ACE-011).  
Anti-drug antibody testing will be performed at Day 281/Termination visit and if positive, the 
patient may be asked to return to the clinical site for additional monthly anti-drug antibody 
testing for up to 12 months, after their last dose.
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8. 
SELECTION AND WITHDRAWL OF PATIENTS 
8.1. 
Number of Patients 
The study will include three dose levels of ACE-011 at 0.1 mg/kg, 0.3 mg/kg and 0.5 mg/kg and 
a placebo group. A total of 105 will be treated with ACE-011 or placebo. 
8.2. 
Entry Criteria 
8.2.1. 
Patient Inclusion Criteria 
1. Women > 18 years of age. 
2. Histologically confirmed diagnosis of breast cancer documented by cytology or biopsy. 
3. Evidence of metastatic breast cancer with a minimum of one measurable lesion or non 
measurable lesion per RECIST criteria (Appendix 1). 
4. Receiving a multicycle myelosuppressive chemotherapy regimen including one of the 
following: anthracycline, taxane, gemcitabine or vinorelbine. 
5. Planned treatment with the same myelosuppressive chemotherapy regimen for a 
minimum of 9 weeks after Day 1 of ACE-011/placebo administration.  
6. Hemoglobin value between ≥ 6.5 to < 11.0 g/dL (≥ 65 to < 110 g/L).  
7. ≥ 30 days must have elapsed (from Day 1) since previous treatment with erythropoiesis-
stimulating agent (including concurrent treatment with IV iron) for chemotherapy 
induced anemia.  
8. ≥ 7 days have elapsed (from Day 1) since the last RBC blood transfusion and receipt of ≤ 
2 units of blood in the past 30 days.  
9. ECOG Performance status of 0 – 2 (Appendix 2). 
10. Adequate renal (creatinine ≤ 1.5 x ULN or creatinine clearance ≥ 40 mL/min) and hepatic 
function (bilirubin < 1.5 x ULN; AST/ALT < 2.5 x ULN). 
11. Females of childbearing potential  participating in the study are to use adequate birth 
control measures (i.e. oral contraceptives or two forms of barrier method birth control) 
during study participation. Females of childbearing potential must have a negative serum 
pregnancy test within 3 days to ACE-011/placebo administration (Day 1). A female of 
childbearing potential is a sexually mature woman who has not undergone a 
hysterectomy or who has not been postmenopausal for at least 24 consecutive months 
(i.e. who has had menses at some time in the preceding 24 months). 
12. Life expectancy of ≥ 6 months. 
13. Is willing to adhere to the study visit schedule, understand and comply with all protocol 
requirements. 
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14. Understand and sign a written informed consent. 
8.2.2. 
Patient Exclusion Criteria 
1. At the time of screening patients who have any grade > 3 toxicity (as per NCI CTCAE 
v3.0 (Appendix 3)) (except for the following disease related toxicities:  hematological 
events- anemia, thrombocytopenia or neutropenia or non hematological events- nausea, 
vomiting, fatigue, or muscle or bone/joint pain).  
2. Prior radiation therapy to > 20% of the whole skeleton. Use of palliative radiation if the 
area being treated is <15% of body surface area with no pelvic radiation or no more than 
10% of the bone marrow reserve is radiated is permitted during patient participation in 
the study, at the discretion of the investigator. 
3. Have received more than 5 prior chemotherapy treatment regimens for metastatic breast 
cancer.  
4. Concurrent use of bevacizumab with the chemotherapy regimen during study 
participation. 
5. Clinically significant pulmonary, endocrine, neurologic, gastrointestinal, hepatic or 
genitourinary disease unrelated to underlying hematologic disorder.  
6. Patients with heart failure as classified by the New York Heart Association (NYHA) 
classification of 3 or higher (Appendix 4). 
7. History of thrombosis, deep vein thrombosis (DVT), pulmonary emboli, or embolic 
stroke. 
8. Untreated CNS metastases (exception: CNS metastases treated with whole brain 
radiotherapy > 6 months prior to randomization). 
9. Diagnosis of a myeloid malignancy or known history of myelodysplasia.  
10. History of second malignancy within 5 years (except excised and cured basal cell 
carcinoma, squamous cell carcinoma of the skin or cervical carcinoma in situ).  
11. Patients with a recent history (within 14 days of Day 1) of administration of systemic (IV 
or oral) antibiotics. Patients should be free of infection at least 14 days after the last dose 
of systemic antibiotic treatment (from Day 1). 
12. Uncontrolled hypertension. If hypertension is considered clinically stable, systolic blood 
pressure (BP) must be < 150 mmHg and diastolic BP must be < 100 mmHg.  
13. Known history of hepatitis C antibody (HCV), hepatitis B surface antigen (HBsAg and 
HB core Ab), or human immunodeficiency virus (HIV) antibody.   
14. Deficiency in iron (serum ferritin< 100 ng/mL (< 224.7 pmol/L)), vitamin B12, or folate. 
15. History of anemia as a result of inherited hemoglobinopathy such as sickle cell anemia or 
thalassemia.  
16. History of autoimmune or hereditary hemolysis or gastrointestinal bleeding. 
17. Patient received treatment with another investigational drug or device within 1 month 
prior to Day 1, or if the half life of the previous product is known, within 5 times the half 
life prior to dosing, whichever may be longer.  
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18. Pregnant or lactating females. 
19. History of severe allergic or anaphylactic reactions or hypersensitivity to recombinant 
proteins or excipients in the investigational product.     
8.3. 
Patient Withdrawal Criteria 
Patients will be informed that they have the right to withdraw from the study at any time for any 
reason without prejudice to their medical care.   
Patients must be withdrawn from the study for any of the following reasons:  
• Patient request 
• Patient is unwilling or unable to comply with the protocol 
• ESA administration during the treatment period 
• Medical reason, such as cancer or treatment related toxicity, or at the discretion of the 
Investigator and/or the Medical Monitor(s) 
The reasons for withdrawal must be recorded in the patient’s case report form (CRF).  The 
Investigator must notify the Medical Monitor and the contract research organization (CRO) 
immediately when a patient has been discontinued/withdrawn due to an AE.  All patients who 
are withdrawn from the study should complete the tests and evaluations scheduled for Day 
281/Termination at the time of withdrawal. Discontinued/withdrawn patients may be followed 
for survival only 7 months from the last dose of ACE-011/placebo.  Patients who withdraw due 
to ESA administration during the treatment period may enter the treatment follow-up period.  
 
 
 
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9. 
TREATMENT OF PATIENTS 
9.1. 
Concomitant Medications 
9.1.1. 
General Concomitant Medication Usage 
During screening, and during the study, patients may take only stable doses of medications for 
chronic conditions that are not specifically excluded by the protocol (see Sections 8.2.1 Patient 
Inclusion Criteria and 8.2.2 Patient Exclusion Criteria).  The Medical Monitor should be 
consulted by the Investigator if there are any concerns about what constitutes a stable dose or 
what is a chronic condition. 
9.1.2. 
Concomitant treatment for anemia 
Concurrent therapy with a new prescription medication related to treatment of anemia during the 
course of the study must first be discussed with the Investigator and Medical Monitor prior to 
administration, unless appropriate medical care necessitates that medication should begin before 
the Medical Monitor can be consulted.  
9.1.2.1. 
Iron supplementation 
Iron supplementation within 7 days of Day 1 (besides an oral general multivitamin with iron) 
will not be allowed. If a patient becomes iron replete during study treatment (ferritin < 100 
ng/mL (< 224.7 pmol/L) or transferrin < 20%), treatment with iron supplementation is at the 
discretion of the investigator.  
9.1.2.2. 
Erythropoiesis-stimulating agents (ESAs) 
If concurrent treatment with erythropoiesis-stimulating agent is required in the opinion of the 
investigator, the erythropoiesis-stimulating agent label instructions are to be followed. The 
patient is to discontinue further treatment with ACE-011/placebo and enter the treatment follow 
up period of the study. See Table 7 for Schedule of Events.  
9.1.2.3. 
RBC Transfusions 
Concurrent treatment for chemotherapy induced anemia with blood transfusions is recommended 
when hemoglobin value is < 8 g/dL or at investigator discretion if the hemoglobin value is above 
8 g/dL and associated with anemia symptoms such as hemodynamic or pulmonary compromise 
requiring treatment. If a transfusion is given to a patient during the treatment period, ACE-
011/placebo should be administered no sooner than 7 days from the date of the transfusion.  
After the transfusion, the hemoglobin value should be assessed no later than 7 days from the date 
of the transfusion.  On the day of ACE-011/placebo administration, the hemoglobin value and 
blood pressure will be assessed. See Figure 1 for ACE-011/placebo dose modification rules.  
 
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9.2. 
Chemotherapy 
Chemotherapy treatment for metastatic breast cancer is to be given as per standard of care at the 
site.  ACE-011/placebo administration should be given prior to chemotherapy administration on 
ACE-011/placebo administration days.  Continuation of treatment with the same chemotherapy 
regimen through the treatment or post-treatment follow-up period of the study is at the discretion 
of the investigator. 
9.3. 
Treatment Compliance 
Each dose of ACE-011/placebo will be administered as a SC injection at the clinical site by the 
study staff and will be documented in the study record.  Monitoring for patient compliance with 
the treatment regimen is therefore unnecessary.  
9.4. 
Randomization  
Patients will be randomized to limit scientific bias within the study. Randomization assignments 
will be generated through a computerized system, provided by an Interactive Web/Voice 
Response System (IWRS/IVRS). Patients will be stratified according to frequency of the planned 
chemotherapy regimen (weekly chemotherapy vs. less frequent chemotherapy administration). 
9.4.1. 
Blinding 
The Investigators, patients, and sponsor or representative will remain blinded to the treatment 
arm assignment of each patient. The unblinded statistician will remain uninvolved in the study 
conduct until database lock and unblinding of the data has occurred.  
Safety parameters will be reviewed on an ongoing basis throughout the study to review blinded 
adverse events, serious adverse events, laboratory listings, and vital signs. If substantial toxicity 
trends are observed in one treatment group versus another, the DMC may request unblinding the 
treatment code assignment schema.  
9.4.2. 
Unblinding 
In the event of a medical emergency for an individual patient in which knowledge of the study 
medication is critical to the patient’s medical management, the investigator may break the blind 
for that patient. However, prior to breaking the blind, every effort must be made by the 
investigator to first discuss the need to break the blind with the sponsor or sponsor 
representative. Further, it must be determined by the investigator that breaking the treatment 
blind is necessary information for the medical management of that patient. If the blind is broken, 
the patient must withdraw from the study by completing the Day 281/Termination visit 
procedures and be followed for survival only. 
 
 
 
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9.5. 
Treatments Administered 
9.5.1. 
Selection of Doses in the Study 
Single dose administration of ACE-011 up to 3.0 mg/kg was previously demonstrated to be safe 
and to have durable effects on markers of bone formation and resorption as well as red blood 
cells following a single IV administration.  A dose-limiting pharmacodynamic effect of ACE-
011 with increases in hemoglobin and hematocrit and RBCs was established in healthy post-
menopausal women at the 1.0 mg/kg dose level following multiple SC administration.  This 
study will confirm the safety in following repeated SC administration of ACE-011 and further 
evaluate the potential efficacy in patients with chemotherapy induced anemia.  The safety and 
preliminary efficacy of ACE-011 following multiple doses up to 0.5 mg/kg will be assessed 
using a parallel randomization design. 
9.5.2. 
Selection and Timing of Dosing for Each Patient 
Patients will be enrolled and receive their assigned dose of ACE-011/placebo every 28 days (i.e. 
on Days 1, 29, 57, and 85). Patients will be receiving chemotherapy, concurrently for metastatic 
breast cancer. After completion of the treatment, patients will return to the site monthly for 2 
follow-up assessments (i.e., Days 113 and 141).  Subsequently, the patient will return to the site 
for 4 post treatment follow-up assessments (i.e. Days 169, 197, 225, and 253). The patient will 
return to the site for a termination visit approximately 1 month after the post treatment follow-up 
period (Day 281).  Patients will be discontinued from the ACE-011/placebo treatment for 
unacceptable toxicity, if the chemotherapy regimen is discontinued or for disease progression 
that requires the initiation of another chemotherapy treatment. 
9.5.2.1. 
ACE-011 Dose Modification Rules 
Throughout the study blood pressure and hemoglobin values will be evaluated for patient safety. 
The local hemoglobin values and blood pressure values will be evaluated on each ACE-
011/placebo dosing day.  The hemoglobin values from the previous 28 days between each ACE-
011/placebo dosing day and blood pressure will be reviewed and evaluated for dose 
modifications.  The parameters below outline rules for dosing modifications (Figure 1). Table 8 
outlines the dose reduction levels of ACE-011.  
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10. 
STUDY PROCEDURES AND SCHEDULE 
10.1.1. 
Written Informed consent 
Patients will be required to sign an Institutional Review Board/Institutional Ethics Committee 
(IRB/IEC) approved informed consent form (ICF) prior to any study related procedures, 
including screening evaluations. 
Screen failure information will be maintained, including but not limited to, reason for failure.   
10.1.2. 
Screening (Within 14 days of dosing) 
The following will be collected within 14 days prior to the initial dosing Day 1: 
• Informed consent 
• Assessment of inclusion/exclusion criteria 
• Complete Medical History and Physical Examination 
• Vital signs including weight (kg), heart rate (beats/min), seated systolic and diastolic 
blood pressure (mmHg), temperature (°C) and height. 
• FACT-Fatigue survey 
• 12 lead Electrocardiogram (ECG)- including measurement of the QT interval 
• Serum iron, total iron binding capacity (TIBC), transferrin and serum ferritin  
• Vitamin B12 and serum folate levels 
• Coagulation 
• Serum chemistry  
• Hematology 
• LH, FSH, testosterone, progesterone, and estradiol  
• Back-up blood sample to be drawn for future testing 
• Serum Pregnancy Test for females of childbearing potential- to be assessed within 3 
days of Day 1. 
• Urinalysis 
• Evaluation of transfusion frequency (including history of transfusion up to 8 weeks 
prior to Day 1 
• Documentation of concomitant medications (any treatments taken 28 days prior to 
Day 1 
• Females of childbearing potential- collection of menstrual cycle information (date of 
last menstruation, date of menstrual period onset and duration of menstruation) 
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• CT/MRI scan: Head, neck, thoracic, abdominal, and pelvic scans are to be acquired.  
A CT/MRI scan acquired within 4 weeks of initiating the current chemotherapy 
regimen may be used for the screening assessment. One measurable or non-
measurable lesion per RECIST is to be identified by the scan.  
o Brain (head) CT only to be done to rule out CNS metastases in patients with 
suspicious clinical symptoms or prior history of CNS metastases.  
• Dual-energy X-ray absorptiometry (DXA) of  lumbar spine and hip 
• Bone scans (only for patients with bone metastases) acquired within 4 weeks of the 
initiation of the current chemotherapy regimen may be used for the screening 
assessment. 
10.1.3. 
Initial Dosing: Day 1  
Patients will be dosed on Day 1.  Results from screening evaluations must be reviewed prior to 
randomization to confirm patient eligibility.  A patient will be considered randomized once a 
multi-digit patient identification number has been assigned to the patient through the IVRS.  
After assignment of the patient identification number, ACE-011/placebo administration may 
begin. 
Chemotherapy regimen will be administered per standard of care at the site. The following tests 
must be performed prior to ACE-011/placebo administration: 
• Confirm eligibility of patient by inclusion/exclusion criteria. The local hemoglobin 
value should be drawn prior to ACE-011/placebo administration.  
• Physical Examination 
• Vital signs including weight (kg), heart rate (beats/min), seated systolic and diastolic 
blood pressure (mmHg), and temperature (°C)  
• FACT-Fatigue survey 
• 12 lead ECG- including measurement of the QT interval 
• Serum iron, total iron binding capacity, transferrin and serum ferritin 
• Coagulation 
• Chemistry   
• Hematology 
• Serum erythropoietin marker  
• Peripheral blood smear 
• LH, FSH, testosterone, progesterone, and estradiol  
• Anti-drug antibody test 
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• Bone biomarkers- osteocalcin (OC), procollagen type 1 N-terminal propeptide 
(P1NP), serum bone specific alkaline phosphatase (BSAP), C-terminal type 1 
collagen telopeptide (CTX) and Serum tartrate-resistant acid phosphatase isoform-5b 
(TRACP-5b), and urine N-telopeptide (uNTX).  
o Please refer to the Study Reference Guide, provided under separate cover, for 
the Bone Biomarker Collection and Handling Guidelines for instructions the 
collection of serum and urine for the biomarkers.  
• Back-up blood sample to be drawn for future testing 
• Females of childbearing potential- Urine (dipstick) pregnancy test to be collected and 
resulted prior to ACE-011/placebo dosing 
• Urinalysis 
• Evaluation of transfusion frequency  
• Documentation of concomitant medications  
• Evaluation of adverse events (after study drug administration)  
• Females of childbearing potential- collection of menstrual cycle information (date of 
last menstruation from day 1, date of menstrual period onset and duration of 
menstruation)  
Patients will be administered ACE-011/placebo before the chemotherapy regimen begins during 
the study visits.  
After ACE-011/placebo and chemotherapy are administered, the patient may leave the clinic, 
based on the clinical judgment of the staff.   
10.1.4. 
ACE-011/placebo administration : Days 29, 57, and 85 (± 3 days)  
Chemotherapy regimen will be administered per standard of care at the site. ACE-011/placebo 
will be administered approximately every 28 days. The following procedures must be performed 
prior to ACE-011/placebo administration: 
• Physical Examination 
• Vital signs including weight (kg), heart rate (beats/min), seated systolic and diastolic 
blood pressure (mmHg), and temperature (°C)  
• FACT-Fatigue survey 
• 12 lead ECG -including measurement of the QT interval (Day 29 only) 
• Serum iron, total iron binding capacity, transferrin and serum ferritin  
• Coagulation 
• Serum chemistry  
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• Hematology 
• Serum erythropoietin marker  
• Peripheral blood sample 
• LH, FSH, testosterone, progesterone, and estradiol 
• Anti-drug antibody test 
• Bone biomarkers- OC, BSAP, PINP, CTX, TRACP-5b, and uNTX 
o Please refer to the Study Reference Guide, provided under separate cover, for 
the Bone Biomarker Collection and Handling Guidelines for instructions the 
collection of serum and urine for the biomarkers.  
• Back-up blood sample to be drawn for future testing 
• Females of childbearing potential -Urine (dipstick) pregnancy test  
• Urinalysis (Day 85 only) 
• Evaluation of transfusion frequency  
• Documentation of concomitant medications 
• Evaluation of adverse events  
• Females of childbearing potential- collection of menstrual cycle information (date of 
last menstruation, date of menstrual period onset and duration of menstruation)  
Hemoglobin (HgB) and Hematocrit values (Hct) and blood pressure (BP) measurement must be 
assessed prior to ACE-011/placebo dose administration by review of local laboratory values.  
10.1.5. 
Additional visits during Treatment Period: Days 8, 15, 22, 36 (± 1 day), 43, 64 
and 71 (± 2 days) 
 
Chemotherapy regimen will be administered per standard of care at the site.  The following 
procedures are to be performed during the study visit:  
• Vital signs including weight (kg), heart rate (beats/min), seated systolic and diastolic 
blood pressure (mmHg), and temperature (°C)  
• 12 lead ECG -including measurement of the QT interval (Day 15 only) 
• Serum folate (Day 36 only) 
• Coagulation 
• Serum chemistry  
• Hematology  
• Back-up blood sample to be drawn for future testing 
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• Evaluation of transfusion frequency  
• Documentation of concomitant medications 
• Evaluation of adverse events  
• CT/MRI scan (Day 64 only, +/- 5 day window).  Same modality as acquired for 
baseline should be used for follow up scans. Tumor response assessments to be 
evaluated by the investigator. 
• Bone scan (Day 64 only, +/- 5 day window). Follow-up scan to be acquired if 
performed at baseline. 
If patient terminates the treatment early, prior to receiving a fourth dose of ACE-011/placebo, the 
patient will enter the treatment period follow up. However, if patient terminates ACE-
011/placebo early and begins a new chemotherapy regimen, the patient should complete the Day 
281/Termination visit procedures and enter the post treatment follow up period. 
10.1.6. 
Treatment Period Follow-up visits : Days 113 and 141 (± 7 days) 
Chemotherapy regimen will be administered per standard of care at the site.  The following 
procedures are to be performed during the study visit: 
• Physical Examination 
• Vital signs including weight (kg), heart rate (beats/min), seated systolic and diastolic 
blood pressure (mmHg), and temperature (°C)  
• 12 lead ECG-including measurement of the QT interval (Day 113 only) 
• Serum folate (Day 113 only) 
• Coagulation  
• Serum chemistry  
• Hematology   
• Serum erythropoietin marker  (Day 141 only) 
• LH, FSH, testosterone, progesterone, and estradiol  
• Anti-drug antibody test 
• Bone biomarkers- OC, BSAP, PINP, CTX, TRACP-5b, and uNTX  
o Please refer to the Study Reference Guide, provided under separate cover, for 
the Bone Biomarker Collection and Handling Guidelines for instructions the 
collection of serum and urine for the biomarkers. 
• Back-up blood sample to be drawn for future testing 
• Evaluation of transfusion frequency  
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• Documentation of concomitant medications 
• Evaluation of adverse events  
• Females of childbearing potential- collection of menstrual cycle information (date of 
last menstruation, date of menstrual period onset and duration of menstruation)  
• CT/MRI scan (Day 113 only, +/- 5 day window). Same modality as acquired for 
baseline should be used for follow up scans. Tumor response assessments to be 
evaluated by the investigator. 
• DXA of  lumbar spine and hip (Day 113 only) 
• Bone scan (Day 113 only, +/- 5 day window). Follow-up scan to be acquired if 
performed at baseline. 
10.1.7. 
Post Treatment Period Follow-up visits : Days 169, 197, 225, and 253 (± 7 days) 
If a CT/MRI and bone scan (if applicable) is performed as per standard of care during the post 
treatment period follow up, results may be collected within the eCRF to capture the status of the 
disease. Chemotherapy regimen will be administered per standard of care at the site. The 
following procedures are to be performed during the study visit: 
• Hematology 
• Back-up blood sample to be drawn for future testing 
• Evaluation of transfusion frequency  
• Documentation of concomitant medications 
• Evaluation of adverse events  
10.1.8. 
Termination Visit:  Day 281 (± 7 days) 
Day 281 is the final visit.  If a patient terminates the study early, the Day 281 procedures should 
be followed. Chemotherapy regimen will be administered per standard of care at the site. The 
following procedures are to be performed during the study visit: 
• Physical Examination 
• Vital signs including weight (kg), heart rate (beats/min), seated systolic and diastolic 
blood pressure (mmHg), and temperature (°C)  
• FACT-Fatigue survey 
• 12 lead ECG -including measurement of the QT interval 
• Serum iron, total iron binding capacity, transferrin and serum ferritin  
• Serum folate 
• Coagulation 
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• Serum chemistry  
• Hematology  
• Serum erythropoietin marker 
• Peripheral blood smear 
• Anti-drug antibody test 
• Bone biomarkers- OC, BSAP, PINP, CTX, TRACP-5b, and uNTX  
o Please refer to the Study Reference Guide, provided under separate cover, for 
the Bone Biomarker Collection and Handling Guidelines for instructions the 
collection of serum and urine for the biomarkers. 
• Back-up blood sample to be drawn for future testing 
• Females of childbearing potential -Urine (dipstick) pregnancy test  
• Urinalysis 
• Evaluation of transfusion frequency  
• Documentation of concomitant medications  
• Evaluation of adverse events  
• DXA of  lumbar spine and hip 
• Bone scan (Day 281, +/- 5 day window). Follow-up scan to be acquired if performed 
at baseline. 
If a patient has a positive anti-drug antibody result at Day 281/Termination visit, the patient may 
be asked to return to the clinical site for additional monthly anti-drug antibody testing, 12 months 
after their last dose. 
10.2. 
Discontinuation of study 
The Sponsor may terminate this study, after consultation with the Investigator, at any time for 
safety or administrative reasons.  The Sponsor may terminate the study if the occurrence of 
serious adverse events (SAEs) or other findings suggest unacceptable risk to the health of the 
patients.   
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11. 
INVESTIGATIONAL PRODUCT MATERIALS AND 
MANAGEMENT 
11.1. 
Reference Product 
The placebo (control agent) to be used in this study will be sterile normal saline (0.9% Sodium 
Chloride for Injection) administered as a SC injection.  Sterile, normal saline will be supplied to 
the investigational site’s pharmacist.  The manufacturer’s directions for placebo storage and 
handling are to be followed, as are standard clinical practices for ensuring sterility of the 
placebo. 
11.2. 
Investigational Product Packaging and Labeling 
ACE-011 will be supplied in 2 mL clear glass vials with gray stoppers and red flip-top seals that 
contain 1 mL of ACE-011.  The drug product consists of ACE-011 in PBS at a nominal 
concentration of approximately 50 mg/mL. 
11.3. 
Investigational Product Storage 
ACE-011 is recommended to be stored at ≤ -65°C. 
11.4. 
Investigational Product Preparation 
See Investigational Product Preparation Manual. 
11.5. 
Administration 
ACE-011/placebo will be administered by subcutaneous injection (SC). Subcutaneous injections 
will be given in the upper arm and/or thigh. Please refer to Investigational Product Handling and 
Administration document for further information. 
Dose modifications will be determined by the investigator after reference to the dose 
modification rules listed in Figure 1. In the case of a dose interruption or dose reduction of ACE-
011, the investigator or designee will notify the pharmacy staff, who is unblinded, of the 
treatment decision for appropriate preparation of the study drug to maintain the blind of the 
study.  
11.6. 
Drug Accountability 
Accountability for ACE-011/placebo is the responsibility of the Investigator.  Investigational 
clinical supplies must be received by a designated person at the clinical site and kept in a secured 
location.  The investigational site must maintain accurate records demonstrating dates and 
amounts of ACE-011/placebo received, to whom it was dispensed (patient-by-patient 
accounting), and accounts of any ACE-011/placebo accidentally or deliberately destroyed or 
returned.  Unless otherwise notified, all vials of ACE-011/placebo, both used and unused, must 
be saved for drug accountability.  The used vials may be discarded, per the institution’s standard  
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practice, after drug accountability has been completed by the monitor. The Investigator must 
return all unused vials of ACE-011 to the Sponsor at the end of the study, or the study drug 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. 
11.7. 
Investigational Product Handling and Disposal 
Please refer to the Study Reference Guide, provided under separate cover, for detailed drug 
handling, administration, and storage instructions.   
 
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12. 
ASSESSMENT OF EFFICACY 
Efficacy measurements will include assessments for hematopoietic response which is defined as 
an increase in hemoglobin of ≥ 0.5 g/dL, ≥ 1 g/dL, ≥ 2 g/dL and/or hemoglobin concentration ≥ 
11 g/dL above the study baseline value for 28 consecutive days during the treatment period 
including up to 2 months after the last dose of ACE-011, in the absence of any RBC transfusions 
and/or ESAs, at each dose level. The hematopoietic endpoints will be determined by the 
monitoring of hematologic laboratory values and RBC transfusion and/or ESA administration. 
Secondary endpoints associated with assessment of disease progression will be evaluated by 
CT/MRI scan and bone mineral density by DXA scans, respectively. Bone biomarkers and 
incidence of skeletal related events (SREs) will also be evaluated for all patients. SREs are 
defined as pathologic fracture, radiation therapy to bone, surgery to bone, or spinal cord 
compression. Quality of life assessment (FACT-Fatigue) will be evaluated for each patient.  
 
 
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13. 
ASSESSMENT OF SAFETY 
13.1. 
Safety Parameters 
13.1.1. 
Adverse Events 
All patients will be assessed for safety by monitoring adverse events, clinical laboratory tests, 
vital signs and physical examinations. AE information will be collected throughout the study.  
See Section 14 Adverse Events for a full description of AE definitions, AE and SAE reporting 
procedures, and emergency procedures. 
13.1.2. 
Clinical Laboratory Tests 
The following laboratory safety assessments will be drawn at the investigational site’s local 
laboratory according to the laboratory collection recommendations. The samples will then be 
sent to the central lab for value reporting. Please refer to Lab Reference Manual for further 
information. Hemoglobin and hematocrit lab tests will be drawn and evaluated by the local 
laboratory at each visit day throughout the study. The local hemoglobin laboratory value will be 
used in the evaluation of ACE-011/placebo dose modifications. The sponsor may request 
additional safety tests be performed based on ongoing data review during the study.  
• Iron studies: Serum iron, total iron binding capacity (TIBC), transferrin and serum ferritin on  
 
specified days. 
• 
Nutritional tests: Serum folate and vitamin B12 
• 
Coagulation (central lab only): prothrombin time (PT), partial thromboplastin time (PTT), 
and fibrinogen 
• 
Serum chemistry (central lab only): AST, ALT, lactate dehydrogenase (LDH), total bilirubin, 
indirect bilirubin, alkaline phosphatase, total protein, albumin, sodium, potassium, chloride, 
carbon dioxide, calcium, phosphorus, blood urea nitrogen (BUN), creatinine, uric acid, 
glucose, amylase, and lipase.  
• 
Hematology: complete blood count (CBC) with differential and platelet.  CBC includes red 
blood cells (RBC), white blood cells (WBC), hemoglobin, hematocrit, mean corpuscular 
volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin 
concentration (MCHC), and erythropoietin levels.  Reticulocyte percent and peripheral blood 
smear will be collected on specified days.  
• 
Bone biomarkers:  (serum) osteocalcin (OC), procollagen type 1 N-terminal propeptide 
(P1NP), serum bone specific alkaline phosphatase (BSAP), C-terminal type 1 collagen 
telopeptide (CTX), tartrate-resistant acid phosphatase isoform-5b (TRACP-5b), and urine N-
telopeptide (uNTX).  
• 
Pregnancy test for females of child bearing potential 
• Urinalysis: including determination of pH, specific gravity, protein, glucose, ketones, blood, 
leukocyte esterase and nitrite. Microscopy required only to follow-up abnormal findings.  
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13.1.3. 
Other Safety Assessments  
• Physical examinations 
• Vital signs: weight (kg), heart rate (beats/min), seated blood pressure (mmHg) and 
oral temperature (°C).  Height will be collected at screening only. 
• FACT-Fatigue survey 
• 12-lead ECG -including measurement of the QT interval 
• LH, FSH, testosterone, progesterone, and estradiol 
• Anti-drug antibody test 
• CT/MRI scan   
• DXA 
• Bone scans (for those patients with baseline bone metastases) 
13.2. 
Pharmacokinetics 
 See Appendix 5 for further details regarding PK sampling.  
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14. 
ADVERSE EVENT 
Adverse Event 
An adverse event (AE) is any untoward medical occurrence in a patient administered a 
pharmaceutical product, which does not necessarily have a causal relationship with the treatment.  
An AE can be any unfavorable and unintended sign (e.g., including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of the study drug, whether or 
not it is considered to be study drug related.  This includes any newly occurring event or 
previous condition that has increased in severity or frequency since the administration of study 
drug (treatment-emergent). 
Serious Adverse Event 
A serious adverse event (SAE) is any AE, occurring at any dose level and regardless of causality 
that: 
• Results in death. 
• Is life-threatening:  Life-threatening means that the patient was at immediate risk of death 
from the reaction as it occurred, (i.e., it does not include a reaction which hypothetically 
might have caused death had it occurred in a more severe form). 
• Requires inpatient hospitalization or prolongation of existing hospitalization.  
• Results in persistent or significant disability/incapacity. 
• Is a congenital anomaly/birth defect. 
• Is an important medical event: an important medical event is an event that may not result 
in death, be life-threatening, or require hospitalization but may be considered an SAE 
when, based upon appropriate medical judgment, it may jeopardize the patient and may 
require medical or surgical intervention to prevent one of the outcomes listed in the 
definitions for SAEs.  Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, blood dyscrasias or 
convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse.   
• A hospitalization for an elective procedure will not be considered a SAE.  
Unexpected Adverse Event 
An unexpected AE is an AE that is not reported in the Investigator Brochure or in the case of an 
AE already described, the severity of which is not described in the Investigator Brochure.  
 
 
 
 
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14.1. 
Adverse Event Classification 
The following classifications should be used when evaluating the relationship of AEs and SAEs 
to the investigational drug. 
None: 
No relationship between the experience and the administration of study 
drug; related to other etiologies such as concomitant medications or 
patient’s clinical state. 
Unlikely:  
 
 
The current state of knowledge indicates that a relationship is unlikely.   
Possibly: 
A reaction that follows a plausible temporal sequence from administration 
of the study drug and follows a known response pattern to the suspected 
study drug.  The reaction might have been produced by the patient’s 
clinical state or other modes of therapy administered to the patient. 
Probably: 
A reaction that follows a plausible temporal sequence from administration 
of the study drug and follows a known response pattern to the suspected 
study drug.  The reaction cannot be reasonably explained by the known 
characteristics of the patient’s clinical state or other modes of therapy 
administered to the patient. 
Definitely: 
A reaction that follows a plausible temporal sequence from administration 
of the study drug and follows a known response pattern to the suspected 
study drug and can be confirmed with a positive re-challenge test or 
supporting laboratory data. 
Severity of AEs will be graded by the investigator using the National Cancer Institute (NCI; US) 
Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 guidelines (Appendix 
3). 
14.2. 
Recording Adverse Events 
Patients will be evaluated and questioned generally for AEs during the course of the study, 
starting from baseline (Day 1).  The Medical History CRF should be comprehensive of patient’s 
medical history up to Day 1. All AEs occurring after ACE-011/placebo administration until the 
Day 281/Termination visit are to be documented on AE CRF. The specific disease or syndrome 
rather than individual associated signs and symptoms should be identified by the investigator and 
recorded on the CRF.  
 
 
 
 
 
 
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Serious Adverse Events (SAEs) 
For SAEs, a SAE form must be completed with as much information as possible and submitted 
in the time frame described in Section 14.3.  
When new significant information is obtained as well as when the outcome of an event is known, 
the investigator should record the information on a new SAE form.  If the patient was 
hospitalized, a copy of the discharge summary must be included as part of the patient medical 
file.  In all instances, the investigator should follow up with patients until the outcome of the 
SAE is known. 
14.3. 
Reporting Adverse Events 
All AEs spontaneously reported by the patient and/or in response to an open question from study 
personnel or revealed by observation, physical examination or other diagnostic procedures will 
be recorded on the AE CRF.  Any clinically relevant change in laboratory assessments or other 
clinical findings is considered an AE and must be recorded on the AE CRF. Clinically significant 
laboratory abnormalities are those that are identified as such by the investigator and/or those that 
require intervention. All AEs are to be followed until the event resolves or the clinical course is 
stabilized.  
Serious Adverse Events 
For SAEs, a SAE form must be completed with as much information as possible and submitted 
in the time frame described below. 
All SAEs that occur during the course of the study (from the signing of the ICF until the last 
study visit) must be reported by the Investigator to PPD and Sponsor by faxing the SAE form 
within 24 hours from the point in time when the Investigator becomes aware of the SAE.  All 
SAEs and deaths must be reported whether or not considered causally related to the study drug.   
SAE Reporting: 
PPD Medical Monitor 
PPD Inc. 
If there are serious, unexpected AEs associated with the use of the study drug, the Sponsor will 
notify the appropriate regulatory agency(ies) and all appropriate parties on an expedited basis.  It 
is the responsibility of the Investigator to promptly notify the Institutional Review Board (IRB) 
of all unexpected SAEs involving risk to human patients. 
 
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14.4. 
Emergency Sponsor Contact 
In the event of a medical emergency (i.e., an event that requires immediate attention regarding 
the treatment of a patient, operation of the clinical study, and/or the use of investigational drug), 
investigational site personnel must immediately contact the Medical Monitor. 
 
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15. 
STATISTICS 
Statistics Analysis Overview 
The study will be considered complete with regard to the primary endpoint once all eligible 
subjects have completed up to 2 months after the last dose of ACE-011. Patients will be 
randomized to one of three ACE-011 treatment groups (0.1, 0.3 and 0.5 mg/kg) or placebo with a 
ratio of 2:2:2:1.  Patients will be stratified according to administration of either single agent 
weekly chemotherapy or less frequent chemotherapy regimens.  
15.1. 
Determination of Sample Size 
With an anticipated dropout rate of 20%, a sample size of 30 patients per dose level is estimated 
to achieve at least 80% power with 2 sided significance level of 0.05 to differentiate targeted 
response rate of p1=0.45 from null hypothesis p0=0.20. An additional 15 patients will be 
enrolled to the placebo group for safety comparison. A total of 105 patients will be randomized 
to three ACE-011 dose groups (0.1, 0.3, and 0.5 mg/kg) and placebo with a ratio of 2:2:2:1.  
15.2. 
Analysis Populations 
For this study, the following populations will be defined and used in the analysis and 
presentation of the data. 
Modified Intent-to-Treat (MITT) population: The MITT population is defined as all patients 
randomized who received at least one dose of study drug. 
Per-Protocol (PP) population: The PP population is defined as all patients randomized who have 
confirmed chemotherapy induced anemia, received at least one dose of ACE-011 and on study 
(treatment) for at least 2 months (57 days). 
Safety population: The safety population is defined as all patients who received at least one dose 
of study drug ACE-011 or placebo. 
15.3. 
Background and Demographic Characteristics 
Summary statistics (mean, standard deviation, median, minimum and maximum) will be 
provided for those variables measured on a continuous scale.  The frequency distribution 
(number and percentage) will be provided for those variables measured on a nominal scale. 
15.3.1. 
Patient Disposition 
Patient disposition (analysis population allocation, entered, discontinued, along with primary 
reason for discontinuation) will be summarized using frequency and percent for each dose group.  
A summary of patients enrolled by site will be provided.  
 
 
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15.3.2. 
ACE-011 
ACE-011 treatment exposure (total dosage received) will be summarized for each dose group as 
well as for each cycle for each dose level.  Listings for dose adjustment will be provided. 
15.3.3. 
Concomitant Therapy 
By-patient listings will be provided for all concomitant medications and therapies taken during 
the study.  All concomitant medications will be coded and categorized by the WHO drug coding 
system.  Usage frequency of each coded concomitant medications will be summarized by each 
dose group. 
15.4. 
Efficacy Evaluation 
15.4.1. 
Primary Efficacy Analysis 
The primary efficacy endpoint is the hematopoietic response rate at each dose level.  It is defined 
as the proportion of patients who have a hematopoietic response of an increase in hemoglobin of 
≥ 0.5 g/dL for 28 consecutive days during the treatment period including up to 2 months after the 
last dose of ACE-011, in the absence of any RBC transfusions and/or ESAs. The ACE-011 
treatment period is defined as from the time of first ACE-011 dose to up to 2 months after the 
last dose of ACE-011 treatment.  To be considered as a responder, all hemoglobin measurements 
during a 28 consecutive day period or longer must have an increase of ≥ 0.5 g/dL from baseline. 
If RBC transfusions and/or ESAs are required, no hemoglobin measurements within 28 days will 
be used to determine the hemoglobin response. Primary efficacy analysis will be based on PP 
population.  Primary efficacy analysis will also be conducted on MITT population as supportive 
to the PP based analysis.  Patients who do not receive ACE-011 will be excluded from primary 
efficacy analysis.  Patients who discontinue the ACE-011 treatment prematurely will be counted 
as non-responder in the calculation of response rate.     
A 95% confidence interval (CI) for the response rate for each dose level will be provided to 
assess whether 95% CI of response rate contains null hypothesis response rate, p0=0.20.  The 
response rate and 95% CI will also be provided for patients with chemotherapy on weekly basis 
versus those with chemotherapy on a less frequent basis for each dose level as well as overall (all 
three doses levels analyzed together).  
An exploratory analysis with the Kaplan Meier approach will be considered to account for those 
patients who discontinue the ACE-011 treatment prematurely if the drop out rate is greater than 
20%.  Exploratory analysis of comparing hematopoietic response rates between active and 
placebo will be performed using Fisher’s exact test.  Due to the nature of the study (phase 2 dose 
determination study), no multiplicity adjustment will made for the multiple comparisons.  
 
 
 
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15.4.2. 
Secondary Efficacy Analyses 
The secondary efficacy endpoints include: 
• Proportion of patients achieving an increase in hemoglobin of ≥ 1 g/dl, ≥ 2 g/dL and/or 
hemoglobin concentration ≥ 11 g/dL for 28 consecutive days during the treatment period 
and up to 2 months after the last dose of ACE-011 in the absence of any RBC 
transfusions and/or ESAs.   
• Duration of hematopoietic response (days) defined as the first time hemoglobin increases 
at least 0.5 g/dL, ≥ 1 g/dl, ≥ 2 g/dL and/or hemoglobin concentration ≥ 11 g/dL from 
baseline to the last time there is hemoglobin ≥ 0.5 g/dL, ≥ 1 g/dl, ≥ 2 g/dL and/or 
hemoglobin concentration ≥ 11 g/dL increase from baseline.  Duration of response is only 
calculated for a responder and will be at least 28 days.  The duration of response will be 
at least 28 days is only calculated for a patient who meets the primary efficacy endpoint.  
• Time to achieve hematopoietic response (days) defined as time from first dose of ACE-
011 to the first time a hemoglobin result at least 0.5 g/dL, ≥ 1 g/dl, ≥ 2 g/dL and/or 
hemoglobin concentration ≥ 11 g/dL increase from baseline and maintained for a period 
of at least 28 consecutive days. 
• Proportion of patients receiving red blood cell (RBC) transfusions and/or ESAs in each 
dose group as well as within each cycle of each ACE-011 dose level. 
• Objective tumor response rate for each dose level using RECIST criteria. 
• Progression-Free Survival is defined as the time from randomization into the study to the 
first observation of documented disease progression or death due to any cause.  If the 
subject has not progressed or died at the time of final analysis, PFS will be censored at 
the time of last tumor assessment.   
The statistical analysis for binary endpoints will be similar to the primary efficacy analysis.  For 
time to event endpoints, the Kaplan-Meier method will be used to estimate the survival curve and 
median time to event.  These analyses will be performed for each dose group and all ACE-011 
groups combined.   
15.5. 
Safety Evaluation 
Safety variables will be tabulated and presented for all patients who receive ACE-011.  Adverse 
events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA).  
Incidence of treatment-emergent adverse events will be presented by system organ class (SOC) 
and preferred term.  Adverse events will also be presented by severity, and relationship to study 
drug.  Change from baseline in clinical laboratory parameters and vital signs will be summarized 
across time.  Shift tables will be presented for selected laboratory parameters.  Physical 
examination results will be presented in listings.  
Data from all patients who receive one or more doses of study drug will be included in the safety 
analyses. To assess clinical safety, adverse events, vital sign measurements and clinical  
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laboratory information will be summarized by visit. Adverse events and laboratory results will 
also be summarized by severity grade (NCI CTCAE v3.0). Descriptive statistics will be 
generated and shift tables provided as appropriate.  
15.6. 
Pharmacokinetic Evaluation 
Listing of individual patient serum ACE-011 concentrations, actual blood sampling times and 
graphs of concentration vs. time will be prepared for each dose group.  Summaries of PK 
parameters will be summarized by dose group. The trough concentrations will be summarized for 
all patients who provide pharmacokinetic samples by dose group. Exploratory analyses will be 
performed to correlate trough concentrations with efficacy, bone biomarker data, and safety data, 
however these analyses will be data-driven and only conducted if warranted by the data.  
15.6.1. 
Anti-drug Antibody Data 
The results of anti-drug and neutralizing antibodies will be presented over time.  Exploratory 
analysis will be performed on the potential effect of anti-drug antibody on ACE-011 PK and 
drug exposure if anti-drug antibody tests are deemed positive. 
15.7. 
Interim Analysis  
There is no planned interim analysis for this study.   
15.8. 
Deviation from Original Analysis Plan 
Deviations from the statistical analyses outlined in this protocol will be indicated in the statistical 
analysis plan; any further modifications will be noted in the final clinical study report. 
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16. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
16.1. 
Study Monitoring 
The Clinical Monitor will arrange to visit the Investigator sites at regular intervals during the 
study.  The monitoring visits must be conducted according to the applicable ICH and GCP 
guidelines to ensure protocol adherence, quality of data, drug accountability, compliance with 
regulatory requirements, and continued adequacy of the investigational site and its facilities.  
During these visits, CRFs and other data related to the study will be reviewed and any 
discrepancies or omissions will be resolved.  The Clinical Monitor will be given access to study 
relevant source documents (including medical records) for purposes of source data verification. 
During and/or after completion of the study, quality assurance officers named by the Sponsor or 
the regulatory authorities may wish to perform on-site audits.  The Investigator is expected to 
cooperate with any audit and provide assistance and documentation (including source data) as 
requested. 
16.2. 
Audits and Inspections 
The Investigators and clinical sites will permit trial related monitoring, audits, IRB review, and 
regulatory inspections as requested by FDA, the Sponsor or designee, including direct access to 
source data/documents (i.e., original medical records, laboratory reports, hospital documents, 
progress reports, signed ICFs, etc.) in addition to CRFs. 
 
 
 
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17. 
QUALITY CONTROL AND QUALITY ASSURANCE 
17.1. 
Data Quality Control and Quality Assurance 
17.1.1. 
Investigator responsibility 
The investigator is responsible for ensuring the study is conducted according to the protocol, 
Code of Federal Regulations (CFR), GCP, and any other applicable regulatory requirements. 
These responsibilities outlined in these documents along with the documentation that a signed 
informed consent must be obtained prior to a patient participation in the study. 
17.1.2. 
Protocol modifications 
The investigator may not modify the protocol without agreement from the Sponsor and prior 
review or approval by the IRB. Any deviations from the protocol should be documented by the 
investigator or designee.  
17.2. 
Financing and Insurance 
Financing and insurance are addressed in a separate document. 
17.3. 
Confidentiality 
To maintain patient privacy, all eCRFs, study drug accountability records, study reports and 
communications will identify the patient by the assigned patient identification number.  The 
Investigator will grant monitor(s) and auditor(s) from the Sponsor or designee and regulatory 
authority(ies) access to the patient’s original medical records for verification of data gathered on 
the CRFs and to audit the data collection process.  The patient’s confidentiality will be 
maintained and will not be made publicly available to the extent permitted by the applicable laws 
and regulations. 
All information regarding the investigational product supplied by the Sponsor to the Investigator 
is privileged and confidential information.  The Investigator agrees to use this information to 
accomplish the study and will not use it for other purposes without consent from the Sponsor.  It 
is understood that there is an obligation to provide the Sponsor with complete data obtained 
during the study.  The information obtained from the clinical study will be used towards the 
development of the investigational product and may be disclosed to regulatory authority(ies), 
other Investigators, corporate partners, or consultants as required. 
17.4. 
Publication Policy 
All information concerning ACE-011 is considered confidential and shall remain the sole 
property of the Sponsor.  The Investigator agrees to use this information only in conducting the 
study and shall not use it for any other purposes without the Sponsor’s written approval.  The 
Investigator agrees not to disclose the Sponsor’s confidential information to anyone except to  
 
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people involved in the study that need such information to assist in conducting the study, and 
then only on like terms of confidentiality and nonuse. 
It is understood by the Investigator that the information developed from this clinical study will 
be used by the Sponsor in connection with the development of ACE-011, and therefore may be 
disclosed as required to regulatory agencies.  To allow for the use of the information derived 
from clinical studies, it is understood that there is an obligation to provide the Sponsor with 
complete test results and all data developed in the study. 
No publication or disclosure of study results will be permitted except as specified in a separate, 
written, agreement between the Sponsor and the Investigator. 
17.5. 
Protocol Amendments 
Protocol amendments that impact patient safety change the scope of the investigation, or affect 
the scientific quality of the study must be approved by the IRB and submitted to the appropriate 
regulatory authorities before implementation of such modifications to the study. 
In the event that the protocol needs to be modified immediately to eliminate an apparent hazard 
to a patient, the Sponsor will amend and implement the protocol change and subsequently notify 
the regulatory authorities and/or the IRB, as appropriate. 
 
 
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18. 
ETHICS 
18.1. 
Institutional Review Board or Independent Ethics Committee 
The Investigator must obtain written IRB approval of the protocol, approval for relevant 
supporting information and all types of patient recruitment and advertisement and ICF prior to 
starting the study.  The IRB will meet all Food and Drug Administration (FDA) requirements 
governing IRBs (Code of Federal Regulations, Title 21, Part 56). 
The Sponsor or designee must approve the ICF submitted to the investigational site’s IRB. All 
patient recruitment and advertisements must be submitted to the Sponsor or designee prior to 
submission to the IRB, for review. 
18.2. 
Ethical Conduct of the Study 
The Sponsor and the Investigator must comply with all instructions, regulations, and agreements 
in this protocol and in the applicable International Conference on Harmonisation (ICH) and GCP 
guidelines, and must also conduct the study in accordance with local regulations.   
18.3. 
Written Informed Consent 
18.3.1. 
Informed Consent 
Informed written consent is required from each patient prior to any testing under this protocol, 
including screening tests and evaluations.  The consent form, as specified by the clinical site’s 
IRB, must follow the Protection of Human Patients regulations listed in the Code of Federal 
Regulations, Title 21, Part 50.   
The background of the proposed study and the benefits and risks of the procedures and study 
must be explained to the patients.  It is the responsibility of the Investigator to obtain consent and 
to provide the patient with a copy of the signed and dated ICF.  Confirmation of a patient’s 
informed consent must also be documented in the patient’s medical record prior to any testing 
under this protocol, including screening tests and evaluations. 
All ICFs used in this study must be approved by the appropriate IRB and by the Sponsor or 
designee.  The ICF must not be altered without the prior agreement of the relevant IRB and the 
Sponsor.   
18.3.2. 
Patient Data Protection 
Prior to any testing under this protocol, including screening tests and evaluations, patients must 
authorize the release and use of protected health information (PHI), as required by local law. 
The patient will not be identified by name in the CRF or in any study reports.  These reports will 
be used for research purposes only.  The Sponsor, its designee, and various government health 
agencies may inspect the records of this study.  Every effort will be made to keep the patient’s 
personal medical data confidential. 
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19. 
DATA HANDLING AND RECORDKEEPING 
19.1. 
Case Report Form Completion 
CRFs will be completed for each randomized patient.  It is the Investigator’s responsibility to 
ensure the accuracy, completeness, and timeliness of the data reported in the patient’s CRF.  
Source documentation supporting the CRF data should indicate the patient’s participation in the 
study and should document the dates and details of study procedures, AEs, and patient status. 
Investigators will maintain copies of the CRFs at the clinical site.  For patients who discontinue 
or terminate from the study, the CRFs will be completed as much as possible, and the reason for 
the discontinuation or termination clearly and concisely specified on the appropriate CRF. 
19.2. 
Retention of Records 
The Investigator will maintain all study records according to ICH-GCP and applicable regulatory 
requirements.  Records will be retained for at least 2 years after the last marketing application 
approval or 2 years after formal discontinuation of the clinical development of the investigational 
product or according to applicable regulatory requirements.  If the Investigator withdraws from 
the responsibility of keeping the study records, custody must be transferred to a person willing to 
accept the responsibility.  The Sponsor must be notified in writing if a custodial change occurs. 
 
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20. 
REFERENCES 
 
      1.   Groopman JE, Itri LM. (1999). Chemotherapy-Induced Anemia in Adults: Incidence and  
 
   Treatment. Journal of the National Cancer Institute 91, 1616-1634.  
2. NCCN Clinical Practice Guidelines in Oncology: Cancer and Chemotherapy Induced 
Anemia, V.3. 2009 http://www.nccn.org/professionals/physician_gls/PDF/anemia.pdf; 
2008. 
3. Ying S-Y. (1988). Inhibins, activins, and follistatins: gonadal proteins modulating the 
secretion of follicle-stimulating hormone. Endocrine Rev 9, 267-93. 
4. Woodruff TK. (1998). Regulation of cellular and system function by activin. Biochem 
Pharmacol 55, 953-63. 
5. Perrien DS, Akel NS, Edwards PK, Carver AA, Bendre MS, Swain FL, Skinner RA, 
Hoque WR, Nicks KM, Pierson TM, Suva LJ, and Gaddy D. (2007). Inhibin A is an 
endocrine stimulator of bone mass and strength. Endocrinology 148, 1654-65. 
6. Rivier J, Spiess J, McClintock R, Vaughan J and Vale W. (1985). Purification and partial 
characterization of inhibin from porcine follicular fluid. Biochem Biophys Res Commun 
133, 120-7. 
7. Murata M, Onomichi K, Eto Y, Shibai H, and Muramatsu M. (1988). Expression of 
erythroid differentiation factor (EDF) in Chinese hamster ovary cells.  Biochem Biophys 
Res Commun 151, 230-5. 
8. Shiozaki M, Sakai R, Tabuchi M, Nakamura T, Sugino K, Sugino H, and Eto Y. (1992). 
Evidence for the participation of endogenous activin A/erythroid differentiation factor in 
the regulation of erythropoiesis.  Proc Natl Acad Sci USA 89, 1553-6. 
9. Shiozaki M, Sakai R, Tabuchi M, Eto Y, Kosaka M, and Shibai H. (1989). In vivo 
treatment with erythroid differentiation factor (EDF/activin A) increases erythroid 
precursors (CFU-E and BFU-E) in mice. Biochem Biophys Res Commun 165, 1155-61. 
10. Nakao K, Kosaka M and Saito S. (1991). Effects of erythroid differentiation factor (EDF) 
on proliferation and differentiation of human hematopoietic progenitors. Exp Hematol 19, 
1090-5 
11. Chen Y-G, Lui HM, Lin S-L, Lee JM, and Ying S-Y. (2002). Regulation of cell 
proliferation, apoptosis, and carcinogenesis by activin. Exp Biol Med 227, 75-87. 
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12. Mathews LS. (1994). Activin receptors and cellular signaling by the receptor serine 
kinase family. Endocr Rev 15, 310-25. 
13. Chantry A, Heath D, Mulivor A, Coulton L, Evans H, Abdul N, Werner ED, Bouxsein 
ML, Pearsall RS, Seehra J, Vanderkerken K, and Croucher PI. (2008). Inhibiting activin-
A signalling stimulates bone formation, prevents tumor-induced osteolytic bone 
destruction and blocks bone metastasis. Submitted 2008. 
14. Pearsall RS, Canalis E, Cornwall-Brady M, Underwood KW, Haigis B, Ucran J, Kumar 
R, Pobre E, Grinberg A, Werner ED, Glatt V, Stadmeyer L, Smith D, Seehra J, and 
Bouxsein ML. (2008). A soluble activin type IIA receptor induces bone formation and 
improves skeletal integrity. Proc Natl Acad Sci USA 105, 7082-7 
15. Lotinun S, Fajardo RJ, Pearsall RS, Bouxsein ML, and Baron R. (2008). A soluble 
activin receptor type IIA fusion protein, ACE-011, increases bone mass by stimulating 
bone formation and inhibiting bone resorption in cynomolgus monkeys. ASBMR 30th 
annual meeting, 2008. 
16. Ruckle J, Jacobs M, Kramer W, Pearsall AE, Kumar R, Underwood KW, Seehra J, Yang 
Y, Condon CH, Sherman ML. (2008).  A single-dose, randomized, double-blind, 
placebo-controlled study of ACE-011 (ActRIIA-IgG1) in postmenopausal women.  J 
Bone Miner Res: 1-42.  Posted online on 2 Dec 2008. 
17. Functional Assessment of Chronic Illness, FACT-Fatigue Version 4. 
http://www.facit.org/qview/qlist.aspx. 2003. 
 
 
 
 
 
 
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21. 
APPENDICES 
Appendix 1: Response Evaluation Criteria in Solid Tumors 
 
 
Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 
  
Terms 
Definition 
Measurable disease  
 The presence of at least one measurable lesion by CT or MRI. If the 
measurable disease is restricted to a solitary lesion, its neoplastic nature 
should be confirmed by cytology/histology. 
All measurements should be taken and recorded in metric notation, using a 
ruler or calipers. All baseline evaluations should be performed as closely as 
possible to the beginning of treatment and never more than 4 weeks before 
the beginning of the treatment.  
Measurable lesions 
Lesions that can be accurately measured in least one dimension by CT scan  
with longest diameter > 10 mm (CT scan thickness no greater than 5 mm). 
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during 
follow-up.  
Non-measurable lesion 
All other lesions, including small lesions (longest diameter <10mm or 
pathological lymph nodes with P10 to <15mm short axis) as well as truly 
non-measurable lesions. Lesions considered truly non-measurable include: 
leptomeningeal disease, ascites, pleural or pericardial effusion, 
inflammatory breast disease, lymphangitic involvement of skin or lung, 
abdominal masses/abdominal organomegaly identified by physical exam 
that is not measurable by reproducible imaging techniques. 
 
 
 
 
 
 
 
 
 
 
 
 
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RECIST Criteria-Response Evaluation 
Evaluation of target lesions 
  
  
Complete Response (CR) 
 Disappearance of all target lesions. 
Any pathological lymph nodes (whether target or non-target) 
must have reduction in short axis to <10 mm. 
Partial Response (PR): 
At least a 30% decrease in the sum of diameters of target lesions, 
taking as reference the baseline sum diameters. 
Stable Disease (SD):   
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum 
diameters while on study. 
Progressive Disease (PD):  
At least a 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest sum on study (this includes the 
baseline sum if that is the smallest on study). In addition to 
the relative increase of 20%, the sum must also demonstrate 
an absolute increase of at least 5 mm.  
(Note: the appearance of one or more new lesions is also 
considered progression). 
 
 
 
 
 
Evaluation of non-target 
lesions 
  
  
Complete Response (CR):  
  
Disappearance of all non-target lesions and normalisation of 
tumour marker level. All lymph nodes must be non-pathological 
in size (<10mm short axis). 
 
Non-CR/Non-PD 
 
Persistence of one or more non-target lesion(s) and/or 
maintenance of tumour marker level above the normal limits. 
Progressive Disease (PD):  
Unequivocal progression (see comments below) of existing non-
target lesions.  
(Note: the appearance of one or more new lesions is also 
considered progression). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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RECIST Criteria-Response 
Evaluation cont- 
 
 
 
 
 
 
 
 
Evaluation of best overall 
response 
The best overall response is the best response recorded 
from the start of the treatment until disease 
progression/recurrence (taking as reference for PD the 
smallest measurements recorded since the treatment 
started). In general, the patient's best response assignment 
will depend on the achievement of both measurement and 
confirmation criteria. 
 
Patients with a global deterioration of health status 
requiring discontinuation of treatment without objective 
evidence of disease progression at that time should be 
classified as having “symptomatic deterioration”. Every 
effort should be made to document the objective 
progression even after discontinuation of treatment.  
 
In some circumstances it may be difficult to distinguish 
residual disease from normal tissue. When the evaluation of 
complete response depends on this determination, it is 
recommended that the residual lesion be investigated (fine 
needle aspirate/biopsy) to confirm the complete response 
status.  
 
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R,  Dancey J, Arbuck S, Gwyther S, Mooney M, 
Rubinstein L, Shankar L, Dodd L, Kaplan R,  Lacombe D, Verweij J.New response evaluation criteria in solid tumours: Revised 
RECIST guideline (version 1.1)  (2009). European Journal of Cancer 45, 228-247. 
 
 
 
 
 
 
 
 
 
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Appendix 2: ECOG Performance Status 
The ECOG scale is used to assess a patient’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 
patient.  
 
Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., Carbone, P.P. (1982) Toxicity And Response 
Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Onco 5:649-655. 
 
 
 
 
 
 
 
 
 
 
 
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, e.g., 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 
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Appendix 3:  National Cancer Institute (NCI) Common Terminology Criteria 
for Adverse Events (CTCAE) Version 3.0 
 
See http://ctep.cancer.gov/reporting/ctc.html  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Appendix 4: New York Heart Association- Classification of heart failure 
Class 1 - Class 1 heart failure - no limitation of activities. No symptoms from ordinary activities. 
Class 2 - Class 2 heart failure- mild limitation of activity. Comfortable with rest or mild exertion. 
Class 3 - Class 3 heart failure- marked limitation of activity and be comfortable only at rest. 
Class 4 –Class 4 heart failure- complete rest, confined to bed or chair; any physical activity brings on  
discomfort and symptoms occur at rest. 
 National Heart, Lung, and Blood Institute, National Institutes of Health. New York Heart Association Classification. 2008. 
 
 
 
 
 
 
 
 
 
 
 
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Protocol Amendment – Summary of Changes 
CLINICAL STUDY PROTOCOL 
A Phase 2, Double-Blind, Randomized, Placebo-Controlled 
Study of ACE-011 for the Treatment of Chemotherapy 
Induced Anemia in Patients with Metastatic Breast Cancer 
 
 
STUDY DRUG: 
 
 
ACE-011 
 
PROTOCOL NUMBER: 
 
 
A011-08 
 
SPONSOR: 
 
           Acceleron Pharma, Inc. 
                       128 Sidney Street 
                       Cambridge, MA 02139  
 
                     
                     
 
MEDICAL MONITOR: 
                 PPD Inc. 
 
                
 
                                                          
 
 
 
 
 
          
 
 
 
 
 
          
 
      
 
 
PROTOCOL DATE: 
                 13 March 2009 
AMENDMENT #1 : 
                 22 April 2009 
 
 
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                                 CLINICAL STUDY PROTOCOL 
A Phase 2, Double-Blind, Randomized, Placebo-Controlled 
Study of ACE-011 for the Treatment of Chemotherapy Induced 
Anemia in Patients with Metastatic Breast Cancer 
 
 
STUDY DRUG: 
 
 
ACE-011 
 
PROTOCOL NUMBER: 
 
 
A011-08 
 
SPONSOR: 
 
      Acceleron Pharma, Inc. 
            128 Sidney Street 
            Cambridge, MA 02139  
 
         
         
 
MEDICAL MONITOR: 
      PPD Inc. 
 
     
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
     
 
 
 
 
 
 
 
 
 
 
  
 
     
 
 
PROTOCOL DATE: 
     13 March 2009 
AMENDMENT #1 : 
     22 April 2009 
 
 
 
Confidentiality Statement 
This confidential information in this document is provided to you as an investigator or consultant for review by you, your staff, 
and the applicable institutional Review Board/Independent Ethics Committee.  Your acceptance of this document constitutes 
agreement that you will not disclose the information contained herein to others without written authorization from the Sponsor. 
 
 
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PROCEDURES IN CASE OF EMERGENCY 
 
Table 1: 
Emergency Contact Information 
Role in Study 
Name 
Address and Telephone number 
PPD Medical Monitor 
PPD Inc. 
1800 Perimeter Park Drive,  Suite 275 
Morrisville, NC 27560-7200 USA 
Clinical Trial Manager 
Acceleron Pharma, Inc. 
128 Sidney Street  
Cambridge, MA 02139 USA  
 
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2.
PROTOCOL SYNOPSIS
Name of Sponsor/Company:  Acceleron Pharma, Inc. 
128 Sidney Street 
Cambridge, MA 02139 
Name of Investigational Product: ACE-011 
Name of Active Ingredient:   
ACE-011 is a fully human fusion protein consisting of the extracellular domain (ECD) of the 
activin receptor IIA (ActRIIA) linked to the human IgG1 Fc domain.  
Mechanism of Action: ACE-011 is a disulfide-linked, glycosylated, dimeric protein. ACE-011 
competes with the activin receptor IIA that binds a number of TGF-β superfamily ligands 
including activin, myostatin (growth differentiation factor [GDF]-8), and GDF-11. 
Title of Study:  A Phase 2, Double-blind, Randomized, Placebo-Controlled Study of ACE-011 
for the Treatment of Chemotherapy Induced Anemia in Patients with Metastatic Breast 
Cancer. 
Study center(s): approximately 25-35 centers  
Phase of development: 2 
Objectives 
Primary:  
1. To evaluate the proportion of patients in each ACE-011 dose regimen who achieve a
hematopoietic response during the treatment period including up to 2 months after the
last dose of ACE-011 treatment of chemotherapy induced anemia in patients with
metastatic breast cancer.
Secondary: 
1. To evaluate the safety and tolerability of ACE-011 for the treatment of chemotherapy
induced anemia in patients with metastatic breast cancer.
2. To evaluate the percentage of patients who achieve an increase in hemoglobin of ≥ 1
g/dL,  ≥ 2 g/dL and/or hemoglobin concentration ≥ 11 g/dL for 28 consecutive days
during the treatment period including up to 2 months after the last dose of ACE-011 in
the absence of any RBC transfusions and/or ESAs.
3. To estimate the duration of the hematopoietic response associated with each ACE-011
dose regimen.
4. To estimate the time to the hematopoietic response associated with each ACE-011 dose
regimen.
5. To estimate the proportion of patients receiving red blood cell (RBC) transfusions
and/or ESAs within each cycle of ACE-011 with each dose regimen.
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6. To estimate the effect of each ACE-011 dose regimen on progression free survival 
(PFS) and objective response rate (ORR). 
Exploratory objectives: 
1. To estimate the effect of each ACE-011 dose regimen on serum bone biomarkers (OC, 
BSAP, PINP, CTX, TRACP-5b), urine bone biomarker (uNTX), bone mineral density 
(DXA scans of lumbar spine and hip) and incidence of skeletal related events (SREs). 
2. To evaluate the quality of life during the study in relation to the treatment of 
chemotherapy induced anemia in patients with metastatic breast cancer during the 
study. 
Methodology: This is a Phase 2, double-blind, randomized, placebo controlled study to 
evaluate the efficacy, safety, and tolerability of ACE-011 for the treatment of chemotherapy 
induced anemia in patients with metastatic breast cancer. Patients will be randomized to one of 
three treatment arms or placebo: 
 
1. ACE-011 0.1 mg/kg subcutaneously (SC) every 28 days for up to 4 doses. 
2. ACE-011 0.3 mg/kg SC every 28 days for up to 4 doses.  
3. ACE-011 0.5 mg/kg SC every 28 days for up to 4 doses. 
4. Placebo SC every 28 days for up to 4 doses. 
 
  
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Number of patients (planned): 105 patients 
Diagnosis and main criteria for inclusion 
 
Inclusion Criteria: 
1. Women > 18 years of age. 
2. Histologically confirmed diagnosis of breast cancer documented by cytology or biopsy. 
3. Evidence of metastatic breast cancer with a minimum of one measurable lesion or non 
measurable lesion per RECIST criteria (Appendix 1). 
4. Receiving a multicycle myelosuppressive chemotherapy regimen including one of the 
following: anthracycline, taxane, gemcitabine or vinorelbine. 
5. Planned treatment with the same myelosuppressive chemotherapy regimen for a minimum 
of 9 weeks after Day 1 of ACE-011/placebo administration.  
6. Hemoglobin value between ≥ 6.5 to < 11.0 g/dL (≥ 65 to < 110 g/L).  
7. ≥ 30 days must have elapsed (from Day 1) since previous treatment with erythropoiesis-
stimulating agent (including concurrent treatment with IV iron) for chemotherapy induced 
anemia.  
8. ≥ 7 days have elapsed (from Day 1) since the last RBC blood transfusion and receipt of ≤ 2 
units of blood in the past 30 days.  
9. ECOG Performance status of 0 – 2 (Appendix 2). 
10. Adequate renal (creatinine ≤ 1.5 x ULN or creatinine clearance ≥ 40 mL/min) and hepatic 
function (bilirubin < 1.5 x ULN; AST/ALT < 2.5 x ULN). 
11. Females of childbearing potential  participating in the study are to use adequate birth 
control measures (i.e. oral contraceptives or two forms of barrier method birth control) 
during study participation. Females of childbearing potential must have a negative serum 
pregnancy test within 3 days to ACE-011/placebo administration (Day 1). A female of 
childbearing potential is a sexually mature woman who has not undergone a hysterectomy 
or who has not been postmenopausal for at least 24 consecutive months (i.e. who has had 
menses at some time in the preceding 24 months). 
12. Life expectancy of ≥ 6 months. 
13. Is willing to adhere to the study visit schedule, understand and comply with all protocol 
requirements. 
14. Understand and sign a written informed consent. 
 
 
 
 
 
 
 
 
 
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Exclusion Criteria: 
1. At the time of screening patients who have any grade > 3 toxicity (as per NCI CTCAE 
v3.0 (Appendix 3)) (except for the following disease related toxicities:  hematological 
events- anemia, thrombocytopenia or neutropenia or non hematological events- nausea, 
vomiting, fatigue, or muscle or bone/joint pain).  
2. Prior radiation therapy to > 20% of the whole skeleton. Use of palliative radiation if the 
area being treated is <15% of body surface area with no pelvic radiation or no more than 
10% of the bone marrow reserve is radiated is permitted during patient participation in the 
study, at the discretion of the investigator. 
3. Have received more than 5 prior chemotherapy treatment regimens for metastatic breast 
cancer.  
4. Concurrent use of bevacizumab with the chemotherapy regimen during study participation. 
5. Clinically significant pulmonary, endocrine, neurologic, gastrointestinal, hepatic or 
genitourinary disease unrelated to underlying hematologic disorder.  
6. Patients with heart failure as classified by the New York Heart Association (NYHA) 
classification of 3 or higher (Appendix 4). 
7. History of thrombosis, deep vein thrombosis (DVT), pulmonary emboli, or embolic stroke. 
8. Untreated CNS metastases (exception: CNS metastases treated with whole brain 
radiotherapy > 6 months prior to randomization). 
9. Diagnosis of a myeloid malignancy or known history of myelodysplasia.  
10. History of second malignancy within 5 years (except excised and cured basal cell 
carcinoma, squamous cell carcinoma of the skin or cervical carcinoma in situ).  
11. Patients with a recent history (within 14 days of Day 1) of administration of systemic (IV 
or oral) antibiotics. Patients should be free of infection at least 14 days after the last dose 
of systemic antibiotic treatment (from Day 1). 
12. Uncontrolled hypertension. If hypertension is considered clinically stable, systolic blood 
pressure (BP) must be < 150 mmHg and diastolic BP must be < 100 mmHg.  
13. Known history of hepatitis C antibody (HCV), hepatitis B surface antigen (HBsAg and HB 
core Ab), or human immunodeficiency virus (HIV) antibody.   
14. Deficiency in iron (serum ferritin < 100 ng/mL (< 224.7 pmol/L)), vitamin B12, or folate. 
15. History of anemia as a result of inherited hemoglobinopathy such as sickle cell anemia or 
thalassemia.  
16. History of autoimmune or hereditary hemolysis or gastrointestinal bleeding. 
17. Patient received treatment with another investigational drug or device within 1 month prior 
to Day 1, or if the half life of the previous product is known, within 5 times the half life 
prior to dosing, whichever may be longer.  
18. Pregnant or lactating females. 
19. History of severe allergic or anaphylactic reactions or hypersensitivity to recombinant 
proteins or excipients in the investigational product.    
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Investigational product, dosage and mode of administration:  
ACE-011/placebo will be administered as a SC injection, approximately every 28 days, on 
days 1, 29, 57, and 85 of the treatment period.  Each patient will be randomized to one of three 
treatment arms or placebo: 
 
 
 
 
 
 
 
 
Patients with grade ≥3 toxicity related to ACE-011 will be discontinued from ACE-011/ 
placebo treatment except for the following.  Patients with grade 3 hypertension that decreases 
to grade ≤ 1 within 7 days after treatment with anti-hypertensive therapy may continue on 
ACE-011/placebo treatment.  Dose reduction rules will apply at the subsequent scheduled 
dosing day(s).  Patients with a hemoglobin level above the upper limit of normal at any time 
during the study after Day 1 will be discontinued.   
ACE-011/placebo dose modification rules are based on hemoglobin values and blood pressure 
measurements during each treatment cycle. ACE-011/placebo dose interruption and dose 
reduction rules will be implemented for those patients with hemoglobin of ≥ 11 g/dL, an 
increase of ≥ 2 g/dL/ 28 days, or hypertension ≥ Grade 2 within each cycle (see Figure 1). 
Dose  
Number of  Patients 
0.1 mg/kg 
30 
0.3 mg/kg 
30 
0.5 mg/kg 
30 
Placebo 
15 
Total patients enrolled: 105 
Duration of study: Patients will be followed for a minimum of 7 months following their last 
dose of study drug. Study participation for each patient is approximately 10.5 months (14 day 
screening period, 3 month treatment period with a 2 month treatment follow up period, and a 5 
month post treatment follow-up period). The start date of the chemotherapy regimen used in 
this protocol to treat metastatic breast cancer will be recorded. If a patient begins a new 
chemotherapy regimen during the study, the patient will discontinue further ACE-011/placebo 
treatment and be followed for survival only. If a patient has a positive anti-drug antibody result 
at the Day 281/Termination visit, they may be asked to return to the clinical site for additional 
monthly repeat anti-drug antibody testing for up to 12 months.  The study is complete when 
the last patient enrolled has completed the last protocol required follow up visit. 
Criteria for evaluation 
Efficacy: The primary endpoint is to establish the proportion of patients who have a 
hematopoietic response of an increase in hemoglobin of ≥ 0.5 g/dL above the study baseline 
value for 28 consecutive days during the treatment period including up to 2 months after the 
last dose of ACE-011, in the absence of any RBC transfusions and/or ESAs.   
The proportion of patients with an increase in hemoglobin of ≥ 1g/dL, ≥ 2 g/dL and/or 
hemoglobin concentration ≥ 11 g/dL for 28 consecutive days during the treatment period up to 
2 months after the last dose of ACE-011 in the absence of any RBC transfusions and/or ESAs 
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will be evaluated as a secondary efficacy endpoint. 
The hematopoietic endpoints will be determined by the monitoring of hematologic laboratory 
values, RBC transfusion and/or ESAs administration. The evaluation of response will be from 
the first dose of ACE-011 through 2 months after the last dose (for each patient).  Additional 
endpoints will be evaluated with the assessment of disease progression by CT/MRI and bone 
scan and bone mineral density by DXA scans.  Bone biomarkers will be evaluated in all 
patients and incidence of SREs will be recorded, as applicable. SREs are defined as pathologic 
fracture, radiation therapy to bone, surgery to bone, or spinal cord compression. 
Safety: Throughout the study, safety will be evaluated by the sponsor, medical monitor and 
principal investigator.  Additionally, the DMC will review safety parameters for patients 
enrolled in the study. All patients will be assessed for safety by monitoring adverse events, 
clinical laboratory tests, and assessment of quality of life, vital signs and physical 
examinations on an ongoing basis.  ECGs will also be performed during screening, prior to 
dosing on the first and second cycle, Day 15, and Day 113 (28 days after the last dose of ACE-
011) and at Day 281/Termination visit to monitor safety.  Blood pressure and lab values will 
be assessed at each study visit; weekly for the first two treatment (dosing) periods and 
approximately every one to two weeks for subsequent treatment (dosing) periods.  
Pharmacokinetics: The blood samples will be collected at selected study sites from 
approximately one-third of patients for the evaluation of serum concentrations of ACE-011.  
Pre-dose PK samples will be collected on Day 1.  See Appendix 5 for PK sampling schedule. 
Statistical methods  
Sample size determination: With an anticipated dropout rate of 20%, a sample size of 30 
patients per dose level is planned to achieve at least 80% power with 2 sided significance level 
of 0.05 to differentiate targeted response rate of p1=0.45 from null hypothesis p0=0.20. An 
additional 15 patients will be enrolled into the placebo group for safety comparison. A total of 
105 patients will be randomized to three ACE-011 dose groups or placebo with a ratio of 
2:2:2:1. 
Efficacy analysis: The primary endpoint is the proportion of patients who have a 
hematopoietic response of an increase in hemoglobin of ≥ 0.5 g/dL for 28 consecutive days 
during the treatment period including up to 2 months after the last dose of ACE-011, in the 
absence of any RBC transfusions and/or ESAs. The proportion of responders will be 
determined together with 95% confidence interval.  
For binary endpoints, the proportion of responders and 95% confidence interval will be 
calculated. For time to event endpoints, the Kaplan-Meier method will be used to estimate the 
survival curve and median time to event.  Due to the nature of the study, no multiplicity 
adjustment will be made for efficacy analysis. 
Safety analysis: Data from all patients who receive at least one dose of ACE-011/placebo will 
be included in the safety analyses. To assess clinical safety, adverse events, vital sign 
measurements and clinical laboratory information will be summarized. Adverse events and 
laboratory results will also be summarized by severity grade (NCI CTCAE v3.0). Changes 
from baseline clinical laboratory values and vital signs will be summarized over time. 
Descriptive statistics and shift tables will be generated as appropriate.  
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3. 
TABLE OF CONTENTS, LIST OF TABLES AND LIST OF 
FIGURES  
TABLE OF CONTENTS 
1. 
TITLE PAGE..............................................................................................................1 
2. 
PROTOCOL SYNOPSIS .............................................................................................4 
3. 
TABLE OF CONTENTS, LIST OF TABLES AND LIST OF FIGURES................12 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................18 
5. 
INTRODUCTION......................................................................................................21 
5.1. 
Indication and Rationale.............................................................................................21 
5.2. 
Description of ACE-011.............................................................................................21 
5.3. 
Activin Biology ..........................................................................................................22 
5.3.1. 
Pharmacology Studies ................................................................................................22 
5.3.2. 
Toxicology..................................................................................................................24 
5.4. 
Summary of Clinical Experience................................................................................25 
5.4.1. 
A011-01: A Phase 1a Study in Healthy Postmenopausal Women .............................25 
5.4.2. 
A011-02: A Phase 1b Study in Healthy Postmenopausal Women.............................26 
5.4.3. 
A011-04: A Phase 2a Study in Patients with Osteolytic Lesions of Multiple 
Myeloma.....................................................................................................................29 
5.5. 
Potential Risks for Human Use...................................................................................31 
6. 
TRIAL OBJECTIVES AND PURPOSE....................................................................33 
6.1. 
Primary objective........................................................................................................33 
6.2. 
Secondary objectives ..................................................................................................33 
6.3. 
Exploratory objectives................................................................................................33 
7. 
INVESTIGATIONAL PLAN.....................................................................................34 
7.1. 
Overall Study Design and Plan...................................................................................34 
8. 
SELECTION AND WITHDRAWL OF PATIENTS.................................................38 
8.1. 
Number of Patients .....................................................................................................38 
8.2. 
Entry Criteria ..............................................................................................................38 
8.2.1. 
Patient Inclusion Criteria............................................................................................38 
8.2.2. 
Patient Exclusion Criteria...........................................................................................39 
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8.3. 
Patient Withdrawal Criteria........................................................................................40 
9. 
TREATMENT OF PATIENTS..................................................................................41 
9.1. 
Concomitant Medications...........................................................................................41 
9.1.1. 
General Concomitant Medication Usage....................................................................41 
9.1.2. 
Concomitant treatment for anemia .............................................................................41 
9.1.2.1. 
Iron supplementation ..................................................................................................41 
9.1.2.2. 
Erythropoiesis-stimulating agents (ESAs)..................................................................41 
9.1.2.3. 
RBC Transfusions.......................................................................................................41 
9.2. 
Chemotherapy.............................................................................................................42 
9.3. 
Treatment Compliance................................................................................................42 
9.4. 
Randomization............................................................................................................42 
9.4.1. 
Blinding ......................................................................................................................42 
9.4.2. 
Unblinding..................................................................................................................42 
9.5. 
Treatments Administered............................................................................................43 
9.5.1. 
Selection of Doses in the Study..................................................................................43 
9.5.2. 
Selection and Timing of Dosing for Each Patient ......................................................43 
9.5.2.1. 
ACE-011 Treatment Related Toxicity........................................................................43 
9.5.2.2. 
ACE-011 Dose Modification Rules............................................................................43 
10. 
STUDY PROCEDURES AND SCHEDULE ............................................................47 
10.1.1. 
Written Informed consent...........................................................................................47 
10.1.2. 
Screening (Within 14 days of dosing) ........................................................................47 
10.1.3. 
Initial Dosing: Day 1 ..................................................................................................48 
10.1.4. 
ACE-011/placebo administration : Days 29, 57, and 85 (± 3 days)...........................49 
10.1.5. 
Additional visits during Treatment Period: Days 8, 15, 22, 36 (± 1 day), 43, 
64 and 71 (± 2 days) ...................................................................................................50 
10.1.6. 
Treatment Period Follow-up visits : Days 113 and 141 (± 7 days)............................51 
10.1.7. 
Post Treatment Period Follow-up visits : Days 169, 197, 225, and 253 (± 7 
days)............................................................................................................................52 
10.1.8. 
Termination Visit:  Day 281 (± 7 days)......................................................................52 
10.2. 
Discontinuation of study.............................................................................................53 
11. 
INVESTIGATIONAL PRODUCT MATERIALS AND MANAGEMENT.............54 
11.1. 
Reference Product.......................................................................................................54 
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11.2. 
Investigational Product Packaging and Labeling .......................................................54 
11.3. 
Investigational Product Storage..................................................................................54 
11.4. 
Investigational Product Preparation............................................................................54 
11.5. 
Administration............................................................................................................54 
11.6. 
Drug Accountability ...................................................................................................54 
11.7. 
Investigational Product Handling and Disposal .........................................................55 
12. 
ASSESSMENT OF EFFICACY ................................................................................56 
13. 
ASSESSMENT OF SAFETY.....................................................................................57 
13.1. 
Safety Parameters .......................................................................................................57 
13.1.1. 
Adverse Events...........................................................................................................57 
13.1.2. 
Clinical Laboratory Tests ...........................................................................................57 
13.1.3. 
Other Safety Assessments...........................................................................................58 
13.2. 
Pharmacokinetics........................................................................................................58 
14. 
ADVERSE EVENT....................................................................................................59 
14.1. 
Adverse Event Classification......................................................................................60 
14.2. 
Recording Adverse Events .........................................................................................60 
14.3. 
Reporting Adverse Events..........................................................................................61 
14.4. 
Emergency Sponsor Contact.......................................................................................62 
15. 
STATISTICS..............................................................................................................63 
15.1. 
Determination of Sample Size....................................................................................63 
15.2. 
Analysis Populations ..................................................................................................63 
15.3. 
Background and Demographic Characteristics ..........................................................63 
15.3.1. 
Patient Disposition......................................................................................................63 
15.3.2. 
ACE-011.....................................................................................................................64 
15.3.3. 
Concomitant Therapy .................................................................................................64 
15.4. 
Efficacy Evaluation ....................................................................................................64 
15.4.1. 
Primary Efficacy Analysis..........................................................................................64 
15.4.2. 
Secondary Efficacy Analyses .....................................................................................65 
15.5. 
Safety Evaluation........................................................................................................65 
15.6. 
Pharmacokinetic Evaluation.......................................................................................66 
15.6.1. 
Anti-drug Antibody Data............................................................................................66 
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15.7. 
Interim Analysis..........................................................................................................66 
15.8. 
Deviation from Original Analysis Plan ......................................................................66 
16. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................67 
16.1. 
Study Monitoring........................................................................................................67 
16.2. 
Audits and Inspections................................................................................................67 
17. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................68 
17.1. 
Data Quality Control and Quality Assurance.............................................................68 
17.1.1. 
Investigator responsibility ..........................................................................................68 
17.1.2. 
Protocol modifications................................................................................................68 
17.2. 
Financing and Insurance.............................................................................................68 
17.3. 
Confidentiality............................................................................................................68 
17.4. 
Publication Policy.......................................................................................................68 
17.5. 
Protocol Amendments ................................................................................................69 
18. 
ETHICS ......................................................................................................................70 
18.1. 
Institutional Review Board or Independent Ethics Committee ..................................70 
18.2. 
Ethical Conduct of the Study......................................................................................70 
18.3. 
Written Informed Consent..........................................................................................70 
18.3.1. 
Informed Consent .......................................................................................................70 
18.3.2. 
Patient Data Protection ...............................................................................................70 
19. 
DATA HANDLING AND RECORDKEEPING.......................................................71 
19.1. 
Case Report Form Completion...................................................................................71 
19.2. 
Retention of Records ..................................................................................................71 
20. 
REFERENCES ...........................................................................................................72 
21. 
APPENDICES............................................................................................................74 
Appendix 1: Response Evaluation Criteria in Solid Tumors.........................................................74 
Appendix 2: ECOG Performance Status........................................................................................77 
Appendix 3:  National Cancer Institute (NCI) Common Terminology Criteria for 
Adverse Events (CTCAE) Version 3.0.......................................................................78 
Appendix 4: New York Heart Association- Classification of heart failure...................................79 
Appendix 5- Pharmacokinetic Sampling .......................................................................................80 
  
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LIST OF TABLES 
 
Table 1: 
Emergency Contact Information...................................................................................3 
Table 2: 
Abbreviations and Specialist Terms ...........................................................................18 
Table 3: 
A011-02: A Phase 1b Study in Healthy Postmenopausal Women: 
Hemoglobin Evaluation..............................................................................................27 
Table 4: 
A011-02: Incidence of Most Common Adverse Events.............................................28 
Table 5: 
A011-02: A Phase 1b Study in Healthy Postmenopausal Women: BMD..................29 
Table 6: 
Study Design...............................................................................................................34 
Table 7: 
Schedule of Events .....................................................................................................36 
Table 8: 
ACE-011/Placebo Dose Reduction Levels.................................................................46 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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LIST OF FIGURES 
Figure 1: 
ACE-011/placebo Dose Modification Rules (after initial dose of ACE-
011/placebo) ...............................................................................................................45 
 
 
 
 
 
 
 
 
 
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4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
The following abbreviations and specialist terms are used in this study protocol. 
Table 2: 
Abbreviations and Specialist Terms   
Term 
Definition 
ACTH 
Adrenocorticotropic hormone 
ActRIIA 
Activin receptor IIA  
AE 
Adverse event 
ALT 
Alanine aminotransferase  
AST 
Aspartate aminotransferase  
AUC 
Area under the plasma concentration - time curve 
AUC(0-last) 
AUC from time 0 to time of last quantifiable sample  
AUC(0-∞) 
AUC extrapolated to infinity  
BMD 
Bone mineral density 
BP 
Blood pressure 
BSAP 
Bone specific alkaline phosphatase 
BUN 
Blood urea nitrogen 
CBC 
Complete Blood Count 
CFR 
Code of Federal Regulations (US) 
CH 
Constant domain 
CI 
Confidence interval 
CIA 
Chemotherapy induced anemia 
CL 
Clearance 
CL/F 
Total clearance 
Cmax 
Maximum observed concentration  
CNS 
Central nervous system 
CO2 
Carbon dioxide 
CRF 
Case report form 
CRO 
Clinical research organization 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTX 
Serum C-terminal type I collagen telopeptide 
DLT 
Dose-limiting toxicity 
DXA 
Dual-energy x-ray absorptiometry 
DMC 
Data Monitoring Committee 
DVT 
Deep vein thrombosis 
ECD 
Extracellular domain 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EDF 
Erythroid differentiation factor  
ESA 
Erythropoiesis-stimulating agents 
F 
Bioavailability (absolute) 
FACT 
Functional Assessment of Chronic Illness 
FDA 
Food and Drug Administration  
FSH 
Follicle-stimulating hormone 
GCP 
Good Clinical Practices 
GH 
Growth hormone 
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Term 
Definition 
HBV 
Hepatitis B virus 
Hct 
Hematocrit 
HCV 
Hepatitis C virus 
Hgb 
Hemoglobin 
HIV 
Human immunodeficiency virus 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug 
IP 
Intraperitoneal 
IRB 
Institutional Review Board 
IV 
Intravenous 
IVRS 
Interactive Voice Response System 
Kd 
Binding coefficient 
λz 
Elimination rate constant 
LDH 
Lactate dehydrogenase 
LH 
Luteinizing hormone 
MCH 
Mean corpuscular hemoglobin 
MCHC 
Mean corpuscular hemoglobin concentration 
MCV 
Mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MITT 
Modified Intent to Treat (population) 
MRI 
Magnetic resonance imaging 
NOAEL 
No adverse events level  
NYHA 
New York Heart Association 
OC 
Osteocalcin 
ORR 
Objective response rate 
OVX 
Ovariectomized 
PD 
Progressive disease 
PFS 
Progression free survival 
PHI 
Protected health information 
PINP 
Serum intact procollagen type I N terminal propeptide 
PK 
Pharmacokinetic 
PP 
Per-protocol (population) 
PT 
Prothrombin time 
PTH 
Parathyroid hormone 
PTT 
Partial thromboplastin time 
RAP-011 
Murine version of ACE-011, ActRIIA mFc 
RBC 
Red blood cell (count) 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SC 
Subcutaneous 
SERM 
Selective estrogen receptor modulator 
SHAM 
Sham-operated 
SPEP 
Serum protein electrophoresis 
SRE 
Skeletal-related event 
T1/2 
Elimination half-life  
TIBC 
Total iron binding capacity 
Tmax 
Time to Cmax 
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Term 
Definition 
TRACP-5b 
Serum tartrate-resistant acid phosphatase isoform-5b 
ULN 
Upper limit of normal 
Vz/F 
Volume of distribution 
WBC 
White blood cell (count) 
 
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5. 
INTRODUCTION 
5.1. 
Indication and Rationale 
This study is designed to evaluate the efficacy, safety, and tolerability of ACE-011 for the 
treatment of chemotherapy induced anemia in patients with metastatic breast cancer. 
Treatment of patients with metastatic breast cancer with myelosuppressive chemotherapy is 
frequently associated with anemia. Chemotherapy induced anemia (CIA) is a significant problem 
for patients with cancer, causing fatigue and reduced quality of life (1).  Patients with CIA are 
currently treated with blood transfusion and/or erythropoiesis-stimulating agents (2). However, 
with these treatment options CIA is still an area of unmet medical need. Erythropoiesis-
stimulating agents (ESAs) can successfully mitigate transfusion need in a proportion of these 
patients, but concerns have emerged regarding apparent negative effects on survival and/or tumor 
progression in certain patient populations. The murine surrogate to ACE-011, RAP-011, has been 
tested as a single agent in breast cancer cell lines MDA-MB-231 and MCF-7 and no effect on 
enhanced proliferation of these cell lines has been observed in vitro. Therefore, treatment with 
ACE-011 may provide a distinct benefit/risk profile to patients with chemotherapy induced 
anemia.  
In both a Phase 1 single dose and multiple dose study of ACE-011 in postmenopausal women, 
increases in hemoglobin and hematocrit were observed following ACE-011 treatment and 
remained elevated over the course of study.  The observed hemoglobin and hematocrit effects of 
ACE-011 were dose and time dependent.  Please refer to the Investigator Brochure for further 
information.  
Based on the effect of ACE-011 on hematopoiesis and consistent biological phenomena observed 
in both non clinical and clinical studies, it is hypothesized that the blockade of ActRIIA receptor 
signaling impedes the terminal differentiation step in erythropoiesis to allow additional rounds of 
cell replication before cells enter the final differentiation phase. The result is a substantial 
increase in mature erythrocytes released into the circulation.  Since this proposed mechanism is 
different to that of known ESAs, ACE-011 may provide a different clinical profile in the 
treatment of CIA.  
This study will provide information on the pharmacodynamics (PD) properties regarding the 
ability of ACE-011 to increase hemoglobin in patients with CIA. 
5.2. 
Description of ACE-011 
ACE-011 (ActRIIA-IgG1) is a fully human fusion protein consisting of the extracellular domain 
(ECD) of activin receptor IIA (ActRIIA) linked to the human IgG1 Fc domain, which includes 
the heavy chain hinge and constant domains, CH2 and CH3.  ACE-011 avidly binds to activin A 
with a binding coefficient (Kd) approximately 8.9 pM and prevents its binding to endogenous 
receptors, thereby inhibiting biological effects of activin.   
 
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5.3. 
Activin Biology 
Activin A was initially identified as a gonadal differentiation factor involved in modulating 
follicle stimulating hormone (FSH) secretion from the pituitary (3). Subsequently, the pleiotropic 
nature of activin A has become more apparent (4).   There is a growing body of data suggesting a 
role for activin A in bone remodeling, specifically as a negative regulator of bone growth (5).  
Before the two molecules were shown to be identical (6), activin A was also described as 
erythroid differentiation factor (EDF), effecting red blood cells in the later stages of maturation 
(7).  The mechanism(s) by which activin A influences erythropoiesis remain under investigation 
and, in fact, there are data from studies in vitro and in animals that support erythropoiesis-
stimulatory (8,9) and -inhibitory effects (10).   
At the cellular level, activin A binds initially to the high-affinity Type II receptor (ActRIIA).  The 
ligand-bound ActRIIA then recruits the low-affinity Type I receptor (ActRIA or ALK-4).  The 
receptor heterocomplex, through its cytoplasmic protein kinase activity, then activates the Smad 
signal cascade to eventually influence nuclear transcriptional factors (11, 12).  The competitive 
binding of activin A in the blood by the ACE-011 soluble fusion protein can result in inhibition 
of ActRIIA receptor signaling pathway by impeding biological processes attributed to activin A.  
Activin has also been attributed to erythroid differentiation and has been reported to have 
proerythrocytic effects and to induce terminal differentiation of RBCs.  Inhibition of activin may 
lead to increases in proliferation of the erythroid lineage.  Based on its pharmacologic effects, 
ACE-011 (ActRIIA-IgG1) is being developed for the treatment of bone loss associated with 
various disease states (e.g., osteoporosis and treatment of osteolytic lesions in patients with 
multiple myeloma), and treatment of anemia associated with a variety of disorders, such as 
chemotherapy induced anemia. 
The extracellular domain sequence of ActRIIA is completely conserved among numerous species 
including mouse, rat, cynomolgus monkey and humans, thus ACE-011 is active in these animals.  
However, in order to reduce the potential immunogenicity of the fully human molecule, ACE-
011, in mice and to maximize the opportunity to maintain exposures in chronic models, a murine 
surrogate molecule was constructed by exchanging the human immunoglobulin Fc sequence 
portion of ACE-011 with its murine IgG2a homolog.  The resultant construct is referred to as 
RAP-011 (ActRIIA-mIgG2aFc).   
5.3.1. 
Pharmacology Studies 
RAP-011 was evaluated in a broad range of animal pharmacology studies to assess the effects of 
inhibition of activin A on the biological processes attributed to that regulatory protein.  RAP-011 
has been shown to have significant effects on the red cell compartment.  RAP-011 treatment of 
mice at 10, 30 and 50 mg/kg by intraperitoneal injection (IP) twice per week for 3 months 
resulted in a 16-26% increase in red blood cell (RBC) counts compared to control animals.  Rats 
treated with RAP-011 at 0.3, 3 and 30 mg/kg once per week for 3 months showed RBC count 
increases of 6-15% over control animals.  Finally, in cynomolgus monkeys treated with 10, 30 or  
 
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50 mg/kg of ACE-011 twice per month for 3 months there was a 21- 24% increase in RBC counts 
compared to controls animals.  In this study, the RBC count increase was apparent as early as 2 
weeks following the initial dose of ACE-011.   
While the mechanism(s) underlying the stimulation effect of ACE-011 on erythropoiesis are not 
yet fully understood, it is hypothesized that a blockade of ActRIIA receptor signaling impedes the 
terminal differentiation step in erythropoiesis to allow additional rounds of erythroid cell 
replication before cells enter the terminal differentiation phase.  The result is a substantial 
increase in mature erythrocytes released into circulation.   
RAP-011 administered at 10 mg/kg to mice three days prior to administration of paclitaxel at 30 
mg/kg was sufficient to prevent decreases in red blood cell parameters seen three days later.  
Mice receiving paclitaxel alone had decreased hematocrit from 43% to 38% three days later.  
RAP-011 administered 3 days prior to paclitaxel injection was sufficient to keep the hematocrit 
above 42% at three days and up to two weeks after paclitaxel administration.  Therefore 
prophylactic treatment with RAP-011 was able to prevent paclitaxel induced anemia in mice. 
RAP-011 has also been shown to significantly increase bone mineral density and strength in 
normal animals and in a variety of animal models of bone loss (13, 14, 15).  In a murine 
ovariectomy (OVX)-induced model of osteopenia, RAP-011 (10 mg/kg IV, twice per week x 12 
weeks) increased trabecular BMD > 25% in 6-12 weeks compared to the phosphate buffered 
saline (PBS)-treated controls (p<0.002).  RAP-011 treatment was able to reverse the accelerated 
bone loss associated with ovariectomy.  As expected sham-operated (SHAM) mice (i.e., intact 
ovaries) started the study with a greater trabecular BMD than OVX mice.  PBS-treated SHAM 
mice showed a 10% decrease in trabecular BMD after 12 weeks of treatment compared to 
baseline, while SHAM-RAP-011 mice had a 32% increase in trabecular BMD over the same 
period.  These data demonstrate that RAP-011 is able to increase trabecular BMD in both the 
normal state and in a model of established bone loss.  The femurs of both the RAP-011 treated 
OVX and SHAM mice showed statistically significant increases in all measured parameters of 
bone strength (i.e., maximum load, stiffness, energy, ultimate strength, and elastic modulus).  In 
summary, treatment with RAP-011 produced bone of superior quality consistent with an anabolic 
agent. 
RAP-011 was evaluated in a mouse model of skeletal metastasis using luciferase-tagged, human 
MDA-MB-231 breast cancer cells (estrogen receptor negative).  Mice were pretreated for 2 
weeks with RAP-011 (10 mg/kg, biweekly, SC) prior to intracardiac injection of tumor cells.  
Treatment with RAP-011 was continued for an additional 5 weeks following tumor implantation. 
A parallel study was conducted to examine the effect of RAP-011 treatment, as described above, 
on survival of MDA-MB-231 bearing mice. 
The data demonstrate that RAP-011 treatment acts to inhibit MDA-MB-231 metastasis to bone 
and may also play a role in inhibiting tumor growth in soft tissue.  Furthermore, in the presence 
of tumor cells, RAP-011 is able to prevent lytic disease through an anabolic mechanism of bone 
formation.  Lastly, inhibition of tumor growth and metastasis with RAP-011 leads to a greater 
than 25% survival benefit in this model.  
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The efficacy of RAP-011 was examined in an orthotopic model of breast cancer using luciferase-
tagged human MCF-7 breast cancer cells (estrogen receptor positive). Mice were pretreated for 2 
weeks with RAP-011 (10 mg/kg, biweekly, SC) prior to the implantation of tumor cells into the 
mammary fat pad of female nude mice. Treatment with RAP-011 was continued for an additional 
7 weeks following tumor implantation at which time mice were sacrificed and assessed for tumor 
burden. RAP-011 effectively lowered the tumor burden in mice as detected by bio-luminescence. 
In addition, a 60% reduction in tumor weight was observed in the RAP-011 treated mice.  
The ability of RAP-011 to repair osteolytic lesions caused by metastatic disease was investigated 
in mice.  In this model athymic nude mice received an intratibial injection of MDA-MB-231-Luc 
cells to mimic bone metastasis.  Mice were treated with a chemotherapy regimen of paclitaxel (20 
mg/kg, IP, every three days) starting seven days after tumor injection and continuing for the 
duration of the study.  On study day 42 mice with a detectable tumor burden by bioluminescent 
imaging were divided into two groups and began treatment with RAP-011 (10 mg/kg, SC, 
biweekly) or vehicle.  Prior to dosing, μCT scans of the tumor bearing tibia were conducted to 
identify osteolytic lesions.  RAP-011 treatment continued for four weeks (to study day 70) and a 
final μCT scan of the tibia was performed.  On study day 70 osteolytic lesions remained the same 
or had progressed further when compared to study day 42 in the vehicle treated mice.  While 
some mice showed progression of osteolytic lesions (most likely related to tumor burden) on 
study day 70, a majority of mice treated with RAP-011 demonstrated repair of the osteolytic 
lesions seen on study day 42.  Therefore treatment with RAP-011 has the ability to repair 
osteolytic lesions caused by tumors and after cytoxic chemotherapy with paclitaxel. 
5.3.2. 
Toxicology 
ACE-011 has been evaluated for toxicological effects in two species, Sprague-Dawley rats and 
cynomolgus monkeys.  The dose levels ranged from 0.3 to 30 mg/kg in rats and from 1 to 50 
mg/kg in monkeys.  These dose ranges were designed to support Phase 1a single-dose levels of 
0.01 to 3.0 mg/kg IV and Phase 1b multiple doses of 0.1 to 2 mg/kg (monthly, SC).  Weekly 
dosing in animals was designed to provide continuous, but fluctuating serum concentrations of 
ACE-011, which would be mimicked by a one-month dosing interval in humans. 
Initial studies utilized IV dosing to identify target organs while longer-term studies (3 months in 
rats; 3 and 6 months in monkeys) utilized SC dosing to mimic the intended dosing regimen for 
patients.  The expected pharmacologic effect, increased red blood cells (RBCs), hemoglobin 
(Hb), hematocrit (HCT) and reticulocytes, was observed in all studies, presumably based on the 
ability of ACE-011 to inhibit activin.  A second expected pharmacologic effect of ACE-011, 
based on inhibition of activin, was the reversible reduction in sperm production and testicular 
tubular damage in rats.  Since male cynomolgus monkeys were sexually immature in these 
studies, it was not possible to monitor this effect in this species. 
Effects on the adrenal gland were only seen in rats and were more pronounced in female rats. 
This toxicological observation may not be relevant for predicting effects in humans since adrenal 
toxicity was not seen in cynomolgus monkeys.  Dose-limiting toxicity and no observable adverse 
effect levels (NOAELs) were primarily based on renal toxicity in both rats and monkeys.  There  
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was some indication that kidney toxicity was an indirect effect, based on the formation of 
antibody/antigen complexes, but since these studies were not designed to investigate 
toxicological mechanisms, a definitive cause of renal impairment and renal damage was not 
determined.  Development of antibodies to ACE-011 was noted in all of these studies, which is 
an expected immune reaction in rats and monkeys dosed with a human protein.  
The no observable adverse effect level (NOAELs) from the 3 month SC studies was 3 and 30 
mg/kg in rats and monkeys, respectively. Because the kidney findings were observed at all dose 
levels, the NOAEL from the 6 month monkey study is < 10 mg/kg.  
5.4. 
Summary of Clinical Experience 
5.4.1. 
A011-01: A Phase 1a Study in Healthy Postmenopausal Women  
ACE-011 was first studied in a randomized, Phase 1a, single dose, dose escalation study in 
healthy, post-menopausal females (16).  ACE-011 was diluted in normal saline administered as 
an IV infusion (over approximately 1 hour) or as a SC injection on Day 1.  Dose levels were 0.01, 
0.03, 0.1, 0.3, 1.0, and 3.0 mg/kg IV and 0.03 and 0.1 mg/kg SC.  A total of 48 subjects were 
enrolled; 5 active and 1 placebo at each of the IV and SC dose levels.  All subjects were followed 
for 4 months following a single dose administration. 
The pharmacokinetics of ACE-011 was linear for all IV and SC doses.  Across IV doses ranging 
from 0.1 through 3.0 mg/kg, the mean clearance (CL) ranged from 0.092 to 0.128 mL/h/kg, the 
volume of distribution ranged from 73.7 to 110 mL/kg, and the mean T1/2 ranged from 23.7 to 
31.8 days, with no apparent dependence on dose.  After SC administration of 0.03 and 0.1 mg/kg, 
ACE-011 was completely absorbed, and the mean T1/2 was approximately 30 days, with no 
apparent dependence on dose.   
The most commonly occurring treatment-emergent adverse events (AEs; i.e., those occurring in 
more than 1 subject in any treatment group) were headache, infusion site reaction, injection site 
hemorrhage, and toothache.  The majority of the injection site reactions and injection site 
hemorrhages were in the first IV cohort and were related to infiltration of the IV site.  The 
majority of treatment-emergent AEs were mild in severity and were judged to be unrelated to 
ACE-011.  No deaths, serious AEs (SAEs), or AEs leading to discontinuation were reported.  
Changes in red blood cells (RBCs), hemoglobin, reticulocytes, liver function tests, glucose, uric 
acid, amylase and lipase occurred in some subjects; however, none of these laboratory results 
were reported as adverse events.  Mild, transient elevations in pancreas enzymes, liver enzymes, 
or glucose were reported as AEs in five patients.  There were no clinically significant changes 
from baseline in vital signs, physical examination, endocrine function, or electrocardiogram 
(ECG) data.  Preservation of adrenal cortical function was monitored through evaluation of serum 
electrolytes (sodium and potassium levels) and through cortisol response to adrenocorticotropic 
hormone (ACTH) stimulation.  No clinically significant findings were observed at doses up to 3.0 
mg/kg IV, and ACE-011 was well tolerated in healthy, post-menopausal female volunteers in 
single dose levels up to 0.1 mg/kg SC and 3.0 mg/kg IV, the highest dose levels tested in this 
study. 
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5.4.2. 
A011-02: A Phase 1b Study in Healthy Postmenopausal Women  
ACE-011 was studied in a Phase 1b, single-center, randomized, double-blind, placebo-controlled, 
multi-dose, dose-escalating study to evaluate the safety, tolerability and pharmacodynamics of 
ACE-011 in healthy postmenopausal women.  Four cohorts of 10 subjects each were planned at 
the following dose levels: 0.1, 0.3, 1.0, and 2.0 mg/kg administered subcutaneously.  Within each 
cohort, subjects were to be randomized to either active or placebo treatment in an 8:2 ratio. 
Subjects were to receive one SC injection of ACE-011 or placebo every 28 days for a total of 4 
doses. All subjects were to be followed for 12 weeks after the last dose. 
The treatment phase of the study was terminated early after a dose-limiting pharmacodynamic 
effect was observed.  While on study, one subject in the 1.0 mg/kg cohort experienced a Serious 
Adverse Event (SAE) of progressive and persistent hypertension that was attributed to a rapid 
and significant rise in hemoglobin and hematocrit levels.  Due to symptoms of headaches, nausea, 
eye pain, dizziness and vomiting approximately 1 week following the second dose, the subject 
was hospitalized for monitoring and evaluation of her hypertension.  The head MRI, fundoscopy, 
and ECG performed were reported as normal and headache symptoms resolved following 
therapeutic phlebotomy. The SAE resolved and the subject was discharged from the hospital the 
following day.  The hypertension was monitored closely and managed initially with 
antihypertensive medication.  The hypertension resolved by the end of the study without need of 
any antihypertensive medication. The subject received aspirin prophylactically until the end of 
the study and continued taking ibuprofen as needed for headaches.  Further details can be found 
in the Investigator Brochure.  
Based on the magnitude of the hematopoietic response, the Sponsor suspended dose escalation to 
the 2.0 mg/kg dose level and further dosing in all cohorts as a result of this dose-limiting 
pharmacodynamic effect at the 1.0 mg/kg dose level.  In total, 31 subjects were enrolled and 
treated.  Dose levels of ACE-011 administered included 0.1, 0.3, and 1.0 mg/kg (Cohorts 1, 2, 
and 3 respectively).  All subjects randomized to active treatment in Cohort 1 received all 4 
planned doses of ACE-011.  Due to early discontinuation of study drug, subjects randomized to 
active treatment in Cohort 2 received 3 doses of ACE-011, and subjects randomized to active 
treatment in Cohort 3 received 2 doses of ACE-011.  Subjects randomized to placebo treatment 
received between 1 and 4 doses of study treatment.   
In the analysis of the unblinded data, after the administration of the first dose, a dose and time 
dependent increase in hemoglobin values was observed (see Table 3 below): 
 
 
 
 
 
 
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Table 3: 
A011-02: A Phase 1b Study in Healthy Postmenopausal Women: Hemoglobin 
Evaluation 
       
*The number of placebo subjects with data decreases over time as a result of the early discontinuation of the study (i.e., there were placebo 
subjects in each dosing cohort).  There were seven placebo subjects with data at baseline, Days 8, 15, and 36; six subjects with data at Days 29, 
43, 57, and 85; five subjects with data on Days 71 and 113; four subjects with data on Day 64; three subjects with data on Day 141; two subjects 
with data on Day 99; and one subject with data on Days 92 and 169. 
** Number of doses administered per treatment group: 0.1 mg/kg 4 doses; 0.3 mg/kg 3 doses; 1.0 mg/kg 2 doses.  Data beyond this study day are 
considered follow-up results. 
***n=1 
No severe or life-threatening events were reported. The incidence of the most common treatment-
emergent AEs (i.e., occurring in more than one subject in any treatment group) is presented 
below (see Table 4). The most notable AEs were those related to increases in hematologic 
laboratory measures in the 1.0 mg/kg dose group: hematocrit, hemoglobin, and RBC count.  AEs 
of increased hemoglobin and/or hematocrit were reported for seven of the eight subjects in this 
dose group.  These events were reported as mild or moderate elevations; all were considered 
probably related to study drug treatment. Three of the subjects in the 1.0 mg/kg group with 
elevated hemoglobin levels underwent phlebotomies and all hemoglobin elevations were resolved 
by the end of the follow-up period. No erythroid lineage AEs were reported in the 0.1 or 0.3 
mg/kg treatment groups.   
 
Mean Change from Baseline (g/dL) 
Evaluation Time Point 
Placebo 
 
N=7* 
ACE-011 
0.1 mg/kg 
N=8 
ACE-011 
0.3 mg/kg 
N=8 
ACE-011 
1.0 mg/kg 
N=8 
Baseline Mean, pre-Dose 1 
13.20 
13.11 
13.30 
12.71 
Day 8 
0.17 
0.68 
0.85 
1.21 
Day 15 
-0.27 
0.43 
0.44 
1.75 
Day 29 
0.27 
0.61 
1.21 
    2.68** 
Day 36 
0.56 
0.64 
1.89 
2.96 
Day 43 
-0.02 
0.89 
1.21 
2.85 
Day 57 
0.27 
1.28 
    1.64** 
2.09 
Day 64 
0.53 
1.11 
2.49 
2.21 
Day 71 
-0.10 
1.34 
2.09 
1.66 
Day 85 
0.38 
    1.18** 
2.55 
1.86 
Day 92 
      0.00*** 
1.04 
      1.60*** 
      3.80*** 
Day 99 
-0.20 
1.21 
      3.20*** 
      1.28*** 
Day 113 
-0.02 
1.30 
1.29 
1.04 
Day 141 
 0.30 
0.95 
0.34 
2.30 
Day 169 
       0.20*** 
0.06 
 
      2.00*** 
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Headache was reported frequently in all treatment groups with no apparent dose response trend, 
though the reports in the higher dose groups were more often considered possibly related to 
treatment.  Most headaches were reported as mild (one headache was reported as moderate).  
Paresthesia and dizziness were reported more frequently in the ACE-011 groups, though the 
events were generally not considered drug related.  Other frequently reported events (e.g. fatigue, 
upper respiratory infection) did not appear to increase with dose and were generally mild.  
 
Table 4: 
A011-02: Incidence of Most Common Adverse Events    
Dose Group 
System Organ Class and Preferred Term 
Placebo 
N=7 
n (%) 
0.1 mg/kg 
N=8 
n (%) 
0.3 mg/kg 
N=8 
n (%) 
1.0 mg/kg 
N=8 
n (%) 
GASTROINTESTINAL DISORDERS 
     Diarrhea 
0 (0.0%) 
2 (25.0%) 
0 (0.0%) 
0 (0.0%) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
     Asthenia 
0 (0.0%) 
1 (12.5%) 
2 (25.0%) 
0 (0.0%) 
     Fatigue 
2 (28.6%) 
0 (0.0%) 
1 (12.5%) 
2 (25.0%) 
INFECTIONS AND INFESTATIONS 
     Viral upper respiratory tract infection 
0 (0.0%) 
4 (50.0%) 
0 (0.0%) 
0 (0.0%) 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
     Limb injury 
0 (0.0%) 
1 (12.5%) 
0 (0.0%) 
2 (25.0%) 
INVESTIGATIONS 
     Hematocrit increased 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
6 (75.0%) 
     Hemoglobin increased 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
7 (87.5%) 
     Red blood cell count increased 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
3 (37.5%) 
METABOLISM AND NUTRITION DISORDERS 
     Decreased Appetite 
1 (14.3%) 
0 (0.0%) 
2 (25.0%) 
0 (0.0%) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
     Arthralgia 
2 (28.6%) 
0 (0.0%) 
2 (25.0%) 
0 (0.0%) 
     Muscle spasms 
0 (0.0%) 
1 (12.5%) 
0 (0.0%) 
2 (25.0%) 
NERVOUS SYSTEM DISORDERS 
     Dizziness 
0 (0.0%) 
0 (0.0%) 
2 (25.0%) 
2 (25.0%) 
     Headache 
2 (28.6%) 
4 (50.0%) 
3 (37.5%) 
2 (25.0%) 
     Paresthesia 
1 (14.3%) 
0 (0.0%) 
0 (0.0%) 
3 (37.5%) 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
     Oropharyngeal pain 
2 (28.6%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
VASCULAR DISORDERS 
     Hot flush 
0 (0.0%) 
2 (25.0%) 
0 (0.0%) 
1 (12.5%) 
Note: Table presents AEs reported in more than one subject in any treatment group. 
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Hemoglobin levels for all subjects with elevations had returned to within normal limits by the end 
of the study.   
Adrenal cortical function was monitored through evaluation of serum electrolytes (sodium and 
potassium levels) and through cortisol response to adrenocorticotropic hormone (ACTH) 
stimulation. All ACTH simulation test results were normal. 
PK results confirmed that the PK of ACE-011 is linear following the first SC doses of all three 
dose levels tested, 0.1, 0.3, and 1.0 mg/kg. The terminal half life (T1/2) of ACE-011 following the 
last dose in all three dose groups was identical, with mean T1/2 being approximately 23 days. The 
mean CL/F ranged from 3.05 to 3.90 mL/d/kg, the mean Vz/F ranged from 97.47 to 103.03 
mL/kg, and the mean T1/2 ranged from 20.92 to 23.34 days in all 3 dose levels, with no apparent 
dependence on dose.  
Bone mineral density was assessed by dual-energy X-ray absorptiometry (DXA).  Mean change 
and mean percent change in BMD results from baseline to study end are summarized in the table 
below.  A dose-dependent increase in the BMD of the total hip from baseline to end of study was 
observed, with a significant and rapid increase of 2.4% in the 1.0 mg/kg dose group, compared to 
a 0.7% decrease in the placebo group.  BMD results for lumbar spine showed slight increases of 
0.4% to 1.0% from baseline to study end in all active treatment groups, compared with a 0.5% 
decrease in the placebo group (see Table 5 below): 
Table 5: 
A011-02: A Phase 1b Study in Healthy Postmenopausal Women: BMD 
 
5.4.3. 
A011-04: A Phase 2a Study in Patients with Osteolytic Lesions of Multiple 
Myeloma  
Study A011-04 is an ongoing, non-IND, Phase 2a, multi-center, randomized, multiple-dose study 
to evaluate the safety, tolerability and efficacy of ACE-011 in patients with osteolytic lesions of 
multiple myeloma.  Safety evaluations include adverse events (AEs), clinical laboratory tests, 
standard 12-lead electrocardiogram (ECG), vital signs, Eastern Cooperative Oncology Group  
Treatment Group 
Placebo 
 
N=7 
ACE-011 
0.1 mg/kg 
N=8 
ACE-011 
0.3 mg/kg 
N=8 
ACE-011 
1.0 mg/kg 
N=8 
 
Mean 
Change 
Mean Percent 
Change 
Mean 
Change 
Mean Percent 
Change 
Mean 
Change 
Mean Percent 
Change 
Mean 
Change 
Mean Percent 
Change 
Lumbar Spine 
(g/cm2) 
-0.0020 
-0.5% 
0.0099 
0.7% 
0.0082 
1.0% 
0.0051 
0.4% 
Total Hip 
(g/cm2) 
-0.0062 
-0.7% 
0.0050 
0.6% 
0.0075 
0.9% 
0.0220 
2.4% 
Number of doses administered and day of last dose per treatment group: 0.1 mg/kg 4 doses (Day 85); 0.3 mg/kg 3 doses (Day 57); 1.0 mg/kg 2 
doses (Day 29).  Data beyond this study day are considered follow-up results. 
 
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(ECOG) performance status and physical examinations.  Additionally, the study includes the 
assessment of biochemical markers of bone formation and resorption, skeletal related events 
(SREs), bone mineral density (BMD) by duel-energy x-ray absorptiometry (DXA) and bone pain 
by visual analog scale (VAS).  
In this study, patients are randomized in a 4:1 ratio to one of three dose levels of ACE-011 (0.1, 
0.3 and 0.5 mg/kg) or placebo, to be administered to patients every 28 days by subcutaneous 
injection, for up to four doses over a 3-month period.  The test article is being evaluated in 
combination with the anti-myeloma therapy of melphalan (4 mg/m2 on days 1-7), prednisolone 
(40 mg/m2 on days 1-7) and thalidomide (100 mg per day) (MPT).  The sites, Sponsor and 
Sponsor representatives are blinded to treatment assignment.    
As of 10 March 2009, 30 patients have been randomized, enrollment is complete and treatment is 
ongoing.  Fifteen patients have received multiple doses of their assigned treatment; 7 patients 
have received 4 doses, 3 patients have received 3 doses and 5 patients have received 2 doses.  Of 
the remaining 15 patients, 12 patients have received their first dose of ACE-011 or placebo and 3 
patients have not yet received their first dose.  There have been no ACE-011 related serious 
adverse events (SAEs) reported.  Per the monitored preliminary data on 18 patients presented to 
the Independent Data Monitoring Committee (DMC) on 9 February 2009, there were 8 Grade 
3/severe AEs reported in 4 patients, including neutropenia, platelet count decreased, pain in 
extremity, back pain and anemia.  All Grade 3 AEs were determined to be not related to ACE-
011 and the Grade 3 hematologic adverse events were considered either probably or definitely 
related to the MPT treatment.   
Following preliminary analysis of the blinded central laboratory data, increases in hemoglobin 
values were observed within 28 days after administration of the first dose of ACE-011/placebo.  
Per data available, 11 out of 30 patients had > 1 g/dL increase in hemoglobin within the first 28 
days on the study, 4 patients achieved a > 2 g/dL increase within their first 28 days on study, 
while 8 patients achieved a > 2 g/dL increase in hemoglobin through Day 85.      
Including all visits as of 10 March 2009 through Day 85, 9 out of 30 patients had a dose 
interruption due to a hemoglobin value of > 13 g/dL according to the dose modification rules 
defined in the protocol and 1 of the 9 patients, who had a history of hypertension, also had a dose 
interruption due to Grade 2 hypertension.  Three of the 9 patients that required a dose interruption 
due to a hemoglobin value of > 13 g/dL, as per protocol, had hemoglobin levels above 13 g/dL 
prior to their first dose.  Taken together, these data, suggest a beneficial pharmacodynamic effect 
of ACE-011 on erythropoiesis in a patient population with cancer chemotherapy induced anemia.  
No patients have had a dose reduction in ACE-011/placebo treatment or discontinued treatment.   
One SAE of prolonged hospitalization due to pneumonia, that was considered not related to 
ACE-011, was reported in a 
enrolled in the study.  On 
 four 
days after the first dose of ACE-011/placebo and the initial doses of melphalan, prednisolone and 
thalidomide (MPT), the patient presented with elevated temperatures up to 39º C, cough and 
fatigue.  Chest x-ray performed on
 revealed a pneumonic infiltration in the lower  
 
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lobe of the left lung.  On 
 hospitalization of the patient was prolonged due to the 
event.  The patient was treated with moxifloxacin, doripenem, meropenem and fluconazole.   
On 
 the pneumonic infiltration resolved, as confirmed by chest x-ray.  This SAE 
resolved upon discharge of the patient from the hospital on 
.  
The investigator considered the event of pneumonia not related to ACE-011 and possibly related 
to MPT.  The Sponsor agreed with the Investigator’s assessment of causality.  Pneumonia is 
considered a labeled event per the current package insert for thalidomide.  The SAE was 
considered serious, related and expected with respect to thalidomide and unrelated to ACE-011. 
The A011-04 study has completed enrollment, while treatment, follow-up and data monitoring 
are ongoing.   
5.5. 
Potential Risks for Human Use 
The 1-month safety study in rats suggested that ACE-011 may affect sperm count and motility in 
a dose-dependent manner, although these findings appeared to be reversible upon drug 
discontinuation.  These reproductive effects are likely a result of the expected biological activity 
of activin inhibition.   
The 1-month safety study in rats also suggested that ACE-011 induces adrenocortical necrosis in 
rats.  At present, the mechanism by which ACE-011 has induced this lesion in rats and the basis 
for its apparent species specificity are unknown; the finding has not been observed in mice or 
cynomolgus monkeys at similar dose levels.  Adrenal cortical function was monitored in human 
subjects receiving ACE-011 by the evaluation of serum electrolytes including sodium and 
potassium levels and by the evaluation of cortisol response to ACTH stimulation in both the 
Phase 1a single dose and Phase 1b multiple dose healthy volunteer clinical studies.  These 
parameters were evaluated up to doses of 3.0 mg/kg IV and 1.0 mg/kg SC, and no clinically 
significant perturbations in adrenal function were observed.     
Laboratory findings from the Phase 1a single dose study showed elevations in hematology 
results, pancreas and liver enzymes, and uric acid.  The most commonly seen treatment-emergent 
adverse events in this study were headache, infusion site reaction, injection site hemorrhage, and 
toothache.  
Based on data from the Phase 1b study, the most notable AEs were increases in hematologic 
laboratory measures in the 1.0 mg/kg dose group: hematocrit, hemoglobin, and RBC count.  AEs 
of increased hemoglobin and/or hematocrit were reported for seven of the eight subjects in this 
dose group.  These events were reported as mild or moderate elevations; all were considered 
probably related to study drug treatment.  No erythroid lineage AEs were reported in the 0.1 or 
0.3 mg/kg treatment groups.  Hematologic parameters will be monitored carefully in this study.   
Headache was reported frequently in all treatment groups with no apparent dose response trend, 
though the reports in the higher dose groups were more often considered possibly related to 
treatment.  Most headaches were reported as mild (one headache was reported as moderate).  
Paresthesia and dizziness were reported more frequently in the ACE-011 groups, though the  
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events were generally not considered drug related.  Other frequently reported events (e.g. fatigue, 
upper respiratory infection) did not appear to increase with dose and were generally mild. 
In the Phase 1b multiple-dose healthy volunteer study, some subjects treated with ACE-011 
showed elevations in blood pressure.  One subject who had received two doses of ACE-011 at the 
1.0 mg/kg dose level had a serious adverse event.  The patient was hospitalized for further 
evaluation of increases in blood pressure and symptoms that may have been caused by the 
increase in blood pressure.  The symptoms that the subject experienced included headache, 
dizziness, nausea, vomiting, and elevated hematology values (increases in the number of red 
blood cells).  This serious adverse event was judged to be probably related to the study drug and 
resolved following discharge from hospital the following day. Throughout the course of the 
follow up period hematologic parameters were monitored frequently until the hemoglobin and 
hematocrit levels returned to within normal limits. Further details are outlined in the Investigator 
Brochure.  
As with all biologics there is the potential for anti-drug antibodies that can be associated with 
increased drug clearance and hypersensitivity reactions.  An immune response to ACE-011 has 
been seen in monkeys that received the drug for 1 month and longer.  Some of those animals 
developed kidney inflammation possibly related to that immune response.  Anti-drug antibody 
formation will be assessed in this study to examine the immunogenicity of ACE-011, and to 
monitor reversibility of any AEs over time.   
Please refer to the Investigator Brochure for more information. 
 
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6. 
TRIAL OBJECTIVES AND PURPOSE 
6.1. 
Primary objective  
1. To evaluate the proportion of patients in each ACE-011 dose regimen who achieve a 
hematopoietic response during the treatment period including up to 2 months after the last 
dose of ACE-011 treatment of chemotherapy induced anemia in patients with metastatic 
breast cancer. 
6.2. 
Secondary objectives 
1. To evaluate the safety and tolerability of ACE-011 for the treatment of chemotherapy 
induced anemia in patients with metastatic breast cancer.  
2. To estimate the duration of the hematopoietic response associated with each ACE-011 
dose regimen. 
3. To estimate the time to the hematopoietic response associated with each ACE-011 dose 
regimen. 
4. To estimate the proportion of patients receiving red blood cell (RBC) transfusions and/or 
ESAs within each cycle of ACE-011 with each dose regimen. 
5. To evaluate the percentage of patients who achieve an increase in hemoglobin of ≥ 1 g/dl, 
≥ 2 g/dL and/or hemoglobin concentration ≥ 11 g/dL for a consecutive 28 day period 
during the treatment period including up to 2 months after the last dose of ACE-011 in the 
absence of any RBC transfusions and/or ESAs.   
6. To estimate the effect of each ACE-011 dose regimen on progression free survival (PFS) 
and objective response rate (ORR). 
6.3. 
Exploratory objectives  
1. To estimate the effect of each ACE-011 dose regimen on serum bone biomarkers (OC, 
BSAP, PINP, CTX, TRACP-5b), urine bone biomarker (uNTX), bone mineral density 
(DXA scans of lumbar spine and hip) and incidence of skeletal related events (SREs). 
2. To evaluate the quality of life during the study in relation to the treatment of 
chemotherapy induced anemia in patients with metastatic breast cancer during the study. 
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7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design and Plan 
This is a Phase 2, double-blind, randomized, placebo-controlled study to evaluate the efficacy, 
safety, and tolerability of ACE-011 for the treatment of chemotherapy induced anemia in patients 
with metastatic breast cancer. A total of 105 patients will be enrolled. 
The Data Monitoring Committee (DMC) is responsible for reviewing the safety. The DMC will 
be comprised of a minimum of 3 members.  The DMC will meet regularly during the study to 
review serious adverse events (SAEs), adverse events (AEs), laboratory results, and vital signs. 
Safety data will be reviewed throughout the study by the DMC, Medical Monitor and the 
Investigator. DMC responsibilities, membership, meeting frequencies and procedures will be 
outlined in the DMC charter.  
Patients will be evaluated for study inclusion/exclusion criteria by the Investigator. Patients who 
meet the study entry criteria will be enrolled within 14 days of the screening visit. Central lab 
values will be utilized for the evaluation of patient eligibility and in the evaluation of patient 
safety throughout the study. Local lab values for hemoglobin and hematocrit will be collected and 
reported from screening through the Day 281/Termination visit.  Three cohorts of 30 patients 
each are planned at the following doses of ACE-011: 0.1 mg/kg, 0.3 mg/kg and 0.5 mg/kg. 15 
patients will be enrolled into the placebo cohort (as shown in Table 6). 
Table 6: 
Study Design    
 
 
 
  
 
 
 
 
Each eligible patient will be randomized to one of the four cohorts to receive a dose administered 
as a subcutaneous injection every 28 days for up to 4 doses. Dosing will be administered on days 
1, 29, 57, and 85. Concurrent treatment with a myelosuppressive chemotherapy regimen for 
metastatic breast cancer will also be administered per standard of care at the site. Patients will be 
stratified according to administration of either single agent weekly chemotherapy or less frequent 
chemotherapy regimens.  
Blood samples will be collected at selected study sites from approximately one-third of patients 
for the evaluation of serum concentrations of ACE-011.  Pre-dose PK samples will be collected 
on Day 1.  See Appendix 5 for PK sampling schedule. 
 
Dose  
Number of  Patients 
0.1 mg/kg 
30 
0.3 mg/kg 
30 
0.5 mg/kg 
30 
Placebo 
15 
Total patients enrolled: 105 
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Patients will be assessed for safety by monitoring adverse events, clinical laboratory tests, 
assessment of quality of life (FACT- Fatigue (17)), vital signs and physical examinations on an 
ongoing basis.  ECGs will be performed during screening, prior to dosing on the first and second 
cycle, Day 15, and Day 113 (28 days after the last dose of ACE-011) and at Day 281/ 
Termination visit to monitor safety.  Blood pressure and lab values will be assessed at each study 
visit during the treatment period; weekly for the first two cycles and approximately every two 
weeks for subsequent cycles.  
Local laboratory hemoglobin values and blood pressure values will be evaluated prior to dosing 
per the dose modification criteria, as applicable.  
Patients will be followed for a minimum of 7 months following their last dose of ACE-011. Study 
participation for each patient is approximately 10.5 months (14 day screening period, 3 month 
treatment period with a 2 month treatment follow up period, and a 5 month post treatment follow-
up period). If a patient discontinues the study due to progression of disease (metastatic breast 
cancer) and/or begins another chemotherapy regimen, the patient will complete the Day 
281/Termination visit procedures and be followed for survival only (a minimum 7 months from 
the last dose of ACE-011).   
Anti-drug antibody testing will be performed at Day 281/Termination visit and if positive, the 
patient may be asked to return to the clinical site for additional monthly anti-drug antibody 
testing for up to 12 months, after their last dose.
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8. 
SELECTION AND WITHDRAWL OF PATIENTS 
8.1. 
Number of Patients 
The study will include three dose levels of ACE-011 at 0.1 mg/kg, 0.3 mg/kg and 0.5 mg/kg and 
a placebo group. A total of 105 will be treated with ACE-011 or placebo. 
8.2. 
Entry Criteria 
8.2.1. 
Patient Inclusion Criteria 
1. Women > 18 years of age. 
2. Histologically confirmed diagnosis of breast cancer documented by cytology or biopsy. 
3. Evidence of metastatic breast cancer with a minimum of one measurable lesion or non 
measurable lesion per RECIST criteria (Appendix 1). 
4. Receiving a multicycle myelosuppressive chemotherapy regimen including one of the 
following: anthracycline, taxane, gemcitabine or vinorelbine. 
5. Planned treatment with the same myelosuppressive chemotherapy regimen for a 
minimum of 9 weeks after Day 1 of ACE-011/placebo administration.  
6. Hemoglobin value between ≥ 6.5 to < 11.0 g/dL (≥ 65 to < 110 g/L).  
7. ≥ 30 days must have elapsed (from Day 1) since previous treatment with erythropoiesis-
stimulating agent (including concurrent treatment with IV iron) for chemotherapy 
induced anemia.  
8. ≥ 7 days have elapsed (from Day 1) since the last RBC blood transfusion and receipt of ≤ 
2 units of blood in the past 30 days.  
9. ECOG Performance status of 0 – 2 (Appendix 2). 
10. Adequate renal (creatinine ≤ 1.5 x ULN or creatinine clearance ≥ 40 mL/min) and hepatic 
function (bilirubin < 1.5 x ULN; AST/ALT < 2.5 x ULN). 
11. Females of childbearing potential  participating in the study are to use adequate birth 
control measures (i.e. oral contraceptives or two forms of barrier method birth control) 
during study participation. Females of childbearing potential must have a negative serum 
pregnancy test within 3 days to ACE-011/placebo administration (Day 1). A female of 
childbearing potential is a sexually mature woman who has not undergone a 
hysterectomy or who has not been postmenopausal for at least 24 consecutive months 
(i.e. who has had menses at some time in the preceding 24 months). 
12. Life expectancy of ≥ 6 months. 
13. Is willing to adhere to the study visit schedule, understand and comply with all protocol 
requirements. 
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14. Understand and sign a written informed consent. 
8.2.2. 
Patient Exclusion Criteria 
1. At the time of screening patients who have any grade > 3 toxicity (as per NCI CTCAE 
v3.0 (Appendix 3)) (except for the following disease related toxicities:  hematological 
events- anemia, thrombocytopenia or neutropenia or non hematological events- nausea, 
vomiting, fatigue, or muscle or bone/joint pain).  
2. Prior radiation therapy to > 20% of the whole skeleton. Use of palliative radiation if the 
area being treated is <15% of body surface area with no pelvic radiation or no more than 
10% of the bone marrow reserve is radiated is permitted during patient participation in 
the study, at the discretion of the investigator. 
3. Have received more than 5 prior chemotherapy treatment regimens for metastatic breast 
cancer.  
4. Concurrent use of bevacizumab with the chemotherapy regimen during study 
participation. 
5. Clinically significant pulmonary, endocrine, neurologic, gastrointestinal, hepatic or 
genitourinary disease unrelated to underlying hematologic disorder.  
6. Patients with heart failure as classified by the New York Heart Association (NYHA) 
classification of 3 or higher (Appendix 4). 
7. History of thrombosis, deep vein thrombosis (DVT), pulmonary emboli, or embolic 
stroke. 
8. Untreated CNS metastases (exception: CNS metastases treated with whole brain 
radiotherapy > 6 months prior to randomization). 
9. Diagnosis of a myeloid malignancy or known history of myelodysplasia.  
10. History of second malignancy within 5 years (except excised and cured basal cell 
carcinoma, squamous cell carcinoma of the skin or cervical carcinoma in situ).  
11. Patients with a recent history (within 14 days of Day 1) of administration of systemic (IV 
or oral) antibiotics. Patients should be free of infection at least 14 days after the last dose 
of systemic antibiotic treatment (from Day 1). 
12. Uncontrolled hypertension. If hypertension is considered clinically stable, systolic blood 
pressure (BP) must be < 150 mmHg and diastolic BP must be < 100 mmHg.  
13. Known history of hepatitis C antibody (HCV), hepatitis B surface antigen (HBsAg and 
HB core Ab), or human immunodeficiency virus (HIV) antibody.   
14. Deficiency in iron (serum ferritin< 100 ng/mL (< 224.7 pmol/L)), vitamin B12, or folate. 
15. History of anemia as a result of inherited hemoglobinopathy such as sickle cell anemia or 
thalassemia.  
16. History of autoimmune or hereditary hemolysis or gastrointestinal bleeding. 
17. Patient received treatment with another investigational drug or device within 1 month 
prior to Day 1, or if the half life of the previous product is known, within 5 times the half 
life prior to dosing, whichever may be longer.  
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18. Pregnant or lactating females. 
19. History of severe allergic or anaphylactic reactions or hypersensitivity to recombinant 
proteins or excipients in the investigational product.     
8.3. 
Patient Withdrawal Criteria 
Patients will be informed that they have the right to withdraw from the study at any time for any 
reason without prejudice to their medical care.   
Patients must be withdrawn from the study for any of the following reasons:  
• Patient request 
• Patient is unwilling or unable to comply with the protocol 
• ESA administration during the treatment period 
• Medical reason, such as cancer or treatment related toxicity, or at the discretion of the 
Investigator and/or the Medical Monitor(s) 
The reasons for withdrawal must be recorded in the patient’s case report form (CRF).  The 
Investigator must notify the Medical Monitor and the contract research organization (CRO) 
immediately when a patient has been discontinued/withdrawn due to an AE.  All patients who 
are withdrawn from the study should complete the tests and evaluations scheduled for Day 
281/Termination at the time of withdrawal. Discontinued/withdrawn patients may be followed 
for survival only 7 months from the last dose of ACE-011/placebo.  Patients who withdraw due 
to ESA administration during the treatment period may enter the treatment follow-up period.  
 
 
 
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9. 
TREATMENT OF PATIENTS 
9.1. 
Concomitant Medications 
9.1.1. 
General Concomitant Medication Usage 
During screening, and during the study, patients may take only stable doses of medications for 
chronic conditions that are not specifically excluded by the protocol (see Sections 8.2.1 Patient 
Inclusion Criteria and 8.2.2 Patient Exclusion Criteria).  The Medical Monitor should be 
consulted by the Investigator if there are any concerns about what constitutes a stable dose or 
what is a chronic condition. 
9.1.2. 
Concomitant treatment for anemia 
Concurrent therapy with a new prescription medication related to treatment of anemia during the 
course of the study must first be discussed with the Investigator and Medical Monitor prior to 
administration, unless appropriate medical care necessitates that medication should begin before 
the Medical Monitor can be consulted.  
9.1.2.1. 
Iron supplementation 
Iron supplementation within 7 days of Day 1 (besides an oral general multivitamin with iron) 
will not be allowed. If a patient becomes iron replete during study treatment (ferritin < 100 
ng/mL (< 224.7 pmol/L) or transferrin < 20%), treatment with iron supplementation is at the 
discretion of the investigator.  
9.1.2.2. 
Erythropoiesis-stimulating agents (ESAs) 
If concurrent treatment with erythropoiesis-stimulating agent is required in the opinion of the 
investigator, the erythropoiesis-stimulating agent label instructions are to be followed. The 
patient is to discontinue further treatment with ACE-011/placebo and enter the treatment follow 
up period of the study. See Table 7 for Schedule of Events.  
9.1.2.3. 
RBC Transfusions 
Concurrent treatment for chemotherapy induced anemia with blood transfusions is recommended 
when hemoglobin value is < 8 g/dL or at investigator discretion if the hemoglobin value is above 
8 g/dL and associated with anemia symptoms such as hemodynamic or pulmonary compromise 
requiring treatment. If a transfusion is given to a patient during the treatment period, ACE-
011/placebo should be administered no sooner than 7 days from the date of the transfusion.  
After the transfusion, the hemoglobin value should be assessed no later than 7 days from the date 
of the transfusion.  On the day of ACE-011/placebo administration, the hemoglobin value and 
blood pressure will be assessed. See Figure 1 for ACE-011/placebo dose modification rules.  
 
 
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9.2. 
Chemotherapy 
Chemotherapy treatment for metastatic breast cancer is to be given as per standard of care at the 
site.  ACE-011/placebo administration should be given prior to chemotherapy administration on 
ACE-011/placebo administration days.  Continuation of treatment with the same chemotherapy 
regimen through the treatment or post-treatment follow-up period of the study is at the discretion 
of the investigator. 
9.3. 
Treatment Compliance 
Each dose of ACE-011/placebo will be administered as a SC injection at the clinical site by the 
study staff and will be documented in the study record.  Monitoring for patient compliance with 
the treatment regimen is therefore unnecessary.  
9.4. 
Randomization  
Patients will be randomized to limit scientific bias within the study. Randomization assignments 
will be generated through a computerized system, provided by an Interactive Web/Voice 
Response System (IWRS/IVRS). Patients will be stratified according to frequency of the planned 
chemotherapy regimen (weekly chemotherapy vs. less frequent chemotherapy administration). 
9.4.1. 
Blinding 
The Investigators, patients, and sponsor or representative will remain blinded to the treatment 
arm assignment of each patient. The unblinded statistician will remain uninvolved in the study 
conduct until database lock and unblinding of the data has occurred.  
Safety parameters will be reviewed on an ongoing basis throughout the study to review blinded 
adverse events, serious adverse events, laboratory listings, and vital signs. If substantial toxicity 
trends are observed in one treatment group versus another, the DMC may request unblinding the 
treatment code assignment schema.  
9.4.2. 
Unblinding 
In the event of a medical emergency for an individual patient in which knowledge of the study 
medication is critical to the patient’s medical management, the investigator may break the blind 
for that patient. However, prior to breaking the blind, every effort must be made by the 
investigator to first discuss the need to break the blind with the sponsor or sponsor 
representative. Further, it must be determined by the investigator that breaking the treatment 
blind is necessary information for the medical management of that patient. If the blind is broken, 
the patient must withdraw from the study by completing the Day 281/Termination visit 
procedures and be followed for survival only. 
 
 
 
 
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9.5. 
Treatments Administered 
9.5.1. 
Selection of Doses in the Study 
Single dose administration of ACE-011 up to 3.0 mg/kg was previously demonstrated to be safe 
and to have durable effects on markers of bone formation and resorption as well as red blood 
cells following a single IV administration.  A dose-limiting pharmacodynamic effect of ACE-
011 with increases in hemoglobin and hematocrit and RBCs was established in healthy post-
menopausal women at the 1.0 mg/kg dose level following multiple SC administration.  This 
study will confirm the safety in following repeated SC administration of ACE-011 and further 
evaluate the potential efficacy in patients with chemotherapy induced anemia.  The safety and 
preliminary efficacy of ACE-011 following multiple doses up to 0.5 mg/kg will be assessed 
using a parallel randomization design. 
9.5.2. 
Selection and Timing of Dosing for Each Patient 
Patients will be enrolled and receive their assigned dose of ACE-011/placebo every 28 days (i.e. 
on Days 1, 29, 57, and 85). Patients will be receiving chemotherapy, concurrently for metastatic 
breast cancer. After completion of the treatment, patients will return to the site monthly for 2 
follow-up assessments (i.e., Days 113 and 141).  Subsequently, the patient will return to the site 
for 4 post treatment follow-up assessments (i.e. Days 169, 197, 225, and 253). The patient will 
return to the site for a termination visit approximately 1 month after the post treatment follow-up 
period (Day 281).  Patients will be discontinued from the ACE-011/placebo treatment for 
unacceptable toxicity, if the chemotherapy regimen is discontinued or for disease progression 
that requires the initiation of another chemotherapy treatment. 
9.5.2.1. 
ACE-011 Treatment Related Toxicity  
Patients with grade ≥3 toxicity related to ACE-011 will be discontinued from ACE-011/placebo 
treatment except for the following.  Patients with grade 3 hypertension that decreases to grade 
≤ 1 within 7 days after treatment with anti-hypertensive therapy may continue on ACE-
011/placebo treatment.  Dose reduction rules will apply at the subsequent scheduled dosing 
day(s).  
Patients with a hemoglobin level above the upper limit of normal at any time during the study 
after Day 1 will be discontinued.   
Patients who discontinue treatment with ACE-011/placebo will enter the treatment follow-up 
period. 
9.5.2.2. 
ACE-011 Dose Modification Rules 
Throughout the study blood pressure and hemoglobin values will be evaluated for patient safety. 
The local hemoglobin values and blood pressure values will be evaluated on each ACE-
011/placebo dosing day.  The hemoglobin values from the previous 28 days between each  
 
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ACE-011/placebo dosing day and blood pressure will be reviewed and evaluated for dose 
modifications.  The parameters below outline rules for dosing modifications (Figure 1).  Table 8 
outlines the dose reduction levels of ACE-011.  
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10. 
STUDY PROCEDURES AND SCHEDULE 
10.1.1. 
Written Informed consent 
Patients will be required to sign an Institutional Review Board/Institutional Ethics Committee 
(IRB/IEC) approved informed consent form (ICF) prior to any study related procedures, 
including screening evaluations. 
Screen failure information will be maintained, including but not limited to, reason for failure.   
10.1.2. 
Screening (Within 14 days of dosing) 
The following will be collected within 14 days prior to the initial dosing Day 1: 
• Informed consent 
• Assessment of inclusion/exclusion criteria 
• Complete Medical History and Physical Examination 
• Vital signs including weight (kg), heart rate (beats/min), seated systolic and diastolic 
blood pressure (mmHg), temperature (°C) and height. 
• FACT-Fatigue survey 
• 12 lead Electrocardiogram (ECG)- including measurement of the QT interval 
• Serum iron, total iron binding capacity (TIBC), transferrin and serum ferritin  
• Vitamin B12 and serum folate levels 
• Coagulation 
• Serum chemistry  
• Hematology 
• LH, FSH, testosterone, progesterone, and estradiol  
• Back-up blood sample to be drawn for future testing 
• Serum Pregnancy Test for females of childbearing potential- to be assessed within 3 
days of Day 1. 
• Urinalysis 
• Evaluation of transfusion frequency (including history of transfusion up to 8 weeks 
prior to Day 1 
• Documentation of concomitant medications (any treatments taken 28 days prior to 
Day 1 
• Females of childbearing potential- collection of menstrual cycle information (date of 
last menstruation, date of menstrual period onset and duration of menstruation) 
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• CT/MRI scan: Head, neck, thoracic, abdominal, and pelvic scans are to be acquired.  
A CT/MRI scan acquired within 4 weeks of initiating the current chemotherapy 
regimen may be used for the screening assessment. One measurable or non-
measurable lesion per RECIST is to be identified by the scan.  
o Brain (head) CT only to be done to rule out CNS metastases in patients with 
suspicious clinical symptoms or prior history of CNS metastases.  
• Dual-energy X-ray absorptiometry (DXA) of  lumbar spine and hip 
• Bone scans (only for patients with bone metastases) acquired within 4 weeks of the 
initiation of the current chemotherapy regimen may be used for the screening 
assessment. 
10.1.3. 
Initial Dosing: Day 1  
Patients will be dosed on Day 1.  Results from screening evaluations must be reviewed prior to 
randomization to confirm patient eligibility.  A patient will be considered randomized once a 
multi-digit patient identification number has been assigned to the patient through the IVRS.  
After assignment of the patient identification number, ACE-011/placebo administration may 
begin. 
Chemotherapy regimen will be administered per standard of care at the site. The following tests 
must be performed prior to ACE-011/placebo administration: 
• Confirm eligibility of patient by inclusion/exclusion criteria. The local hemoglobin 
value should be drawn prior to ACE-011/placebo administration.  
• Physical Examination 
• Vital signs including weight (kg), heart rate (beats/min), seated systolic and diastolic 
blood pressure (mmHg), and temperature (°C)  
• FACT-Fatigue survey 
• 12 lead ECG- including measurement of the QT interval 
• Serum iron, total iron binding capacity, transferrin and serum ferritin 
• Coagulation 
• Chemistry   
• Hematology 
• Serum erythropoietin marker  
• Peripheral blood smear 
• LH, FSH, testosterone, progesterone, and estradiol  
• Anti-drug antibody test 
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• Bone biomarkers- osteocalcin (OC), procollagen type 1 N-terminal propeptide 
(P1NP), serum bone specific alkaline phosphatase (BSAP), C-terminal type 1 
collagen telopeptide (CTX) and Serum tartrate-resistant acid phosphatase isoform-5b 
(TRACP-5b), and urine N-telopeptide (uNTX).  
o Please refer to the Study Reference Guide, provided under separate cover, for 
the Bone Biomarker Collection and Handling Guidelines for instructions the 
collection of serum and urine for the biomarkers.  
• Back-up blood sample to be drawn for future testing 
• Females of childbearing potential- Urine (dipstick) pregnancy test to be collected and 
resulted prior to ACE-011/placebo dosing 
• Urinalysis 
• Evaluation of transfusion frequency  
• Documentation of concomitant medications  
• Evaluation of adverse events (after study drug administration)  
• Females of childbearing potential- collection of menstrual cycle information (date of 
last menstruation from day 1, date of menstrual period onset and duration of 
menstruation)  
Patients will be administered ACE-011/placebo before the chemotherapy regimen begins during 
the study visits.  
After ACE-011/placebo and chemotherapy are administered, the patient may leave the clinic, 
based on the clinical judgment of the staff.   
10.1.4. 
ACE-011/placebo administration : Days 29, 57, and 85 (± 3 days)  
Chemotherapy regimen will be administered per standard of care at the site. ACE-011/placebo 
will be administered approximately every 28 days. The following procedures must be performed 
prior to ACE-011/placebo administration: 
• Physical Examination 
• Vital signs including weight (kg), heart rate (beats/min), seated systolic and diastolic 
blood pressure (mmHg), and temperature (°C)  
• FACT-Fatigue survey 
• 12 lead ECG -including measurement of the QT interval (Day 29 only) 
• Serum iron, total iron binding capacity, transferrin and serum ferritin  
• Coagulation 
• Serum chemistry  
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• Hematology 
• Serum erythropoietin marker  
• Peripheral blood sample 
• LH, FSH, testosterone, progesterone, and estradiol 
• Anti-drug antibody test 
• Bone biomarkers- OC, BSAP, PINP, CTX, TRACP-5b, and uNTX 
o Please refer to the Study Reference Guide, provided under separate cover, for 
the Bone Biomarker Collection and Handling Guidelines for instructions the 
collection of serum and urine for the biomarkers.  
• Back-up blood sample to be drawn for future testing 
• Females of childbearing potential -Urine (dipstick) pregnancy test  
• Urinalysis (Day 85 only) 
• Evaluation of transfusion frequency  
• Documentation of concomitant medications 
• Evaluation of adverse events  
• Females of childbearing potential- collection of menstrual cycle information (date of 
last menstruation, date of menstrual period onset and duration of menstruation)  
Hemoglobin (HgB) and Hematocrit values (Hct) and blood pressure (BP) measurement must be 
assessed prior to ACE-011/placebo dose administration by review of local laboratory values.  
10.1.5. 
Additional visits during Treatment Period: Days 8, 15, 22, 36 (± 1 day), 43, 64 
and 71 (± 2 days) 
 
Chemotherapy regimen will be administered per standard of care at the site.  The following 
procedures are to be performed during the study visit:  
• Vital signs including weight (kg), heart rate (beats/min), seated systolic and diastolic 
blood pressure (mmHg), and temperature (°C)  
• 12 lead ECG -including measurement of the QT interval (Day 15 only) 
• Serum folate (Day 36 only) 
• Coagulation 
• Serum chemistry  
• Hematology  
• Back-up blood sample to be drawn for future testing 
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• Evaluation of transfusion frequency  
• Documentation of concomitant medications 
• Evaluation of adverse events  
• CT/MRI scan (Day 64 only, +/- 5 day window).  Same modality as acquired for 
baseline should be used for follow up scans. Tumor response assessments to be 
evaluated by the investigator. 
• Bone scan (Day 64 only, +/- 5 day window). Follow-up scan to be acquired if 
performed at baseline. 
If patient terminates the treatment early, prior to receiving a fourth dose of ACE-011/placebo, the 
patient will enter the treatment period follow up. However, if patient terminates ACE-
011/placebo early and begins a new chemotherapy regimen, the patient should complete the Day 
281/Termination visit procedures and enter the post treatment follow up period. 
10.1.6. 
Treatment Period Follow-up visits : Days 113 and 141 (± 7 days) 
Chemotherapy regimen will be administered per standard of care at the site.  The following 
procedures are to be performed during the study visit: 
• Physical Examination 
• Vital signs including weight (kg), heart rate (beats/min), seated systolic and diastolic 
blood pressure (mmHg), and temperature (°C)  
• 12 lead ECG-including measurement of the QT interval (Day 113 only) 
• Serum folate (Day 113 only) 
• Coagulation  
• Serum chemistry  
• Hematology   
• Serum erythropoietin marker  (Day 141 only) 
• LH, FSH, testosterone, progesterone, and estradiol  
• Anti-drug antibody test 
• Bone biomarkers- OC, BSAP, PINP, CTX, TRACP-5b, and uNTX  
o Please refer to the Study Reference Guide, provided under separate cover, for 
the Bone Biomarker Collection and Handling Guidelines for instructions the 
collection of serum and urine for the biomarkers. 
• Back-up blood sample to be drawn for future testing 
• Evaluation of transfusion frequency  
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• Documentation of concomitant medications 
• Evaluation of adverse events  
• Females of childbearing potential- collection of menstrual cycle information (date of 
last menstruation, date of menstrual period onset and duration of menstruation)  
• CT/MRI scan (Day 113 only, +/- 5 day window). Same modality as acquired for 
baseline should be used for follow up scans. Tumor response assessments to be 
evaluated by the investigator. 
• DXA of  lumbar spine and hip (Day 113 only) 
• Bone scan (Day 113 only, +/- 5 day window). Follow-up scan to be acquired if 
performed at baseline. 
10.1.7. 
Post Treatment Period Follow-up visits : Days 169, 197, 225, and 253 (± 7 days) 
If a CT/MRI and bone scan (if applicable) is performed as per standard of care during the post 
treatment period follow up, results may be collected within the eCRF to capture the status of the 
disease. Chemotherapy regimen will be administered per standard of care at the site. The 
following procedures are to be performed during the study visit: 
• Hematology 
• Back-up blood sample to be drawn for future testing 
• Evaluation of transfusion frequency  
• Documentation of concomitant medications 
• Evaluation of adverse events  
10.1.8. 
Termination Visit:  Day 281 (± 7 days) 
Day 281 is the final visit.  If a patient terminates the study early, the Day 281 procedures should 
be followed. Chemotherapy regimen will be administered per standard of care at the site. The 
following procedures are to be performed during the study visit: 
• Physical Examination 
• Vital signs including weight (kg), heart rate (beats/min), seated systolic and diastolic 
blood pressure (mmHg), and temperature (°C)  
• FACT-Fatigue survey 
• 12 lead ECG -including measurement of the QT interval 
• Serum iron, total iron binding capacity, transferrin and serum ferritin  
• Serum folate 
• Coagulation 
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• Serum chemistry  
• Hematology  
• Serum erythropoietin marker 
• Peripheral blood smear 
• Anti-drug antibody test 
• Bone biomarkers- OC, BSAP, PINP, CTX, TRACP-5b, and uNTX  
o Please refer to the Study Reference Guide, provided under separate cover, for 
the Bone Biomarker Collection and Handling Guidelines for instructions the 
collection of serum and urine for the biomarkers. 
• Back-up blood sample to be drawn for future testing 
• Females of childbearing potential -Urine (dipstick) pregnancy test  
• Urinalysis 
• Evaluation of transfusion frequency  
• Documentation of concomitant medications  
• Evaluation of adverse events  
• DXA of  lumbar spine and hip 
• Bone scan (Day 281, +/- 5 day window). Follow-up scan to be acquired if performed 
at baseline. 
If a patient has a positive anti-drug antibody result at Day 281/Termination visit, the patient may 
be asked to return to the clinical site for additional monthly anti-drug antibody testing, 12 months 
after their last dose. 
10.2. 
Discontinuation of study 
The Sponsor may terminate this study, after consultation with the Investigator, at any time for 
safety or administrative reasons.  The Sponsor may terminate the study if the occurrence of 
serious adverse events (SAEs) or other findings suggest unacceptable risk to the health of the 
patients.   
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11. 
INVESTIGATIONAL PRODUCT MATERIALS AND 
MANAGEMENT 
11.1. 
Reference Product 
The placebo (control agent) to be used in this study will be sterile normal saline (0.9% Sodium 
Chloride for Injection) administered as a SC injection.  Sterile, normal saline will be supplied to 
the investigational site’s pharmacist.  The manufacturer’s directions for placebo storage and 
handling are to be followed, as are standard clinical practices for ensuring sterility of the 
placebo. 
11.2. 
Investigational Product Packaging and Labeling 
ACE-011 will be supplied in 2 mL clear glass vials with gray stoppers and red flip-top seals that 
contain 1 mL of ACE-011.  The drug product consists of ACE-011 in PBS at a nominal 
concentration of approximately 50 mg/mL. 
11.3. 
Investigational Product Storage 
ACE-011 is recommended to be stored at ≤ -65°C. 
11.4. 
Investigational Product Preparation 
See Investigational Product Preparation Manual. 
11.5. 
Administration 
ACE-011/placebo will be administered by subcutaneous injection (SC). Subcutaneous injections 
will be given in the upper arm and/or thigh. Please refer to Investigational Product Handling and 
Administration document for further information. 
Dose modifications will be determined by the investigator after reference to the dose 
modification rules listed in Figure 1. In the case of a dose interruption or dose reduction of ACE-
011, the investigator or designee will notify the pharmacy staff, who is unblinded, of the 
treatment decision for appropriate preparation of the study drug to maintain the blind of the 
study.  
11.6. 
Drug Accountability 
Accountability for ACE-011/placebo is the responsibility of the Investigator.  Investigational 
clinical supplies must be received by a designated person at the clinical site and kept in a secured 
location.  The investigational site must maintain accurate records demonstrating dates and 
amounts of ACE-011/placebo received, to whom it was dispensed (patient-by-patient 
accounting), and accounts of any ACE-011/placebo accidentally or deliberately destroyed or 
returned.  Unless otherwise notified, all vials of ACE-011/placebo, both used and unused, must 
be saved for drug accountability.  The used vials may be discarded, per the institution’s standard  
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practice, after drug accountability has been completed by the monitor. The Investigator must 
return all unused vials of ACE-011 to the Sponsor at the end of the study, or the study drug 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. 
11.7. 
Investigational Product Handling and Disposal 
Please refer to the Study Reference Guide, provided under separate cover, for detailed drug 
handling, administration, and storage instructions.   
 
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12. 
ASSESSMENT OF EFFICACY 
Efficacy measurements will include assessments for hematopoietic response which is defined as 
an increase in hemoglobin of ≥ 0.5 g/dL, ≥ 1 g/dL, ≥ 2 g/dL and/or hemoglobin concentration ≥ 
11 g/dL above the study baseline value for 28 consecutive days during the treatment period 
including up to 2 months after the last dose of ACE-011, in the absence of any RBC transfusions 
and/or ESAs, at each dose level. The hematopoietic endpoints will be determined by the 
monitoring of hematologic laboratory values and RBC transfusion and/or ESA administration. 
Secondary endpoints associated with assessment of disease progression will be evaluated by 
CT/MRI scan and bone mineral density by DXA scans, respectively. Bone biomarkers and 
incidence of skeletal related events (SREs) will also be evaluated for all patients. SREs are 
defined as pathologic fracture, radiation therapy to bone, surgery to bone, or spinal cord 
compression. Quality of life assessment (FACT-Fatigue) will be evaluated for each patient.  
 
 
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13. 
ASSESSMENT OF SAFETY 
13.1. 
Safety Parameters 
13.1.1. 
Adverse Events 
All patients will be assessed for safety by monitoring adverse events, clinical laboratory tests, 
vital signs and physical examinations. AE information will be collected throughout the study.  
See Section 14 Adverse Events for a full description of AE definitions, AE and SAE reporting 
procedures, and emergency procedures. 
13.1.2. 
Clinical Laboratory Tests 
The following laboratory safety assessments will be drawn at the investigational site’s local 
laboratory according to the laboratory collection recommendations. The samples will then be 
sent to the central lab for value reporting. Please refer to Lab Reference Manual for further 
information. Hemoglobin and hematocrit lab tests will be drawn and evaluated by the local 
laboratory at each visit day throughout the study. The local hemoglobin laboratory value will be 
used in the evaluation of ACE-011/placebo dose modifications. The sponsor may request 
additional safety tests be performed based on ongoing data review during the study.  
• Iron studies: Serum iron, total iron binding capacity (TIBC), transferrin and serum ferritin on  
 
specified days. 
• 
Nutritional tests: Serum folate and vitamin B12 
• 
Coagulation (central lab only): prothrombin time (PT), partial thromboplastin time (PTT), 
and fibrinogen 
• 
Serum chemistry (central lab only): AST, ALT, lactate dehydrogenase (LDH), total bilirubin, 
indirect bilirubin, alkaline phosphatase, total protein, albumin, sodium, potassium, chloride, 
carbon dioxide, calcium, phosphorus, blood urea nitrogen (BUN), creatinine, uric acid, 
glucose, amylase, and lipase.  
• 
Hematology: complete blood count (CBC) with differential and platelet.  CBC includes red 
blood cells (RBC), white blood cells (WBC), hemoglobin, hematocrit, mean corpuscular 
volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin 
concentration (MCHC), and erythropoietin levels.  Reticulocyte percent and peripheral blood 
smear will be collected on specified days.  
• 
Bone biomarkers:  (serum) osteocalcin (OC), procollagen type 1 N-terminal propeptide 
(P1NP), serum bone specific alkaline phosphatase (BSAP), C-terminal type 1 collagen 
telopeptide (CTX), tartrate-resistant acid phosphatase isoform-5b (TRACP-5b), and urine N-
telopeptide (uNTX).  
• 
Pregnancy test for females of child bearing potential 
• Urinalysis: including determination of pH, specific gravity, protein, glucose, ketones, blood, 
leukocyte esterase and nitrite. Microscopy required only to follow-up abnormal findings.  
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13.1.3. 
Other Safety Assessments  
• Physical examinations 
• Vital signs: weight (kg), heart rate (beats/min), seated blood pressure (mmHg) and 
oral temperature (°C).  Height will be collected at screening only. 
• FACT-Fatigue survey 
• 12-lead ECG -including measurement of the QT interval 
• LH, FSH, testosterone, progesterone, and estradiol 
• Anti-drug antibody test 
• CT/MRI scan   
• DXA 
• Bone scans (for those patients with baseline bone metastases) 
13.2. 
Pharmacokinetics 
 See Appendix 5 for further details regarding PK sampling.  
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14. 
ADVERSE EVENT 
Adverse Event 
An adverse event (AE) is any untoward medical occurrence in a patient administered a 
pharmaceutical product, which does not necessarily have a causal relationship with the treatment.  
An AE can be any unfavorable and unintended sign (e.g., including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of the study drug, whether or 
not it is considered to be study drug related.  This includes any newly occurring event or 
previous condition that has increased in severity or frequency since the administration of study 
drug (treatment-emergent). 
Serious Adverse Event 
A serious adverse event (SAE) is any AE, occurring at any dose level and regardless of causality 
that: 
• Results in death. 
• Is life-threatening:  Life-threatening means that the patient was at immediate risk of death 
from the reaction as it occurred, (i.e., it does not include a reaction which hypothetically 
might have caused death had it occurred in a more severe form). 
• Requires inpatient hospitalization or prolongation of existing hospitalization.  
• Results in persistent or significant disability/incapacity. 
• Is a congenital anomaly/birth defect. 
• Is an important medical event: an important medical event is an event that may not result 
in death, be life-threatening, or require hospitalization but may be considered an SAE 
when, based upon appropriate medical judgment, it may jeopardize the patient and may 
require medical or surgical intervention to prevent one of the outcomes listed in the 
definitions for SAEs.  Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, blood dyscrasias or 
convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse.   
• A hospitalization for an elective procedure will not be considered a SAE.  
Unexpected Adverse Event 
An unexpected AE is an AE that is not reported in the Investigator Brochure or in the case of an 
AE already described, the severity of which is not described in the Investigator Brochure.  
 
 
 
 
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14.1. 
Adverse Event Classification 
The following classifications should be used when evaluating the relationship of AEs and SAEs 
to the investigational drug. 
None: 
No relationship between the experience and the administration of study 
drug; related to other etiologies such as concomitant medications or 
patient’s clinical state. 
Unlikely:  
 
 
The current state of knowledge indicates that a relationship is unlikely.   
Possibly: 
A reaction that follows a plausible temporal sequence from administration 
of the study drug and follows a known response pattern to the suspected 
study drug.  The reaction might have been produced by the patient’s 
clinical state or other modes of therapy administered to the patient. 
Probably: 
A reaction that follows a plausible temporal sequence from administration 
of the study drug and follows a known response pattern to the suspected 
study drug.  The reaction cannot be reasonably explained by the known 
characteristics of the patient’s clinical state or other modes of therapy 
administered to the patient. 
Definitely: 
A reaction that follows a plausible temporal sequence from administration 
of the study drug and follows a known response pattern to the suspected 
study drug and can be confirmed with a positive re-challenge test or 
supporting laboratory data. 
Severity of AEs will be graded by the investigator using the National Cancer Institute (NCI; US) 
Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 guidelines (Appendix 
3). 
14.2. 
Recording Adverse Events 
Patients will be evaluated and questioned generally for AEs during the course of the study, 
starting from baseline (Day 1).  The Medical History CRF should be comprehensive of patient’s 
medical history up to Day 1. All AEs occurring after ACE-011/placebo administration until the 
Day 281/Termination visit are to be documented on AE CRF. The specific disease or syndrome 
rather than individual associated signs and symptoms should be identified by the investigator and 
recorded on the CRF.  
 
 
 
 
 
 
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Serious Adverse Events (SAEs) 
For SAEs, a SAE form must be completed with as much information as possible and submitted 
in the time frame described in Section 14.3.  
When new significant information is obtained as well as when the outcome of an event is known, 
the investigator should record the information on a new SAE form.  If the patient was 
hospitalized, a copy of the discharge summary must be included as part of the patient medical 
file.  In all instances, the investigator should follow up with patients until the outcome of the 
SAE is known. 
14.3. 
Reporting Adverse Events 
All AEs spontaneously reported by the patient and/or in response to an open question from study 
personnel or revealed by observation, physical examination or other diagnostic procedures will 
be recorded on the AE CRF.  Any clinically relevant change in laboratory assessments or other 
clinical findings is considered an AE and must be recorded on the AE CRF. Clinically significant 
laboratory abnormalities are those that are identified as such by the investigator and/or those that 
require intervention. All AEs are to be followed until the event resolves or the clinical course is 
stabilized.  
Serious Adverse Events 
For SAEs, a SAE form must be completed with as much information as possible and submitted 
in the time frame described below. 
All SAEs that occur during the course of the study (from the signing of the ICF until the last 
study visit) must be reported by the Investigator to PPD and Sponsor by faxing the SAE form 
within 24 hours from the point in time when the Investigator becomes aware of the SAE.  All 
SAEs and deaths must be reported whether or not considered causally related to the study drug.   
SAE Reporting: 
PPD Medical Monitor 
PPD Inc. 
If there are serious, unexpected AEs associated with the use of the study drug, the Sponsor will 
notify the appropriate regulatory agency(ies) and all appropriate parties on an expedited basis.  It 
is the responsibility of the Investigator to promptly notify the Institutional Review Board (IRB) 
of all unexpected SAEs involving risk to human patients. 
 
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14.4. 
Emergency Sponsor Contact 
In the event of a medical emergency (i.e., an event that requires immediate attention regarding 
the treatment of a patient, operation of the clinical study, and/or the use of investigational drug), 
investigational site personnel must immediately contact the Medical Monitor. 
 
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15. 
STATISTICS 
Statistics Analysis Overview 
The study will be considered complete with regard to the primary endpoint once all eligible 
subjects have completed up to 2 months after the last dose of ACE-011. Patients will be 
randomized to one of three ACE-011 treatment groups (0.1, 0.3 and 0.5 mg/kg) or placebo with a 
ratio of 2:2:2:1.  Patients will be stratified according to administration of either single agent 
weekly chemotherapy or less frequent chemotherapy regimens.  
15.1. 
Determination of Sample Size 
With an anticipated dropout rate of 20%, a sample size of 30 patients per dose level is estimated 
to achieve at least 80% power with 2 sided significance level of 0.05 to differentiate targeted 
response rate of p1=0.45 from null hypothesis p0=0.20. An additional 15 patients will be 
enrolled to the placebo group for safety comparison. A total of 105 patients will be randomized 
to three ACE-011 dose groups (0.1, 0.3, and 0.5 mg/kg) and placebo with a ratio of 2:2:2:1.  
15.2. 
Analysis Populations 
For this study, the following populations will be defined and used in the analysis and 
presentation of the data. 
Modified Intent-to-Treat (MITT) population: The MITT population is defined as all patients 
randomized who received at least one dose of study drug. 
Per-Protocol (PP) population: The PP population is defined as all patients randomized who have 
confirmed chemotherapy induced anemia, received at least one dose of ACE-011 and on study 
(treatment) for at least 2 months (57 days). 
Safety population: The safety population is defined as all patients who received at least one dose 
of study drug ACE-011 or placebo. 
15.3. 
Background and Demographic Characteristics 
Summary statistics (mean, standard deviation, median, minimum and maximum) will be 
provided for those variables measured on a continuous scale.  The frequency distribution 
(number and percentage) will be provided for those variables measured on a nominal scale. 
15.3.1. 
Patient Disposition 
Patient disposition (analysis population allocation, entered, discontinued, along with primary 
reason for discontinuation) will be summarized using frequency and percent for each dose group.  
A summary of patients enrolled by site will be provided.  
 
 
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15.3.2. 
ACE-011 
ACE-011 treatment exposure (total dosage received) will be summarized for each dose group as 
well as for each cycle for each dose level.  Listings for dose adjustment will be provided. 
15.3.3. 
Concomitant Therapy 
By-patient listings will be provided for all concomitant medications and therapies taken during 
the study.  All concomitant medications will be coded and categorized by the WHO drug coding 
system.  Usage frequency of each coded concomitant medications will be summarized by each 
dose group. 
15.4. 
Efficacy Evaluation 
15.4.1. 
Primary Efficacy Analysis 
The primary efficacy endpoint is the hematopoietic response rate at each dose level.  It is defined 
as the proportion of patients who have a hematopoietic response of an increase in hemoglobin of 
≥ 0.5 g/dL for 28 consecutive days during the treatment period including up to 2 months after the 
last dose of ACE-011, in the absence of any RBC transfusions and/or ESAs. The ACE-011 
treatment period is defined as from the time of first ACE-011 dose to up to 2 months after the 
last dose of ACE-011 treatment.  To be considered as a responder, all hemoglobin measurements 
during a 28 consecutive day period or longer must have an increase of ≥ 0.5 g/dL from baseline. 
If RBC transfusions and/or ESAs are required, no hemoglobin measurements within 28 days will 
be used to determine the hemoglobin response. Primary efficacy analysis will be based on PP 
population.  Primary efficacy analysis will also be conducted on MITT population as supportive 
to the PP based analysis.  Patients who do not receive ACE-011 will be excluded from primary 
efficacy analysis.  Patients who discontinue the ACE-011 treatment prematurely will be counted 
as non-responder in the calculation of response rate.     
A 95% confidence interval (CI) for the response rate for each dose level will be provided to 
assess whether 95% CI of response rate contains null hypothesis response rate, p0=0.20.  The 
response rate and 95% CI will also be provided for patients with chemotherapy on weekly basis 
versus those with chemotherapy on a less frequent basis for each dose level as well as overall (all 
three doses levels analyzed together).  
An exploratory analysis with the Kaplan Meier approach will be considered to account for those 
patients who discontinue the ACE-011 treatment prematurely if the drop out rate is greater than 
20%.  Exploratory analysis of comparing hematopoietic response rates between active and 
placebo will be performed using Fisher’s exact test.  Due to the nature of the study (phase 2 dose 
determination study), no multiplicity adjustment will made for the multiple comparisons.  
 
 
 
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15.4.2. 
Secondary Efficacy Analyses 
The secondary efficacy endpoints include: 
• Proportion of patients achieving an increase in hemoglobin of ≥ 1 g/dl, ≥ 2 g/dL and/or 
hemoglobin concentration ≥ 11 g/dL for 28 consecutive days during the treatment period 
and up to 2 months after the last dose of ACE-011 in the absence of any RBC 
transfusions and/or ESAs.   
• Duration of hematopoietic response (days) defined as the first time hemoglobin increases 
at least 0.5 g/dL, ≥ 1 g/dl, ≥ 2 g/dL and/or hemoglobin concentration ≥ 11 g/dL from 
baseline to the last time there is hemoglobin ≥ 0.5 g/dL, ≥ 1 g/dl, ≥ 2 g/dL and/or 
hemoglobin concentration ≥ 11 g/dL increase from baseline.  Duration of response is only 
calculated for a responder and will be at least 28 days.  The duration of response will be 
at least 28 days is only calculated for a patient who meets the primary efficacy endpoint.  
• Time to achieve hematopoietic response (days) defined as time from first dose of ACE-
011 to the first time a hemoglobin result at least 0.5 g/dL, ≥ 1 g/dl, ≥ 2 g/dL and/or 
hemoglobin concentration ≥ 11 g/dL increase from baseline and maintained for a period 
of at least 28 consecutive days. 
• Proportion of patients receiving red blood cell (RBC) transfusions and/or ESAs in each 
dose group as well as within each cycle of each ACE-011 dose level. 
• Objective tumor response rate for each dose level using RECIST criteria. 
• Progression-Free Survival is defined as the time from randomization into the study to the 
first observation of documented disease progression or death due to any cause.  If the 
subject has not progressed or died at the time of final analysis, PFS will be censored at 
the time of last tumor assessment.   
The statistical analysis for binary endpoints will be similar to the primary efficacy analysis.  For 
time to event endpoints, the Kaplan-Meier method will be used to estimate the survival curve and 
median time to event.  These analyses will be performed for each dose group and all ACE-011 
groups combined.   
15.5. 
Safety Evaluation 
Safety variables will be tabulated and presented for all patients who receive ACE-011.  Adverse 
events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA).  
Incidence of treatment-emergent adverse events will be presented by system organ class (SOC) 
and preferred term.  Adverse events will also be presented by severity, and relationship to study 
drug.  Change from baseline in clinical laboratory parameters and vital signs will be summarized 
across time.  Shift tables will be presented for selected laboratory parameters.  Physical 
examination results will be presented in listings.  
Data from all patients who receive one or more doses of study drug will be included in the safety 
analyses. To assess clinical safety, adverse events, vital sign measurements and clinical  
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laboratory information will be summarized by visit. Adverse events and laboratory results will 
also be summarized by severity grade (NCI CTCAE v3.0). Descriptive statistics will be 
generated and shift tables provided as appropriate.  
15.6. 
Pharmacokinetic Evaluation 
Listing of individual patient serum ACE-011 concentrations, actual blood sampling times and 
graphs of concentration vs. time will be prepared for each dose group.  Summaries of PK 
parameters will be summarized by dose group. The trough concentrations will be summarized for 
all patients who provide pharmacokinetic samples by dose group. Exploratory analyses will be 
performed to correlate trough concentrations with efficacy, bone biomarker data, and safety data, 
however these analyses will be data-driven and only conducted if warranted by the data.  
15.6.1. 
Anti-drug Antibody Data 
The results of anti-drug and neutralizing antibodies will be presented over time.  Exploratory 
analysis will be performed on the potential effect of anti-drug antibody on ACE-011 PK and 
drug exposure if anti-drug antibody tests are deemed positive. 
15.7. 
Interim Analysis  
There is no planned interim analysis for this study.   
15.8. 
Deviation from Original Analysis Plan 
Deviations from the statistical analyses outlined in this protocol will be indicated in the statistical 
analysis plan; any further modifications will be noted in the final clinical study report. 
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16. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
16.1. 
Study Monitoring 
The Clinical Monitor will arrange to visit the Investigator sites at regular intervals during the 
study.  The monitoring visits must be conducted according to the applicable ICH and GCP 
guidelines to ensure protocol adherence, quality of data, drug accountability, compliance with 
regulatory requirements, and continued adequacy of the investigational site and its facilities.  
During these visits, CRFs and other data related to the study will be reviewed and any 
discrepancies or omissions will be resolved.  The Clinical Monitor will be given access to study 
relevant source documents (including medical records) for purposes of source data verification. 
During and/or after completion of the study, quality assurance officers named by the Sponsor or 
the regulatory authorities may wish to perform on-site audits.  The Investigator is expected to 
cooperate with any audit and provide assistance and documentation (including source data) as 
requested. 
16.2. 
Audits and Inspections 
The Investigators and clinical sites will permit trial related monitoring, audits, IRB review, and 
regulatory inspections as requested by FDA, the Sponsor or designee, including direct access to 
source data/documents (i.e., original medical records, laboratory reports, hospital documents, 
progress reports, signed ICFs, etc.) in addition to CRFs. 
 
 
 
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17. 
QUALITY CONTROL AND QUALITY ASSURANCE 
17.1. 
Data Quality Control and Quality Assurance 
17.1.1. 
Investigator responsibility 
The investigator is responsible for ensuring the study is conducted according to the protocol, 
Code of Federal Regulations (CFR), GCP, and any other applicable regulatory requirements. 
These responsibilities outlined in these documents along with the documentation that a signed 
informed consent must be obtained prior to a patient participation in the study. 
17.1.2. 
Protocol modifications 
The investigator may not modify the protocol without agreement from the Sponsor and prior 
review or approval by the IRB. Any deviations from the protocol should be documented by the 
investigator or designee.  
17.2. 
Financing and Insurance 
Financing and insurance are addressed in a separate document. 
17.3. 
Confidentiality 
To maintain patient privacy, all eCRFs, study drug accountability records, study reports and 
communications will identify the patient by the assigned patient identification number.  The 
Investigator will grant monitor(s) and auditor(s) from the Sponsor or designee and regulatory 
authority(ies) access to the patient’s original medical records for verification of data gathered on 
the CRFs and to audit the data collection process.  The patient’s confidentiality will be 
maintained and will not be made publicly available to the extent permitted by the applicable laws 
and regulations. 
All information regarding the investigational product supplied by the Sponsor to the Investigator 
is privileged and confidential information.  The Investigator agrees to use this information to 
accomplish the study and will not use it for other purposes without consent from the Sponsor.  It 
is understood that there is an obligation to provide the Sponsor with complete data obtained 
during the study.  The information obtained from the clinical study will be used towards the 
development of the investigational product and may be disclosed to regulatory authority(ies), 
other Investigators, corporate partners, or consultants as required. 
17.4. 
Publication Policy 
All information concerning ACE-011 is considered confidential and shall remain the sole 
property of the Sponsor.  The Investigator agrees to use this information only in conducting the 
study and shall not use it for any other purposes without the Sponsor’s written approval.  The 
Investigator agrees not to disclose the Sponsor’s confidential information to anyone except to  
 
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people involved in the study that need such information to assist in conducting the study, and 
then only on like terms of confidentiality and nonuse. 
It is understood by the Investigator that the information developed from this clinical study will 
be used by the Sponsor in connection with the development of ACE-011, and therefore may be 
disclosed as required to regulatory agencies.  To allow for the use of the information derived 
from clinical studies, it is understood that there is an obligation to provide the Sponsor with 
complete test results and all data developed in the study. 
No publication or disclosure of study results will be permitted except as specified in a separate, 
written, agreement between the Sponsor and the Investigator. 
17.5. 
Protocol Amendments 
Protocol amendments that impact patient safety change the scope of the investigation, or affect 
the scientific quality of the study must be approved by the IRB and submitted to the appropriate 
regulatory authorities before implementation of such modifications to the study. 
In the event that the protocol needs to be modified immediately to eliminate an apparent hazard 
to a patient, the Sponsor will amend and implement the protocol change and subsequently notify 
the regulatory authorities and/or the IRB, as appropriate. 
 
 
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18. 
ETHICS 
18.1. 
Institutional Review Board or Independent Ethics Committee 
The Investigator must obtain written IRB approval of the protocol, approval for relevant 
supporting information and all types of patient recruitment and advertisement and ICF prior to 
starting the study.  The IRB will meet all Food and Drug Administration (FDA) requirements 
governing IRBs (Code of Federal Regulations, Title 21, Part 56). 
The Sponsor or designee must approve the ICF submitted to the investigational site’s IRB. All 
patient recruitment and advertisements must be submitted to the Sponsor or designee prior to 
submission to the IRB, for review. 
18.2. 
Ethical Conduct of the Study 
The Sponsor and the Investigator must comply with all instructions, regulations, and agreements 
in this protocol and in the applicable International Conference on Harmonisation (ICH) and GCP 
guidelines, and must also conduct the study in accordance with local regulations.   
18.3. 
Written Informed Consent 
18.3.1. 
Informed Consent 
Informed written consent is required from each patient prior to any testing under this protocol, 
including screening tests and evaluations.  The consent form, as specified by the clinical site’s 
IRB, must follow the Protection of Human Patients regulations listed in the Code of Federal 
Regulations, Title 21, Part 50.   
The background of the proposed study and the benefits and risks of the procedures and study 
must be explained to the patients.  It is the responsibility of the Investigator to obtain consent and 
to provide the patient with a copy of the signed and dated ICF.  Confirmation of a patient’s 
informed consent must also be documented in the patient’s medical record prior to any testing 
under this protocol, including screening tests and evaluations. 
All ICFs used in this study must be approved by the appropriate IRB and by the Sponsor or 
designee.  The ICF must not be altered without the prior agreement of the relevant IRB and the 
Sponsor.   
18.3.2. 
Patient Data Protection 
Prior to any testing under this protocol, including screening tests and evaluations, patients must 
authorize the release and use of protected health information (PHI), as required by local law. 
The patient will not be identified by name in the CRF or in any study reports.  These reports will 
be used for research purposes only.  The Sponsor, its designee, and various government health 
agencies may inspect the records of this study.  Every effort will be made to keep the patient’s 
personal medical data confidential. 
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19. 
DATA HANDLING AND RECORDKEEPING 
19.1. 
Case Report Form Completion 
CRFs will be completed for each randomized patient.  It is the Investigator’s responsibility to 
ensure the accuracy, completeness, and timeliness of the data reported in the patient’s CRF.  
Source documentation supporting the CRF data should indicate the patient’s participation in the 
study and should document the dates and details of study procedures, AEs, and patient status. 
Investigators will maintain copies of the CRFs at the clinical site.  For patients who discontinue 
or terminate from the study, the CRFs will be completed as much as possible, and the reason for 
the discontinuation or termination clearly and concisely specified on the appropriate CRF. 
19.2. 
Retention of Records 
The Investigator will maintain all study records according to ICH-GCP and applicable regulatory 
requirements.  Records will be retained for at least 2 years after the last marketing application 
approval or 2 years after formal discontinuation of the clinical development of the investigational 
product or according to applicable regulatory requirements.  If the Investigator withdraws from 
the responsibility of keeping the study records, custody must be transferred to a person willing to 
accept the responsibility.  The Sponsor must be notified in writing if a custodial change occurs. 
 
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20. 
REFERENCES 
 
      1.   Groopman JE, Itri LM. (1999). Chemotherapy-Induced Anemia in Adults: Incidence and  
 
   Treatment. Journal of the National Cancer Institute 91, 1616-1634.  
2. NCCN Clinical Practice Guidelines in Oncology: Cancer and Chemotherapy Induced 
Anemia, V.3. 2009 http://www.nccn.org/professionals/physician_gls/PDF/anemia.pdf; 
2008. 
3. Ying S-Y. (1988). Inhibins, activins, and follistatins: gonadal proteins modulating the 
secretion of follicle-stimulating hormone. Endocrine Rev 9, 267-93. 
4. Woodruff TK. (1998). Regulation of cellular and system function by activin. Biochem 
Pharmacol 55, 953-63. 
5. Perrien DS, Akel NS, Edwards PK, Carver AA, Bendre MS, Swain FL, Skinner RA, 
Hoque WR, Nicks KM, Pierson TM, Suva LJ, and Gaddy D. (2007). Inhibin A is an 
endocrine stimulator of bone mass and strength. Endocrinology 148, 1654-65. 
6. Rivier J, Spiess J, McClintock R, Vaughan J and Vale W. (1985). Purification and partial 
characterization of inhibin from porcine follicular fluid. Biochem Biophys Res Commun 
133, 120-7. 
7. Murata M, Onomichi K, Eto Y, Shibai H, and Muramatsu M. (1988). Expression of 
erythroid differentiation factor (EDF) in Chinese hamster ovary cells.  Biochem Biophys 
Res Commun 151, 230-5. 
8. Shiozaki M, Sakai R, Tabuchi M, Nakamura T, Sugino K, Sugino H, and Eto Y. (1992). 
Evidence for the participation of endogenous activin A/erythroid differentiation factor in 
the regulation of erythropoiesis.  Proc Natl Acad Sci USA 89, 1553-6. 
9. Shiozaki M, Sakai R, Tabuchi M, Eto Y, Kosaka M, and Shibai H. (1989). In vivo 
treatment with erythroid differentiation factor (EDF/activin A) increases erythroid 
precursors (CFU-E and BFU-E) in mice. Biochem Biophys Res Commun 165, 1155-61. 
10. Nakao K, Kosaka M and Saito S. (1991). Effects of erythroid differentiation factor (EDF) 
on proliferation and differentiation of human hematopoietic progenitors. Exp Hematol 19, 
1090-5 
11. Chen Y-G, Lui HM, Lin S-L, Lee JM, and Ying S-Y. (2002). Regulation of cell 
proliferation, apoptosis, and carcinogenesis by activin. Exp Biol Med 227, 75-87. 
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12. Mathews LS. (1994). Activin receptors and cellular signaling by the receptor serine 
kinase family. Endocr Rev 15, 310-25. 
13. Chantry A, Heath D, Mulivor A, Coulton L, Evans H, Abdul N, Werner ED, Bouxsein 
ML, Pearsall RS, Seehra J, Vanderkerken K, and Croucher PI. (2008). Inhibiting activin-
A signalling stimulates bone formation, prevents tumor-induced osteolytic bone 
destruction and blocks bone metastasis. Submitted 2008. 
14. Pearsall RS, Canalis E, Cornwall-Brady M, Underwood KW, Haigis B, Ucran J, Kumar 
R, Pobre E, Grinberg A, Werner ED, Glatt V, Stadmeyer L, Smith D, Seehra J, and 
Bouxsein ML. (2008). A soluble activin type IIA receptor induces bone formation and 
improves skeletal integrity. Proc Natl Acad Sci USA 105, 7082-7 
15. Lotinun S, Fajardo RJ, Pearsall RS, Bouxsein ML, and Baron R. (2008). A soluble 
activin receptor type IIA fusion protein, ACE-011, increases bone mass by stimulating 
bone formation and inhibiting bone resorption in cynomolgus monkeys. ASBMR 30th 
annual meeting, 2008. 
16. Ruckle J, Jacobs M, Kramer W, Pearsall AE, Kumar R, Underwood KW, Seehra J, Yang 
Y, Condon CH, Sherman ML. (2008).  A single-dose, randomized, double-blind, 
placebo-controlled study of ACE-011 (ActRIIA-IgG1) in postmenopausal women.  J 
Bone Miner Res: 1-42.  Posted online on 2 Dec 2008. 
17. Functional Assessment of Chronic Illness, FACT-Fatigue Version 4. 
http://www.facit.org/qview/qlist.aspx. 2003. 
 
 
 
 
 
 
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21. 
APPENDICES 
Appendix 1: Response Evaluation Criteria in Solid Tumors 
 
 
Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 
  
Terms 
Definition 
Measurable disease  
 The presence of at least one measurable lesion by CT or MRI. If the 
measurable disease is restricted to a solitary lesion, its neoplastic nature 
should be confirmed by cytology/histology. 
All measurements should be taken and recorded in metric notation, using a 
ruler or calipers. All baseline evaluations should be performed as closely as 
possible to the beginning of treatment and never more than 4 weeks before 
the beginning of the treatment.  
Measurable lesions 
Lesions that can be accurately measured in least one dimension by CT scan  
with longest diameter > 10 mm (CT scan thickness no greater than 5 mm). 
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during 
follow-up.  
Non-measurable lesion 
All other lesions, including small lesions (longest diameter <10mm or 
pathological lymph nodes with P10 to <15mm short axis) as well as truly 
non-measurable lesions. Lesions considered truly non-measurable include: 
leptomeningeal disease, ascites, pleural or pericardial effusion, 
inflammatory breast disease, lymphangitic involvement of skin or lung, 
abdominal masses/abdominal organomegaly identified by physical exam 
that is not measurable by reproducible imaging techniques. 
 
 
 
 
 
 
 
 
 
 
 
 
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RECIST Criteria-Response Evaluation 
Evaluation of target lesions 
  
  
Complete Response (CR) 
 Disappearance of all target lesions. 
Any pathological lymph nodes (whether target or non-target) 
must have reduction in short axis to <10 mm. 
Partial Response (PR): 
At least a 30% decrease in the sum of diameters of target lesions, 
taking as reference the baseline sum diameters. 
Stable Disease (SD):   
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum 
diameters while on study. 
Progressive Disease (PD):  
At least a 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest sum on study (this includes the 
baseline sum if that is the smallest on study). In addition to 
the relative increase of 20%, the sum must also demonstrate 
an absolute increase of at least 5 mm.  
(Note: the appearance of one or more new lesions is also 
considered progression). 
 
 
 
 
 
Evaluation of non-target 
lesions 
  
  
Complete Response (CR):  
  
Disappearance of all non-target lesions and normalisation of 
tumour marker level. All lymph nodes must be non-pathological 
in size (<10mm short axis). 
 
Non-CR/Non-PD 
 
Persistence of one or more non-target lesion(s) and/or 
maintenance of tumour marker level above the normal limits. 
Progressive Disease (PD):  
Unequivocal progression (see comments below) of existing non-
target lesions.  
(Note: the appearance of one or more new lesions is also 
considered progression). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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RECIST Criteria-Response 
Evaluation cont- 
 
 
 
 
 
 
 
 
Evaluation of best overall 
response 
The best overall response is the best response recorded 
from the start of the treatment until disease 
progression/recurrence (taking as reference for PD the 
smallest measurements recorded since the treatment 
started). In general, the patient's best response assignment 
will depend on the achievement of both measurement and 
confirmation criteria. 
 
Patients with a global deterioration of health status 
requiring discontinuation of treatment without objective 
evidence of disease progression at that time should be 
classified as having “symptomatic deterioration”. Every 
effort should be made to document the objective 
progression even after discontinuation of treatment.  
 
In some circumstances it may be difficult to distinguish 
residual disease from normal tissue. When the evaluation of 
complete response depends on this determination, it is 
recommended that the residual lesion be investigated (fine 
needle aspirate/biopsy) to confirm the complete response 
status.  
 
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R,  Dancey J, Arbuck S, Gwyther S, Mooney M, 
Rubinstein L, Shankar L, Dodd L, Kaplan R,  Lacombe D, Verweij J.New response evaluation criteria in solid tumours: Revised 
RECIST guideline (version 1.1)  (2009). European Journal of Cancer 45, 228-247. 
 
 
 
 
 
 
 
 
 
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Appendix 2: ECOG Performance Status 
The ECOG scale is used to assess a patient’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 
patient.  
 
Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., Carbone, P.P. (1982) Toxicity And Response 
Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Onco 5:649-655. 
 
 
 
 
 
 
 
 
 
 
 
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, e.g., 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 
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Appendix 3:  National Cancer Institute (NCI) Common Terminology Criteria 
for Adverse Events (CTCAE) Version 3.0 
 
See http://ctep.cancer.gov/reporting/ctc.html  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Appendix 4: New York Heart Association- Classification of heart failure 
Class 1 - Class 1 heart failure - no limitation of activities. No symptoms from ordinary activities. 
Class 2 - Class 2 heart failure- mild limitation of activity. Comfortable with rest or mild exertion. 
Class 3 - Class 3 heart failure- marked limitation of activity and be comfortable only at rest. 
Class 4 –Class 4 heart failure- complete rest, confined to bed or chair; any physical activity brings on  
discomfort and symptoms occur at rest. 
 National Heart, Lung, and Blood Institute, National Institutes of Health. New York Heart Association Classification. 2008. 
 
 
 
 
 
 
 
 
 
 
 
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Protocol Amendment – Summary of Changes 
CLINICAL STUDY PROTOCOL 
A Phase 2, Double-Blind, Randomized, Placebo-Controlled 
Study of ACE-011 for the Treatment of Chemotherapy 
Induced Anemia in Patients with Metastatic Breast Cancer 
 
 
STUDY DRUG: 
 
 
ACE-011 
 
PROTOCOL NUMBER: 
 
 
A011-08 
 
SPONSOR: 
 
           Acceleron Pharma, Inc. 
                       128 Sidney Street 
                       Cambridge, MA 02139  
 
                     
                     
 
MEDICAL MONITOR: 
                 PPD Inc. 
 
                
 
                                                          
 
 
 
 
 
          
 
 
 
 
 
          
 
      
 
 
PROTOCOL DATE: 
                 13 March 2009 
AMENDMENT #1: 
                 22 April 2009 
AMENDMENT #2:  
 
           21 May 2009 
 
 
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collection of an ECG on Day 29 was deleted.  Footnote added to indicate 
ECGs are to be done in triplicate at each timepoint, at 3 minute intervals (+ 
1 min).  
Added clarification that the physical exam, coagulation/serum chemistry, 
and anti-drug antibody are to be done prior to ACE-011/placebo 
administration, as applicable.  
Added footnote assignment during screening and the following text 
“Confirmatory labs for eligibility criteria must be drawn  and resulted 
within 7 days of Day 1.” 
Deleted back up blood sample for future testing done at screening and Days 
169-253.  
Additional reticulocyte values to be reported on Days 22, 36, and 64.  
Additional clarification added to indicate that “concomitant medications 
would be collected up through 90 days from the last dose of ACE-
011/placebo.” 
Footnote added to clarify that “AEs will be reported 
including up to 90 days after the last dose of ACE 
011/placebo. Additional AEs noted after 90 days from 
the last dose of ACE-011/placebo will be reported at 
the discretion of the investigator.  SREs and SAEs will be 
followed through out the study.  If a patient is followed for 
survival only, SREs and SAEs will be captured up to 90 days 
from the last dose of ACE-011/placebo.”  
Added text “start and end date of last menstrual period since the last 
assessment.” The following text we deleted “date of last menstruation, date 
of menstrual period onset and duration of menstruation”   
Footnote clarification to reference withdrawal criteria in section 8.3 of the 
protocol. 
Section 6. Trial Objectives 
and Purpose 
 
Section 6.2: Secondary Objectives  
Formatting. 
Section 6.3: Exploratory Objectives  
Clarified exploratory objective serum bone biomarker “PINP” to “P1NP”.  
Deleted the text “during the study” within exploratory objective #2 
(evaluation of quality of life). 
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Section 7. Investigational 
Plan 
Formatting.  
Addition of text amending the section regarding the ECG timepoints. 
Additional clarification added for the timeframe of when lab values and 
blood pressure would be collected during the study by the following text 
“during the treatment and treatment follow up period”. The following text 
was deleted “weekly for the first two treatment (dosing) periods and 
approximately every one to two weeks for subsequent treatment (dosing) 
periods.” 
Additional text added regarding central and local lab values.  
Additional text added “Back up (serum) blood samples will be collected for 
future testing for the evaluation of novel tumor markers, such as endoglin 
and ALK-1 (activin receptor-like kinase-1). The samples will the stored at 
the central lab until this evaluation is performed.” 
 Section 8. Selection and 
Withdrawal of Patients  
Section 8.2.2 Patient exclusion criteria 
Addition of exclusion criteria of “Major surgery within 30 days prior to Day 
1 (patients must have completely recovered from any previous surgery prior 
to Day 1).” 
Section 8.3 Patient Withdrawal Criteria  
Additional clarification added to specify that patients who “withdraw due to 
ACE-011/placebo toxicity should” enter the treatment follow-up period.  
Section 9. Treatment of 
Patients 
Formatting.  
Section 9.1.1 General Concomitant Medication Usage 
Additional text added “Concomitant medications will be recorded on the 
eCRF through 90 days from the last dose of ACE-011/placebo.”  
Section 9.5.2 Selection and Timing of dosing for each patient 
Clarification to reference section 8.3 of the protocol for reasons a patient 
may discontinue study treatment.  
Section 9.5.2.2 ACE-011 Dose Modification Rules 
Clarification of “The local hemoglobin values and blood pressure values 
will be evaluated at each study visit and on each ACE-011/placebo dosing 
day.” 
Section 10. Study 
Procedures 
Formatting. 
Clarification of “collection of menstrual cycle information of the start and 
end date of the last menstruation.” was added through out this section. 
Section 10.1.2 Screening ( within 14 days of Day 1) 
Added text “Confirmatory labs for eligibility criteria must be drawn and 
resulted within 7 days of Day 1.” 
Additional text “performed at two time intervals (approximately one hour 
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apart) in triplicate at 3 minute intervals (±1 min).” 
Deleted back up blood samples for future testing. 
Serum pregnancy test to be confirmed within 7 days of Day 1.  
Section 10.1.3 Initial dosing: Day 1 
Deleted text “A patient will be considered randomized once a multi-digit 
patient identification number has been assigned to the patient through the 
IVRS.” 
Text of “and the inclusion/exclusion criteria have been met” was added to 
clarify when ACE-011/placebo administration may begin.  
Additional text added to the 12 lead ECG procedure “performed at two time 
intervals (approximately one hour apart) in triplicate at 3 minute intervals 
(±1 min)”. 
Section 10.1.4 ACE-011/placebo administration: Days 29, 57, and 85 (± 3 
days) 
Deletion of 12 lead ECG procedure. 
Deletion of “and Hematocrit” 
Section 10.1.5 Additional visits during the Treatment Period: Days 8, 15, 
22, 36 (± 1 day), 43, 64 and 71 (± 2 days) 
Deletion of 12 lead ECG procedure for Day 15 only. Addition of “12 lead 
ECG to be performed on Days 8, 36, and 64 only -to be done in triplicate at 
3 minute intervals (±1 min).” 
Clarification of if a patient begins a new chemotherapy regimen; the patient 
will “be followed for survival only.” 
Section 10.1.6 Treatment Period Follow-up visits : Days 99, 113(± 3 days) 
and 141(± 7 days) 
Addition of Day 99 visit. 
Additional text added to the 12 lead ECG procedure “to be done in triplicate 
at 3 minute intervals (±1 min)”. 
Additional text added regarding the procedures to be performed. 
Section 10.1.7 Days 169, 197, 225, and 253 (± 7 days) 
Additional text added regarding concomitant medication and adverse event 
follow up. 
Deleted back up blood samples for future testing.  
Section 10.1.8 Termination Visit: Day 281 (± 7 days) 
Additional text added to the 12 lead ECG procedure “to be done in triplicate 
at 3 minute intervals (±1 min)”. 
Additional text added regarding concomitant medication and adverse event 
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follow up. 
Section 13. Safety 
Assessments 
Deletion of “oral” from temperature assessment.  
Additional text added regarding central and local lab values.  
Section 14. Adverse Event Section 14.2 Recording Adverse Events 
Additional text added “AEs...up to 90 days from the last dose of ACE-
011/placebo are to be documented on AE CRF. The specific disease or 
syndrome rather than individual associated signs and symptoms should be 
identified by the investigator and recorded on the CRF. 
Skeletal related event information is to be captured and reported for the 
duration of the patient participation in the study through Day 
281/Termination visit” 
Text added to specify “SAEs will be captured throughout the patient 
participation in the study through Day 281/Termination visit. SAEs will be 
captured up to 90 days from the last dose of ACE-011/placebo for those 
patients who are followed for survival only.” 
Section 15. Statistics 
Formatting. 
Additional clarification of “study drug” as “ACE-011/placebo”. 
Section 17. Quality 
Control and Quality 
Assurance 
Additional clarification of the investigator responsibility. 
 
Appendix 5: PK Sampling 
Additional text added regarding PK sampling and the specified days of 
collection on Day 1 Post 4h, Day 8, Day 15, Day 22, Day 57, Predose Day 
85, and Day85 Post 4h. 
 
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                                 CLINICAL STUDY PROTOCOL 
A Phase 2, Double-Blind, Randomized, Placebo-Controlled 
Study of ACE-011 for the Treatment of Chemotherapy Induced 
Anemia in Patients with Metastatic Breast Cancer 
 
 
STUDY DRUG: 
 
 
ACE-011 
 
PROTOCOL NUMBER: 
 
 
A011-08 
 
SPONSOR: 
 
      Acceleron Pharma, Inc. 
            128 Sidney Street 
            Cambridge, MA 02139  
 
          
          
 
MEDICAL MONITOR: 
      PPD Inc. 
 
    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
    
 
 
 
 
 
 
 
 
 
 
  
 
      
 
 
PROTOCOL DATE: 
     13 March 2009 
AMENDMENT #1 : 
     22 April 2009 
AMENDMENT #2 : 
     21 May 2009 
 
 
 
Confidentiality Statement 
This confidential information in this document is provided to you as an investigator or consultant for review by you, your staff, 
and the applicable institutional Review Board/Independent Ethics Committee.  Your acceptance of this document constitutes 
agreement that you will not disclose the information contained herein to others without written authorization from the Sponsor. 
 
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PROCEDURES IN CASE OF EMERGENCY 
 
Table 1: 
Emergency Contact Information 
Role in Study 
Name 
Address and Telephone number 
PPD Medical Monitor 
PPD Inc. 
1800 Perimeter Park Drive,  Suite 275 
Morrisville, NC 27560-7200 USA 
Clinical Trial Manager 
Acceleron Pharma, Inc. 
128 Sidney Street  
Cambridge, MA 02139 USA  
 
 
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2. 
PROTOCOL SYNOPSIS 
Name of Sponsor/Company:  Acceleron Pharma, Inc. 
 
 
 
 
                          128 Sidney Street 
 
 
 
 
                          Cambridge, MA 02139 
Name of Investigational Product: ACE-011 
Name of Active Ingredient:   
ACE-011 is a fully human fusion protein consisting of the extracellular domain (ECD) of the 
activin receptor IIA (ActRIIA) linked to the human IgG1 Fc domain.  
Mechanism of Action: ACE-011 is a disulfide-linked, glycosylated, dimeric protein. ACE-011 
competes with the activin receptor IIA that binds a number of TGF-β superfamily ligands 
including activin, myostatin (growth differentiation factor [GDF]-8), and GDF-11. 
Title of Study:  A Phase 2, Double-Blind, Randomized, Placebo-Controlled Study of ACE-011 
for the Treatment of Chemotherapy Induced Anemia in Patients with Metastatic Breast 
Cancer. 
Study center(s): approximately 25-35 centers  
Phase of development: 2 
Objectives 
Primary:  
1. To evaluate the proportion of patients in each ACE-011 dose regimen who achieve a 
hematopoietic response during the treatment period including up to 2 months after the 
last dose of ACE-011 treatment of chemotherapy induced anemia in patients with 
metastatic breast cancer. 
Secondary: 
1. To evaluate the safety and tolerability of ACE-011 for the treatment of chemotherapy 
induced anemia in patients with metastatic breast cancer.  
2. To evaluate the percentage of patients who achieve an increase in hemoglobin of ≥ 1 
g/dL,  ≥ 2 g/dL and/or hemoglobin concentration ≥ 11 g/dL for 28 consecutive days 
during the treatment period including up to 2 months after the last dose of ACE-011 in 
the absence of any RBC transfusions and/or ESAs.   
3. To estimate the duration of the hematopoietic response associated with each ACE-011 
dose regimen. 
4. To estimate the time to the hematopoietic response associated with each ACE-011 dose 
regimen. 
5. To estimate the proportion of patients receiving red blood cell (RBC) transfusions 
and/or ESAs within each cycle of ACE-011 with each dose regimen. 
 
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6. To estimate the effect of each ACE-011 dose regimen on progression free survival 
(PFS) and objective response rate (ORR). 
Exploratory objectives: 
1. To estimate the effect of each ACE-011 dose regimen on serum bone biomarkers (OC, 
BSAP, P1NP, CTX, TRACP-5b), urine bone biomarker (uNTX), bone mineral density 
(DXA scans of lumbar spine and hip) and incidence of skeletal related events (SREs). 
2. To evaluate the quality of life in relation to the treatment of chemotherapy induced 
anemia in patients with metastatic breast cancer during the study. 
Methodology: This is a Phase 2, double-blind, randomized, placebo-controlled study to 
evaluate the efficacy, safety, and tolerability of ACE-011 for the treatment of chemotherapy 
induced anemia in patients with metastatic breast cancer. Patients will be randomized to one of 
three treatment arms or placebo: 
 
1. ACE-011 0.1 mg/kg subcutaneously (SC) every 28 days for up to 4 doses. 
2. ACE-011 0.3 mg/kg SC every 28 days for up to 4 doses.  
3. ACE-011 0.5 mg/kg SC every 28 days for up to 4 doses. 
4. Placebo SC every 28 days for up to 4 doses. 
 
  
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Number of patients (planned): 105 patients 
Diagnosis and main criteria for inclusion 
 
Inclusion Criteria: 
1. Women > 18 years of age. 
2. Histologically confirmed diagnosis of breast cancer documented by cytology or biopsy. 
3. Evidence of metastatic breast cancer with a minimum of one measurable lesion or non 
measurable lesion per RECIST criteria (Appendix 1). 
4. Receiving a multicycle myelosuppressive chemotherapy regimen including one of the 
following: anthracycline, taxane, gemcitabine or vinorelbine. 
5. Planned treatment with the same myelosuppressive chemotherapy regimen for a minimum 
of 9 weeks after Day 1 of ACE-011/placebo administration.  
6. Hemoglobin value between ≥ 6.5 to < 11.0 g/dL (≥ 65 to < 110 g/L).  
7. ≥ 30 days must have elapsed (from Day 1) since previous treatment with erythropoiesis-
stimulating agent (including concurrent treatment with IV iron) for chemotherapy induced 
anemia.  
8. ≥ 7 days have elapsed (from Day 1) since the last RBC blood transfusion and receipt of ≤ 2 
units of blood in the past 30 days.  
9. ECOG Performance status of 0 – 2 (Appendix 2). 
10. Adequate renal (creatinine ≤ 1.5 x ULN or creatinine clearance ≥ 40 mL/min) and hepatic 
function (bilirubin < 1.5 x ULN; AST/ALT < 2.5 x ULN). 
11. Females of childbearing potential  participating in the study are to use adequate birth 
control measures (i.e. oral contraceptives or two forms of barrier method birth control) 
during study participation. Females of childbearing potential must have a negative serum 
pregnancy test within 3 days to ACE-011/placebo administration (Day 1). A female of 
childbearing potential is a sexually mature woman who has not undergone a hysterectomy 
or who has not been postmenopausal for at least 24 consecutive months (i.e. who has had 
menses at some time in the preceding 24 months). 
12. Life expectancy of ≥ 6 months. 
13. Is willing to adhere to the study visit schedule, understand and comply with all protocol 
requirements. 
14. Understand and sign a written informed consent. 
 
 
 
 
 
 
 
 
 
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Exclusion Criteria: 
1. At the time of screening patients who have any grade > 3 toxicity (as per NCI CTCAE 
v3.0 (Appendix 3)) (except for the following disease related toxicities:  hematological 
events- anemia, thrombocytopenia or neutropenia or non hematological events- nausea, 
vomiting, fatigue, or muscle or bone/joint pain).  
2. Prior radiation therapy to > 20% of the whole skeleton. Use of palliative radiation if the 
area being treated is <15% of body surface area with no pelvic radiation or no more than 
10% of the bone marrow reserve is radiated is permitted during patient participation in the 
study, at the discretion of the investigator. 
3. Have received more than 5 prior chemotherapy treatment regimens for metastatic breast 
cancer.  
4. Concurrent use of bevacizumab with the chemotherapy regimen during study participation. 
5. Clinically significant pulmonary, endocrine, neurologic, gastrointestinal, hepatic or 
genitourinary disease unrelated to underlying hematologic disorder.  
6. Patients with heart failure as classified by the New York Heart Association (NYHA) 
classification of 3 or higher (Appendix 4). 
7. History of thrombosis, deep vein thrombosis (DVT), pulmonary emboli, or embolic stroke. 
8. Untreated CNS metastases (exception: CNS metastases treated with whole brain 
radiotherapy > 6 months prior to randomization). 
9. Diagnosis of a myeloid malignancy or known history of myelodysplasia.  
10. History of second malignancy within 5 years (except excised and cured basal cell 
carcinoma, squamous cell carcinoma of the skin or cervical carcinoma in situ).  
11. Patients with a recent history (within 14 days of Day 1) of administration of systemic (IV 
or oral) antibiotics. Patients should be free of infection at least 14 days after the last dose 
of systemic antibiotic treatment (from Day 1). 
12. Uncontrolled hypertension. If hypertension is considered clinically stable, systolic blood 
pressure (BP) must be < 150 mmHg and diastolic BP must be < 100 mmHg.  
13. Known history of hepatitis C antibody (HCV), hepatitis B surface antigen (HBsAg and HB 
core Ab), or human immunodeficiency virus (HIV) antibody.   
14. Deficiency in iron (serum ferritin < 100 ng/mL (< 224.7 pmol/L)), vitamin B12, or folate. 
15. History of anemia as a result of inherited hemoglobinopathy such as sickle cell anemia or 
thalassemia.  
16. History of autoimmune or hereditary hemolysis or gastrointestinal bleeding. 
17. Patient received treatment with another investigational drug or device within 1 month prior 
to Day 1, or if the half life of the previous product is known, within 5 times the half life 
prior to dosing, whichever may be longer.  
18. Pregnant or lactating females. 
19. History of severe allergic or anaphylactic reactions or hypersensitivity to recombinant 
proteins or excipients in the investigational product.    
20. Major surgery within 30 days prior to Day 1 (patients must have completely recovered 
from any previous surgery prior to Day 1). 
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Investigational product, dosage and mode of administration:  
ACE-011/placebo will be administered as a SC injection, approximately every 28 days, on 
days 1, 29, 57, and 85 of the treatment period.  Each patient will be randomized to one of three 
treatment arms or placebo: 
 
 
 
 
 
 
 
 
Patients with grade ≥ 3 toxicity related to ACE-011 will be discontinued from ACE-011/ 
placebo treatment except for the following: Patients with grade 3 hypertension that decreases 
to grade ≤ 1 within 7 days after treatment with anti-hypertensive therapy may continue on 
ACE-011/placebo treatment.  Dose reduction rules will apply at the subsequent scheduled 
dosing day(s).  Patients with a hemoglobin level above the upper limit of normal at any time 
during the study after Day 1 will be discontinued.   
ACE-011/placebo dose modification rules are based on hemoglobin values and blood pressure 
measurements during each treatment cycle. ACE-011/placebo dose interruption and dose 
reduction rules will be implemented for those patients with hemoglobin of ≥ 11 g/dL, an 
increase of ≥ 2 g/dL/ 28 days, or hypertension ≥ Grade 2 within each cycle (see Figure 1). 
Dose  
Number of  Patients 
0.1 mg/kg 
30 
0.3 mg/kg 
30 
0.5 mg/kg 
30 
Placebo 
15 
Total patients enrolled: 105 
Duration of study: Patients will be followed for a minimum of 7 months following their last 
dose of ACE-011/placebo. Study participation for each patient is approximately 10.5 months 
(14 day screening period, 3 month treatment period with a 2 month treatment follow up period, 
and a 5 month post treatment follow-up period). The start date of the chemotherapy regimen 
used in this protocol to treat metastatic breast cancer will be recorded. If a patient begins a new 
chemotherapy regimen during the study, the patient will discontinue further ACE-011/placebo 
treatment, complete the Day 281/Termination visit procedures and be followed for survival 
only. If a patient has a positive anti-drug antibody result at the Day 281/Termination visit, they 
may be asked to return to the clinical site for additional monthly repeat anti-drug antibody 
testing for up to 12 months, following the last dose of ACE-011/placebo.  The study is 
complete when the last patient enrolled has completed the last protocol required follow up 
visit. 
Criteria for evaluation 
Efficacy: The primary endpoint is to establish the proportion of patients who have a 
hematopoietic response of an increase in hemoglobin of ≥ 0.5 g/dL above the study baseline 
value for 28 consecutive days during the treatment period including up to 2 months after the 
last dose of ACE-011, in the absence of any RBC transfusions and/or ESAs.   
The proportion of patients with an increase in hemoglobin of ≥ 1g/dL, ≥ 2 g/dL and/or 
hemoglobin concentration ≥ 11 g/dL for 28 consecutive days during the treatment period up to 
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2 months after the last dose of ACE-011 in the absence of any RBC transfusions and/or ESAs 
will be evaluated as a secondary efficacy endpoint. 
The hematopoietic endpoints will be determined by the monitoring of hematologic laboratory 
values, RBC transfusion and/or ESAs administration. The evaluation of response will be from 
the first dose of ACE-011 through 2 months after the last dose (for each patient).  Additional 
endpoints will be evaluated with the assessment of disease progression by CT/MRI and bone 
scan and bone mineral density by DXA scans.  Bone biomarkers will be evaluated in all 
patients and incidence of SREs will be recorded, as applicable. SREs are defined as pathologic 
fracture, radiation therapy to bone, surgery to bone, or spinal cord compression. 
Safety: Throughout the study, safety will be evaluated by the sponsor, medical monitor and 
principal investigator.  Additionally, the DMC will review safety parameters for patients 
enrolled in the study. All patients will be assessed for safety by monitoring adverse events, 
clinical laboratory tests, assessment of quality of life, vital signs and physical examinations on 
an ongoing basis.  ECGs will also be performed during screening, prior to dosing on the first 
cycle, during the first, second and third cycle, Day 113 (28 days after the last dose of ACE-
011) and at Day 281/Termination visit to monitor safety.  Blood pressure and lab values will 
be assessed at each study visit during the treatment and treatment follow up period.  
Pharmacokinetics: The blood samples will be collected at selected study sites from 
approximately one-third of patients for the evaluation of serum concentrations of ACE-011.  
Pre-dose PK samples will be collected on Day 1.  See Appendix 5 for PK sampling schedule. 
Statistical methods  
Sample size determination: With an anticipated dropout rate of 20%, a sample size of 30 
patients per dose level is planned to achieve at least 80% power with 2 sided significance level 
of 0.05 to differentiate targeted response rate of p1=0.45 from null hypothesis p0=0.20. An 
additional 15 patients will be enrolled into the placebo group for safety comparison. A total of 
105 patients will be randomized to three ACE-011 dose groups or placebo with a ratio of 
2:2:2:1. 
Efficacy analysis: The primary endpoint is the proportion of patients who have a 
hematopoietic response of an increase in hemoglobin of ≥ 0.5 g/dL above the study baseline 
value for 28 consecutive days during the treatment period including up to 2 months after the 
last dose of ACE-011, in the absence of any RBC transfusions and/or ESAs. The proportion of 
responders will be determined together with 95% confidence interval.  
For binary endpoints, the proportion of responders and 95% confidence interval will be 
calculated. For time to event endpoints, the Kaplan-Meier method will be used to estimate the 
survival curve and median time to event.  Due to the nature of the study, no multiplicity 
adjustment will be made for efficacy analysis. 
Safety analysis: Data from all patients who receive at least one dose of ACE-011/placebo will 
be included in the safety analyses. To assess clinical safety, adverse events, vital sign 
measurements and clinical laboratory information will be summarized. Adverse events and 
laboratory results will also be summarized by severity grade (NCI CTCAE v3.0). Changes 
from baseline clinical laboratory values and vital signs will be summarized over time. 
Descriptive statistics and shift tables will be generated as appropriate.  
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3. 
TABLE OF CONTENTS, LIST OF TABLES AND LIST OF 
FIGURES  
TABLE OF CONTENTS 
1. 
TITLE PAGE..............................................................................................................1 
2. 
PROTOCOL SYNOPSIS .............................................................................................4 
3. 
TABLE OF CONTENTS, LIST OF TABLES AND LIST OF FIGURES................12 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................18 
5. 
INTRODUCTION......................................................................................................21 
5.1. 
Indication and Rationale.............................................................................................21 
5.2. 
Description of ACE-011.............................................................................................21 
5.3. 
Activin Biology ..........................................................................................................22 
5.3.1. 
Pharmacology Studies ................................................................................................22 
5.3.2. 
Toxicology..................................................................................................................24 
5.4. 
Summary of Clinical Experience................................................................................25 
5.4.1. 
A011-01: A Phase 1a Study in Healthy Postmenopausal Women .............................25 
5.4.2. 
A011-02: A Phase 1b Study in Healthy Postmenopausal Women.............................26 
5.4.3. 
A011-04: A Phase 2a Study in Patients with Osteolytic Lesions of Multiple 
Myeloma.....................................................................................................................29 
5.5. 
Potential Risks for Human Use...................................................................................31 
6. 
TRIAL OBJECTIVES AND PURPOSE....................................................................33 
6.1. 
Primary objective........................................................................................................33 
6.2. 
Secondary objectives ..................................................................................................33 
6.3. 
Exploratory objectives................................................................................................33 
7. 
INVESTIGATIONAL PLAN.....................................................................................34 
7.1. 
Overall Study Design and Plan...................................................................................34 
8. 
SELECTION AND WITHDRAWL OF PATIENTS.................................................38 
8.1. 
Number of Patients .....................................................................................................38 
8.2. 
Entry Criteria ..............................................................................................................38 
8.2.1. 
Patient Inclusion Criteria............................................................................................38 
8.2.2. 
Patient Exclusion Criteria...........................................................................................39 
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8.3. 
Patient Withdrawal Criteria........................................................................................40 
9. 
TREATMENT OF PATIENTS..................................................................................41 
9.1. 
Concomitant Medications...........................................................................................41 
9.1.1. 
General Concomitant Medication Usage....................................................................41 
9.1.2. 
Concomitant treatment for anemia .............................................................................41 
9.1.2.1. 
Iron supplementation ..................................................................................................41 
9.1.2.2. 
Erythropoiesis-stimulating agents (ESAs)..................................................................41 
9.1.2.3. 
RBC Transfusions.......................................................................................................41 
9.2. 
Chemotherapy.............................................................................................................42 
9.3. 
Treatment Compliance................................................................................................42 
9.4. 
Randomization............................................................................................................42 
9.4.1. 
Blinding ......................................................................................................................42 
9.4.2. 
Unblinding..................................................................................................................42 
9.5. 
Treatments Administered............................................................................................43 
9.5.1. 
Selection of Doses in the Study..................................................................................43 
9.5.2. 
Selection and Timing of Dosing for Each Patient ......................................................43 
9.5.2.1. 
ACE-011 Treatment Related Toxicity........................................................................43 
9.5.2.2. 
ACE-011 Dose Modification Rules............................................................................43 
10. 
STUDY PROCEDURES AND SCHEDULE ............................................................47 
10.1.1. 
Written Informed consent...........................................................................................47 
10.1.2. 
Screening (Within 14 days of dosing) ........................................................................47 
10.1.3. 
Initial Dosing: Day 1 ..................................................................................................48 
10.1.4. 
ACE-011/placebo administration: Days 29, 57, and 85 (± 3 days)............................49 
10.1.5. 
Additional visits during Treatment Period: Days 8, 15, 22, 36 (± 1 day), 43, 
64 and 71 (± 2 days) ...................................................................................................50 
10.1.6. 
Treatment Period Follow-up visits : Days 99, 113 (± 3 days)  and 141 (± 7 
days)............................................................................................................................51 
10.1.7. 
Post Treatment Period Follow-up visits : Days 169, 197, 225, and 253 (± 7 
days)............................................................................................................................52 
10.1.8. 
Termination Visit:  Day 281 (± 7 days)......................................................................52 
10.2. 
Discontinuation of study.............................................................................................54 
11. 
INVESTIGATIONAL PRODUCT MATERIALS AND MANAGEMENT.............55 
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11.1. 
Reference Product.......................................................................................................55 
11.2. 
Investigational Product Packaging and Labeling .......................................................55 
11.3. 
Investigational Product Storage..................................................................................55 
11.4. 
Investigational Product Preparation............................................................................55 
11.5. 
Administration............................................................................................................55 
11.6. 
Drug Accountability ...................................................................................................55 
11.7. 
Investigational Product Handling and Disposal .........................................................56 
12. 
ASSESSMENT OF EFFICACY ................................................................................57 
13. 
ASSESSMENT OF SAFETY.....................................................................................58 
13.1. 
Safety Parameters .......................................................................................................58 
13.1.1. 
Adverse Events...........................................................................................................58 
13.1.2. 
Clinical Laboratory Tests ...........................................................................................58 
13.1.3. 
Other Safety Assessments...........................................................................................59 
13.2. 
Pharmacokinetics........................................................................................................59 
14. 
ADVERSE EVENT....................................................................................................60 
14.1. 
Adverse Event Classification......................................................................................61 
14.2. 
Recording Adverse Events .........................................................................................61 
14.3. 
Reporting Adverse Events..........................................................................................62 
14.4. 
Emergency Sponsor Contact.......................................................................................63 
15. 
STATISTICS..............................................................................................................64 
15.1. 
Determination of Sample Size....................................................................................64 
15.2. 
Analysis Populations ..................................................................................................64 
15.3. 
Background and Demographic Characteristics ..........................................................64 
15.3.1. 
Patient Disposition......................................................................................................64 
15.3.2. 
ACE-011.....................................................................................................................65 
15.3.3. 
Concomitant Therapy .................................................................................................65 
15.4. 
Efficacy Evaluation ....................................................................................................65 
15.4.1. 
Primary Efficacy Analysis..........................................................................................65 
15.4.2. 
Secondary Efficacy Analyses .....................................................................................66 
15.5. 
Safety Evaluation........................................................................................................66 
15.6. 
Pharmacokinetic Evaluation.......................................................................................67 
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15.6.1. 
Anti-drug Antibody Data............................................................................................67 
15.7. 
Interim Analysis..........................................................................................................67 
15.8. 
Deviation from Original Analysis Plan ......................................................................67 
16. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................68 
16.1. 
Study Monitoring........................................................................................................68 
16.2. 
Audits and Inspections................................................................................................68 
17. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................69 
17.1. 
Data Quality Control and Quality Assurance.............................................................69 
17.1.1. 
Investigator responsibility ..........................................................................................69 
17.1.2. 
Protocol modifications................................................................................................69 
17.2. 
Financing and Insurance.............................................................................................69 
17.3. 
Confidentiality............................................................................................................69 
17.4. 
Publication Policy.......................................................................................................69 
17.5. 
Protocol Amendments ................................................................................................70 
18. 
ETHICS ......................................................................................................................71 
18.1. 
Institutional Review Board or Independent Ethics Committee ..................................71 
18.2. 
Ethical Conduct of the Study......................................................................................71 
18.3. 
Written Informed Consent..........................................................................................71 
18.3.1. 
Informed Consent .......................................................................................................71 
18.3.2. 
Patient Data Protection ...............................................................................................71 
19. 
DATA HANDLING AND RECORDKEEPING.......................................................72 
19.1. 
Case Report Form Completion...................................................................................72 
19.2. 
Retention of Records ..................................................................................................72 
20. 
REFERENCES ...........................................................................................................73 
21. 
APPENDICES............................................................................................................75 
Appendix 1: Response Evaluation Criteria in Solid Tumors.........................................................75 
Appendix 2: ECOG Performance Status........................................................................................78 
Appendix 3:  National Cancer Institute (NCI) Common Terminology Criteria for 
Adverse Events (CTCAE) Version 3.0.......................................................................79 
Appendix 4: New York Heart Association- Classification of heart failure...................................80 
Appendix 5- Pharmacokinetic Sampling .......................................................................................81 
  
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LIST OF TABLES 
 
Table 1: 
Emergency Contact Information...................................................................................3 
Table 2: 
Abbreviations and Specialist Terms ...........................................................................18 
Table 3: 
A011-02: A Phase 1b Study in Healthy Postmenopausal Women: 
Hemoglobin Evaluation..............................................................................................27 
Table 4: 
A011-02: Incidence of Most Common Adverse Events.............................................28 
Table 5: 
A011-02: A Phase 1b Study in Healthy Postmenopausal Women: BMD..................29 
Table 6: 
Study Design...............................................................................................................34 
Table 7: 
Schedule of Events .....................................................................................................36 
Table 8: 
ACE-011/Placebo Dose Reduction Levels.................................................................46 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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LIST OF FIGURES 
Figure 1: 
ACE-011/placebo Dose Modification Rules (after initial dose of ACE-
011/placebo) ...............................................................................................................45 
 
 
 
 
 
 
 
 
 
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4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
The following abbreviations and specialist terms are used in this study protocol. 
Table 2: 
Abbreviations and Specialist Terms   
Term 
Definition 
ACTH 
Adrenocorticotropic hormone 
ActRIIA 
Activin receptor IIA  
AE 
Adverse event 
ALT 
Alanine aminotransferase  
AST 
Aspartate aminotransferase  
AUC 
Area under the plasma concentration - time curve 
AUC(0-last) 
AUC from time 0 to time of last quantifiable sample  
AUC(0-∞) 
AUC extrapolated to infinity  
BMD 
Bone mineral density 
BP 
Blood pressure 
BSAP 
Bone specific alkaline phosphatase 
BUN 
Blood urea nitrogen 
CBC 
Complete Blood Count 
CFR 
Code of Federal Regulations (US) 
CH 
Constant domain 
CI 
Confidence interval 
CIA 
Chemotherapy induced anemia 
CL 
Clearance 
CL/F 
Total clearance 
Cmax 
Maximum observed concentration  
CNS 
Central nervous system 
CO2 
Carbon dioxide 
CRF 
Case report form 
CRO 
Clinical research organization 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTX 
Serum C-terminal type I collagen telopeptide 
DLT 
Dose-limiting toxicity 
DXA 
Dual-energy x-ray absorptiometry 
DMC 
Data Monitoring Committee 
DVT 
Deep vein thrombosis 
ECD 
Extracellular domain 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EDF 
Erythroid differentiation factor  
ESA 
Erythropoiesis-stimulating agents 
F 
Bioavailability (absolute) 
FACT 
Functional Assessment of Chronic Illness 
FDA 
Food and Drug Administration  
FSH 
Follicle-stimulating hormone 
GCP 
Good Clinical Practices 
GH 
Growth hormone 
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Term 
Definition 
HBV 
Hepatitis B virus 
Hct 
Hematocrit 
HCV 
Hepatitis C virus 
Hgb 
Hemoglobin 
HIV 
Human immunodeficiency virus 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug 
IP 
Intraperitoneal 
IRB 
Institutional Review Board 
IV 
Intravenous 
IVRS 
Interactive Voice Response System 
Kd 
Binding coefficient 
λz 
Elimination rate constant 
LDH 
Lactate dehydrogenase 
LH 
Luteinizing hormone 
MCH 
Mean corpuscular hemoglobin 
MCHC 
Mean corpuscular hemoglobin concentration 
MCV 
Mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MITT 
Modified Intent to Treat (population) 
MRI 
Magnetic resonance imaging 
NOAEL 
No adverse events level  
NYHA 
New York Heart Association 
OC 
Osteocalcin 
ORR 
Objective response rate 
OVX 
Ovariectomized 
PD 
Progressive disease 
PFS 
Progression free survival 
PHI 
Protected health information 
P1NP 
Serum intact procollagen type I N terminal propeptide 
PK 
Pharmacokinetic 
PP 
Per-protocol (population) 
PT 
Prothrombin time 
PTH 
Parathyroid hormone 
PTT 
Partial thromboplastin time 
RAP-011 
Murine version of ACE-011, ActRIIA mFc 
RBC 
Red blood cell (count) 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SC 
Subcutaneous 
SERM 
Selective estrogen receptor modulator 
SHAM 
Sham-operated 
SPEP 
Serum protein electrophoresis 
SRE 
Skeletal-related event 
T1/2 
Elimination half-life  
TIBC 
Total iron binding capacity 
Tmax 
Time to Cmax 
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Term 
Definition 
TRACP-5b 
Serum tartrate-resistant acid phosphatase isoform-5b 
ULN 
Upper limit of normal 
Vz/F 
Volume of distribution 
WBC 
White blood cell (count) 
 
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5. 
INTRODUCTION 
5.1. 
Indication and Rationale 
This study is designed to evaluate the efficacy, safety, and tolerability of ACE-011 for the 
treatment of chemotherapy induced anemia in patients with metastatic breast cancer. 
Treatment of patients with metastatic breast cancer with myelosuppressive chemotherapy is 
frequently associated with anemia. Chemotherapy induced anemia (CIA) is a significant problem 
for patients with cancer, causing fatigue and reduced quality of life (1).  Patients with CIA are 
currently treated with blood transfusion and/or erythropoiesis-stimulating agents (2). However, 
with these treatment options CIA is still an area of unmet medical need. Erythropoiesis-
stimulating agents (ESAs) can successfully mitigate transfusion need in a proportion of these 
patients, but concerns have emerged regarding apparent negative effects on survival and/or tumor 
progression in certain patient populations. The murine surrogate to ACE-011, RAP-011, has been 
tested as a single agent in breast cancer cell lines MDA-MB-231 and MCF-7 and no effect on 
enhanced proliferation of these cell lines has been observed in vitro. Therefore, treatment with 
ACE-011 may provide a distinct benefit/risk profile to patients with chemotherapy induced 
anemia.  
In both a Phase 1 single dose and multiple dose study of ACE-011 in postmenopausal women, 
increases in hemoglobin and hematocrit were observed following ACE-011 treatment and 
remained elevated over the course of study.  The observed hemoglobin and hematocrit effects of 
ACE-011 were dose and time dependent.  Please refer to the Investigator Brochure for further 
information.  
Based on the effect of ACE-011 on hematopoiesis and consistent biological phenomena observed 
in both non clinical and clinical studies, it is hypothesized that the blockade of ActRIIA receptor 
signaling impedes the terminal differentiation step in erythropoiesis to allow additional rounds of 
cell replication before cells enter the final differentiation phase. The result is a substantial 
increase in mature erythrocytes released into the circulation.  Since this proposed mechanism is 
different to that of known ESAs, ACE-011 may provide a different clinical profile in the 
treatment of CIA.  
This study will provide information on the pharmacodynamics (PD) properties regarding the 
ability of ACE-011 to increase hemoglobin in patients with CIA. 
5.2. 
Description of ACE-011 
ACE-011 (ActRIIA-IgG1) is a fully human fusion protein consisting of the extracellular domain 
(ECD) of activin receptor IIA (ActRIIA) linked to the human IgG1 Fc domain, which includes 
the heavy chain hinge and constant domains, CH2 and CH3.  ACE-011 avidly binds to activin A 
with a binding coefficient (Kd) approximately 8.9 pM and prevents its binding to endogenous 
receptors, thereby inhibiting biological effects of activin.   
 
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5.3. 
Activin Biology 
Activin A was initially identified as a gonadal differentiation factor involved in modulating 
follicle stimulating hormone (FSH) secretion from the pituitary (3). Subsequently, the pleiotropic 
nature of activin A has become more apparent (4).   There is a growing body of data suggesting a 
role for activin A in bone remodeling, specifically as a negative regulator of bone growth (5).  
Before the two molecules were shown to be identical (6), activin A was also described as 
erythroid differentiation factor (EDF), effecting red blood cells in the later stages of maturation 
(7).  The mechanism(s) by which activin A influences erythropoiesis remain under investigation 
and, in fact, there are data from studies in vitro and in animals that support erythropoiesis-
stimulatory (8,9) and -inhibitory effects (10).   
At the cellular level, activin A binds initially to the high-affinity Type II receptor (ActRIIA).  The 
ligand-bound ActRIIA then recruits the low-affinity Type I receptor (ActRIA or ALK-4).  The 
receptor heterocomplex, through its cytoplasmic protein kinase activity, then activates the Smad 
signal cascade to eventually influence nuclear transcriptional factors (11, 12).  The competitive 
binding of activin A in the blood by the ACE-011 soluble fusion protein can result in inhibition 
of ActRIIA receptor signaling pathway by impeding biological processes attributed to activin A.  
Activin has also been attributed to erythroid differentiation and has been reported to have 
proerythrocytic effects and to induce terminal differentiation of RBCs.  Inhibition of activin may 
lead to increases in proliferation of the erythroid lineage.  Based on its pharmacologic effects, 
ACE-011 (ActRIIA-IgG1) is being developed for the treatment of bone loss associated with 
various disease states (e.g., osteoporosis and treatment of osteolytic lesions in patients with 
multiple myeloma), and treatment of anemia associated with a variety of disorders, such as 
chemotherapy induced anemia. 
The extracellular domain sequence of ActRIIA is completely conserved among numerous species 
including mouse, rat, cynomolgus monkey and humans, thus ACE-011 is active in these animals.  
However, in order to reduce the potential immunogenicity of the fully human molecule, ACE-
011, in mice and to maximize the opportunity to maintain exposures in chronic models, a murine 
surrogate molecule was constructed by exchanging the human immunoglobulin Fc sequence 
portion of ACE-011 with its murine IgG2a homolog.  The resultant construct is referred to as 
RAP-011 (ActRIIA-mIgG2aFc).   
5.3.1. 
Pharmacology Studies 
RAP-011 was evaluated in a broad range of animal pharmacology studies to assess the effects of 
inhibition of activin A on the biological processes attributed to that regulatory protein.  RAP-011 
has been shown to have significant effects on the red cell compartment.  RAP-011 treatment of 
mice at 10, 30 and 50 mg/kg by intraperitoneal injection (IP) twice per week for 3 months 
resulted in a 16-26% increase in red blood cell (RBC) counts compared to control animals.  Rats 
treated with RAP-011 at 0.3, 3 and 30 mg/kg once per week for 3 months showed RBC count 
increases of 6-15% over control animals.  Finally, in cynomolgus monkeys treated with 10, 30 or  
 
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50 mg/kg of ACE-011 twice per month for 3 months there was a 21- 24% increase in RBC counts 
compared to controls animals.  In this study, the RBC count increase was apparent as early as 2 
weeks following the initial dose of ACE-011.   
While the mechanism(s) underlying the stimulation effect of ACE-011 on erythropoiesis are not 
yet fully understood, it is hypothesized that a blockade of ActRIIA receptor signaling impedes the 
terminal differentiation step in erythropoiesis to allow additional rounds of erythroid cell 
replication before cells enter the terminal differentiation phase.  The result is a substantial 
increase in mature erythrocytes released into circulation.   
RAP-011 administered at 10 mg/kg to mice three days prior to administration of paclitaxel at 30 
mg/kg was sufficient to prevent decreases in red blood cell parameters seen three days later.  
Mice receiving paclitaxel alone had decreased hematocrit from 43% to 38% three days later.  
RAP-011 administered 3 days prior to paclitaxel injection was sufficient to keep the hematocrit 
above 42% at three days and up to two weeks after paclitaxel administration.  Therefore 
prophylactic treatment with RAP-011 was able to prevent paclitaxel induced anemia in mice. 
RAP-011 has also been shown to significantly increase bone mineral density and strength in 
normal animals and in a variety of animal models of bone loss (13, 14, 15).  In a murine 
ovariectomy (OVX)-induced model of osteopenia, RAP-011 (10 mg/kg IV, twice per week x 12 
weeks) increased trabecular BMD > 25% in 6-12 weeks compared to the phosphate buffered 
saline (PBS)-treated controls (p<0.002).  RAP-011 treatment was able to reverse the accelerated 
bone loss associated with ovariectomy.  As expected sham-operated (SHAM) mice (i.e., intact 
ovaries) started the study with a greater trabecular BMD than OVX mice.  PBS-treated SHAM 
mice showed a 10% decrease in trabecular BMD after 12 weeks of treatment compared to 
baseline, while SHAM-RAP-011 mice had a 32% increase in trabecular BMD over the same 
period.  These data demonstrate that RAP-011 is able to increase trabecular BMD in both the 
normal state and in a model of established bone loss.  The femurs of both the RAP-011 treated 
OVX and SHAM mice showed statistically significant increases in all measured parameters of 
bone strength (i.e., maximum load, stiffness, energy, ultimate strength, and elastic modulus).  In 
summary, treatment with RAP-011 produced bone of superior quality consistent with an anabolic 
agent. 
RAP-011 was evaluated in a mouse model of skeletal metastasis using luciferase-tagged, human 
MDA-MB-231 breast cancer cells (estrogen receptor negative).  Mice were pretreated for 2 
weeks with RAP-011 (10 mg/kg, biweekly, SC) prior to intracardiac injection of tumor cells.  
Treatment with RAP-011 was continued for an additional 5 weeks following tumor implantation. 
A parallel study was conducted to examine the effect of RAP-011 treatment, as described above, 
on survival of MDA-MB-231 bearing mice. 
The data demonstrate that RAP-011 treatment acts to inhibit MDA-MB-231 metastasis to bone 
and may also play a role in inhibiting tumor growth in soft tissue.  Furthermore, in the presence 
of tumor cells, RAP-011 is able to prevent lytic disease through an anabolic mechanism of bone 
formation.  Lastly, inhibition of tumor growth and metastasis with RAP-011 leads to a greater 
than 25% survival benefit in this model.  
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The efficacy of RAP-011 was examined in an orthotopic model of breast cancer using luciferase-
tagged human MCF-7 breast cancer cells (estrogen receptor positive). Mice were pretreated for 2 
weeks with RAP-011 (10 mg/kg, biweekly, SC) prior to the implantation of tumor cells into the 
mammary fat pad of female nude mice. Treatment with RAP-011 was continued for an additional 
7 weeks following tumor implantation at which time mice were sacrificed and assessed for tumor 
burden. RAP-011 effectively lowered the tumor burden in mice as detected by bio-luminescence. 
In addition, a 60% reduction in tumor weight was observed in the RAP-011 treated mice.  
The ability of RAP-011 to repair osteolytic lesions caused by metastatic disease was investigated 
in mice.  In this model athymic nude mice received an intratibial injection of MDA-MB-231-Luc 
cells to mimic bone metastasis.  Mice were treated with a chemotherapy regimen of paclitaxel (20 
mg/kg, IP, every three days) starting seven days after tumor injection and continuing for the 
duration of the study.  On study day 42 mice with a detectable tumor burden by bioluminescent 
imaging were divided into two groups and began treatment with RAP-011 (10 mg/kg, SC, 
biweekly) or vehicle.  Prior to dosing, μCT scans of the tumor bearing tibia were conducted to 
identify osteolytic lesions.  RAP-011 treatment continued for four weeks (to study day 70) and a 
final μCT scan of the tibia was performed.  On study day 70 osteolytic lesions remained the same 
or had progressed further when compared to study day 42 in the vehicle treated mice.  While 
some mice showed progression of osteolytic lesions (most likely related to tumor burden) on 
study day 70, a majority of mice treated with RAP-011 demonstrated repair of the osteolytic 
lesions seen on study day 42.  Therefore treatment with RAP-011 has the ability to repair 
osteolytic lesions caused by tumors and after cytoxic chemotherapy with paclitaxel. 
5.3.2. 
Toxicology 
ACE-011 has been evaluated for toxicological effects in two species, Sprague-Dawley rats and 
cynomolgus monkeys.  The dose levels ranged from 0.3 to 30 mg/kg in rats and from 1 to 50 
mg/kg in monkeys.  These dose ranges were designed to support Phase 1a single-dose levels of 
0.01 to 3.0 mg/kg IV and Phase 1b multiple doses of 0.1 to 2 mg/kg (monthly, SC).  Weekly 
dosing in animals was designed to provide continuous, but fluctuating serum concentrations of 
ACE-011, which would be mimicked by a one-month dosing interval in humans. 
Initial studies utilized IV dosing to identify target organs while longer-term studies (3 months in 
rats; 3 and 6 months in monkeys) utilized SC dosing to mimic the intended dosing regimen for 
patients.  The expected pharmacologic effect, increased red blood cells (RBCs), hemoglobin 
(Hb), hematocrit (HCT) and reticulocytes, was observed in all studies, presumably based on the 
ability of ACE-011 to inhibit activin.  A second expected pharmacologic effect of ACE-011, 
based on inhibition of activin, was the reversible reduction in sperm production and testicular 
tubular damage in rats.  Since male cynomolgus monkeys were sexually immature in these 
studies, it was not possible to monitor this effect in this species. 
Effects on the adrenal gland were only seen in rats and were more pronounced in female rats. 
This toxicological observation may not be relevant for predicting effects in humans since adrenal 
toxicity was not seen in cynomolgus monkeys.  Dose-limiting toxicity and no observable adverse 
effect levels (NOAELs) were primarily based on renal toxicity in both rats and monkeys.  There  
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was some indication that kidney toxicity was an indirect effect, based on the formation of 
antibody/antigen complexes, but since these studies were not designed to investigate 
toxicological mechanisms, a definitive cause of renal impairment and renal damage was not 
determined.  Development of antibodies to ACE-011 was noted in all of these studies, which is 
an expected immune reaction in rats and monkeys dosed with a human protein.  
The no observable adverse effect level (NOAELs) from the 3 month SC studies was 3 and 30 
mg/kg in rats and monkeys, respectively. Because the kidney findings were observed at all dose 
levels, the NOAEL from the 6 month monkey study is < 10 mg/kg.  
5.4. 
Summary of Clinical Experience 
5.4.1. 
A011-01: A Phase 1a Study in Healthy Postmenopausal Women  
ACE-011 was first studied in a randomized, Phase 1a, single dose, dose escalation study in 
healthy, post-menopausal females (16).  ACE-011 was diluted in normal saline administered as 
an IV infusion (over approximately 1 hour) or as a SC injection on Day 1.  Dose levels were 0.01, 
0.03, 0.1, 0.3, 1.0, and 3.0 mg/kg IV and 0.03 and 0.1 mg/kg SC.  A total of 48 subjects were 
enrolled; 5 active and 1 placebo at each of the IV and SC dose levels.  All subjects were followed 
for 4 months following a single dose administration. 
The pharmacokinetics of ACE-011 was linear for all IV and SC doses.  Across IV doses ranging 
from 0.1 through 3.0 mg/kg, the mean clearance (CL) ranged from 0.092 to 0.128 mL/h/kg, the 
volume of distribution ranged from 73.7 to 110 mL/kg, and the mean T1/2 ranged from 23.7 to 
31.8 days, with no apparent dependence on dose.  After SC administration of 0.03 and 0.1 mg/kg, 
ACE-011 was completely absorbed, and the mean T1/2 was approximately 30 days, with no 
apparent dependence on dose.   
The most commonly occurring treatment-emergent adverse events (AEs; i.e., those occurring in 
more than 1 subject in any treatment group) were headache, infusion site reaction, injection site 
hemorrhage, and toothache.  The majority of the injection site reactions and injection site 
hemorrhages were in the first IV cohort and were related to infiltration of the IV site.  The 
majority of treatment-emergent AEs were mild in severity and were judged to be unrelated to 
ACE-011.  No deaths, serious AEs (SAEs), or AEs leading to discontinuation were reported.  
Changes in red blood cells (RBCs), hemoglobin, reticulocytes, liver function tests, glucose, uric 
acid, amylase and lipase occurred in some subjects; however, none of these laboratory results 
were reported as adverse events.  Mild, transient elevations in pancreas enzymes, liver enzymes, 
or glucose were reported as AEs in five patients.  There were no clinically significant changes 
from baseline in vital signs, physical examination, endocrine function, or electrocardiogram 
(ECG) data.  Preservation of adrenal cortical function was monitored through evaluation of serum 
electrolytes (sodium and potassium levels) and through cortisol response to adrenocorticotropic 
hormone (ACTH) stimulation.  No clinically significant findings were observed at doses up to 3.0 
mg/kg IV, and ACE-011 was well tolerated in healthy, post-menopausal female volunteers in 
single dose levels up to 0.1 mg/kg SC and 3.0 mg/kg IV, the highest dose levels tested in this 
study. 
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5.4.2. 
A011-02: A Phase 1b Study in Healthy Postmenopausal Women  
ACE-011 was studied in a Phase 1b, single-center, randomized, double-blind, placebo-controlled, 
multi-dose, dose-escalating study to evaluate the safety, tolerability and pharmacodynamics of 
ACE-011 in healthy postmenopausal women.  Four cohorts of 10 subjects each were planned at 
the following dose levels: 0.1, 0.3, 1.0, and 2.0 mg/kg administered subcutaneously.  Within each 
cohort, subjects were to be randomized to either active or placebo treatment in an 8:2 ratio. 
Subjects were to receive one SC injection of ACE-011 or placebo every 28 days for a total of 4 
doses. All subjects were to be followed for 12 weeks after the last dose. 
The treatment phase of the study was terminated early after a dose-limiting pharmacodynamic 
effect was observed.  While on study, one subject in the 1.0 mg/kg cohort experienced a Serious 
Adverse Event (SAE) of progressive and persistent hypertension that was attributed to a rapid 
and significant rise in hemoglobin and hematocrit levels.  Due to symptoms of headaches, nausea, 
eye pain, dizziness and vomiting approximately 1 week following the second dose, the subject 
was hospitalized for monitoring and evaluation of her hypertension.  The head MRI, fundoscopy, 
and ECG performed were reported as normal and headache symptoms resolved following 
therapeutic phlebotomy. The SAE resolved and the subject was discharged from the hospital the 
following day.  The hypertension was monitored closely and managed initially with 
antihypertensive medication.  The hypertension resolved by the end of the study without need of 
any antihypertensive medication. The subject received aspirin prophylactically until the end of 
the study and continued taking ibuprofen as needed for headaches.  Further details can be found 
in the Investigator Brochure.  
Based on the magnitude of the hematopoietic response, the Sponsor suspended dose escalation to 
the 2.0 mg/kg dose level and further dosing in all cohorts as a result of this dose-limiting 
pharmacodynamic effect at the 1.0 mg/kg dose level.  In total, 31 subjects were enrolled and 
treated.  Dose levels of ACE-011 administered included 0.1, 0.3, and 1.0 mg/kg (Cohorts 1, 2, 
and 3 respectively).  All subjects randomized to active treatment in Cohort 1 received all 4 
planned doses of ACE-011.  Due to early discontinuation of study drug, subjects randomized to 
active treatment in Cohort 2 received 3 doses of ACE-011, and subjects randomized to active 
treatment in Cohort 3 received 2 doses of ACE-011.  Subjects randomized to placebo treatment 
received between 1 and 4 doses of study treatment.   
In the analysis of the unblinded data, after the administration of the first dose, a dose and time 
dependent increase in hemoglobin values was observed (see Table 3 below): 
 
 
 
 
 
 
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Table 3: 
A011-02: A Phase 1b Study in Healthy Postmenopausal Women: Hemoglobin 
Evaluation 
       
*The number of placebo subjects with data decreases over time as a result of the early discontinuation of the study (i.e., there were placebo 
subjects in each dosing cohort).  There were seven placebo subjects with data at baseline, Days 8, 15, and 36; six subjects with data at Days 29, 
43, 57, and 85; five subjects with data on Days 71 and 113; four subjects with data on Day 64; three subjects with data on Day 141; two subjects 
with data on Day 99; and one subject with data on Days 92 and 169. 
** Number of doses administered per treatment group: 0.1 mg/kg 4 doses; 0.3 mg/kg 3 doses; 1.0 mg/kg 2 doses.  Data beyond this study day are 
considered follow-up results. 
***n=1 
No severe or life-threatening events were reported. The incidence of the most common treatment-
emergent AEs (i.e., occurring in more than one subject in any treatment group) is presented 
below (see Table 4). The most notable AEs were those related to increases in hematologic 
laboratory measures in the 1.0 mg/kg dose group: hematocrit, hemoglobin, and RBC count.  AEs 
of increased hemoglobin and/or hematocrit were reported for seven of the eight subjects in this 
dose group.  These events were reported as mild or moderate elevations; all were considered 
probably related to study drug treatment. Three of the subjects in the 1.0 mg/kg group with 
elevated hemoglobin levels underwent phlebotomies and all hemoglobin elevations were resolved 
by the end of the follow-up period. No erythroid lineage AEs were reported in the 0.1 or 0.3 
mg/kg treatment groups.   
 
Mean Change from Baseline (g/dL) 
Evaluation Time Point 
Placebo 
 
N=7* 
ACE-011 
0.1 mg/kg 
N=8 
ACE-011 
0.3 mg/kg 
N=8 
ACE-011 
1.0 mg/kg 
N=8 
Baseline Mean, pre-Dose 1 
13.20 
13.11 
13.30 
12.71 
Day 8 
0.17 
0.68 
0.85 
1.21 
Day 15 
-0.27 
0.43 
0.44 
1.75 
Day 29 
0.27 
0.61 
1.21 
    2.68** 
Day 36 
0.56 
0.64 
1.89 
2.96 
Day 43 
-0.02 
0.89 
1.21 
2.85 
Day 57 
0.27 
1.28 
    1.64** 
2.09 
Day 64 
0.53 
1.11 
2.49 
2.21 
Day 71 
-0.10 
1.34 
2.09 
1.66 
Day 85 
0.38 
    1.18** 
2.55 
1.86 
Day 92 
      0.00*** 
1.04 
      1.60*** 
      3.80*** 
Day 99 
-0.20 
1.21 
      3.20*** 
      1.28*** 
Day 113 
-0.02 
1.30 
1.29 
1.04 
Day 141 
 0.30 
0.95 
0.34 
2.30 
Day 169 
       0.20*** 
0.06 
 
      2.00*** 
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Table 4: 
A011-02: Incidence of Most Common Adverse Events    
Dose Group 
System Organ Class and Preferred Term 
Placebo 
N=7 
n (%) 
0.1 mg/kg 
N=8 
n (%) 
0.3 mg/kg 
1.0 mg/kg 
N=8 
n (%) 
N=8 
n (%) 
GASTROINTESTINAL DISORDERS 
     Diarrhea 
0 (0.0%) 
2 (25.0%) 
0 (0.0%) 
0 (0.0%) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
     Asthenia 
0 (0.0%) 
1 (12.5%) 
2 (25.0%) 
0 (0.0%) 
     Fatigue 
2 (28.6%) 
0 (0.0%) 
1 (12.5%) 
2 (25.0%) 
INFECTIONS AND INFESTATIONS 
     Viral upper respiratory tract infection 
0 (0.0%) 
4 (50.0%) 
0 (0.0%) 
0 (0.0%) 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
     Limb injury 
0 (0.0%) 
1 (12.5%) 
0 (0.0%) 
2 (25.0%) 
INVESTIGATIONS 
     Hematocrit increased 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
6 (75.0%) 
     Hemoglobin increased 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
7 (87.5%) 
     Red blood cell count increased 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
3 (37.5%) 
METABOLISM AND NUTRITION DISORDERS 
     Decreased Appetite 
1 (14.3%) 
0 (0.0%) 
2 (25.0%) 
0 (0.0%) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
     Arthralgia 
2 (28.6%) 
0 (0.0%) 
2 (25.0%) 
0 (0.0%) 
     Muscle spasms 
0 (0.0%) 
1 (12.5%) 
0 (0.0%) 
2 (25.0%) 
NERVOUS SYSTEM DISORDERS 
     Dizziness 
0 (0.0%) 
0 (0.0%) 
2 (25.0%) 
2 (25.0%) 
     Headache 
2 (28.6%) 
4 (50.0%) 
3 (37.5%) 
2 (25.0%) 
     Paresthesia 
1 (14.3%) 
0 (0.0%) 
0 (0.0%) 
3 (37.5%) 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
     Oropharyngeal pain 
2 (28.6%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
VASCULAR DISORDERS 
     Hot flush 
0 (0.0%) 
2 (25.0%) 
0 (0.0%) 
1 (12.5%) 
Note: Table presents AEs reported in more than one subject in any treatment group. 
Headache was reported frequently in all treatment groups with no apparent dose response trend, 
though the reports in the higher dose groups were more often considered possibly related to 
treatment.  Most headaches were reported as mild (one headache was reported as moderate).  
Paresthesia and dizziness were reported more frequently in the ACE-011 groups, though the 
events were generally not considered drug related.  Other frequently reported events (e.g. fatigue, 
upper respiratory infection) did not appear to increase with dose and were generally mild.  
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Hemoglobin levels for all subjects with elevations had returned to within normal limits by the end 
of the study.   
Adrenal cortical function was monitored through evaluation of serum electrolytes (sodium and 
potassium levels) and through cortisol response to adrenocorticotropic hormone (ACTH) 
stimulation. All ACTH simulation test results were normal. 
PK results confirmed that the PK of ACE-011 is linear following the first SC doses of all three 
dose levels tested, 0.1, 0.3, and 1.0 mg/kg. The terminal half life (T1/2) of ACE-011 following the 
last dose in all three dose groups was identical, with mean T1/2 being approximately 23 days. The 
mean CL/F ranged from 3.05 to 3.90 mL/d/kg, the mean Vz/F ranged from 97.47 to 103.03 
mL/kg, and the mean T1/2 ranged from 20.92 to 23.34 days in all 3 dose levels, with no apparent 
dependence on dose.  
Bone mineral density was assessed by dual-energy X-ray absorptiometry (DXA).  Mean change 
and mean percent change in BMD results from baseline to study end are summarized in the table 
below.  A dose-dependent increase in the BMD of the total hip from baseline to end of study was 
observed, with a significant and rapid increase of 2.4% in the 1.0 mg/kg dose group, compared to 
a 0.7% decrease in the placebo group.  BMD results for lumbar spine showed slight increases of 
0.4% to 1.0% from baseline to study end in all active treatment groups, compared with a 0.5% 
decrease in the placebo group (see Table 5 below): 
Table 5: 
A011-02: A Phase 1b Study in Healthy Postmenopausal Women: BMD 
 
5.4.3. 
A011-04: A Phase 2a Study in Patients with Osteolytic Lesions of Multiple 
Myeloma  
Study A011-04 is an ongoing, non-IND, Phase 2a, multi-center, randomized, multiple-dose study 
to evaluate the safety, tolerability and efficacy of ACE-011 in patients with osteolytic lesions of 
multiple myeloma.  Safety evaluations include adverse events (AEs), clinical laboratory tests, 
standard 12-lead electrocardiogram (ECG), vital signs, Eastern Cooperative Oncology Group  
Treatment Group 
 
Placebo 
 
ACE-011 
0.1 mg/kg 
N=8 
ACE-011 
0.3 mg/kg 
N=8 
ACE-011 
1.0 mg/kg 
N=8 
N=7 
Mean 
Change 
Mean Percent 
Change 
Mean 
Change 
Mean Percent 
Change 
Mean 
Change 
Mean Percent 
Change 
Mean 
Change 
Mean Percent 
Change 
Lumbar Spine 
(g/cm2) 
-0.0020 
-0.5% 
0.0099 
0.7% 
0.0082 
1.0% 
0.0051 
0.4% 
Total Hip 
(g/cm2) 
-0.0062 
-0.7% 
0.0050 
0.6% 
0.0075 
0.9% 
0.0220 
2.4% 
Number of doses administered and day of last dose per treatment group: 0.1 mg/kg 4 doses (Day 85); 0.3 mg/kg 3 doses (Day 57); 1.0 mg/kg 2 
doses (Day 29).  Data beyond this study day are considered follow-up results. 
 
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(ECOG) performance status and physical examinations.  Additionally, the study includes the 
assessment of biochemical markers of bone formation and resorption, skeletal related events 
(SREs), bone mineral density (BMD) by duel-energy x-ray absorptiometry (DXA) and bone pain 
by visual analog scale (VAS).  
In this study, patients are randomized in a 4:1 ratio to one of three dose levels of ACE-011 (0.1, 
0.3 and 0.5 mg/kg) or placebo, to be administered to patients every 28 days by subcutaneous 
injection, for up to four doses over a 3-month period.  The test article is being evaluated in 
combination with the anti-myeloma therapy of melphalan (4 mg/m2 on days 1-7), prednisolone 
(40 mg/m2 on days 1-7) and thalidomide (100 mg per day) (MPT).  The sites, Sponsor and 
Sponsor representatives are blinded to treatment assignment.    
As of 10 March 2009, 30 patients have been randomized, enrollment is complete and treatment is 
ongoing.  Fifteen patients have received multiple doses of their assigned treatment; 7 patients 
have received 4 doses, 3 patients have received 3 doses and 5 patients have received 2 doses.  Of 
the remaining 15 patients, 12 patients have received their first dose of ACE-011 or placebo and 3 
patients have not yet received their first dose.  There have been no ACE-011 related serious 
adverse events (SAEs) reported.  Per the monitored preliminary data on 18 patients presented to 
the Independent Data Monitoring Committee (DMC) on 9 February 2009, there were 8 Grade 
3/severe AEs reported in 4 patients, including neutropenia, platelet count decreased, pain in 
extremity, back pain and anemia.  All Grade 3 AEs were determined to be not related to ACE-
011 and the Grade 3 hematologic adverse events were considered either probably or definitely 
related to the MPT treatment.   
Following preliminary analysis of the blinded central laboratory data, increases in hemoglobin 
values were observed within 28 days after administration of the first dose of ACE-011/placebo.  
Per data available, 11 out of 30 patients had > 1 g/dL increase in hemoglobin within the first 28 
days on the study, 4 patients achieved a > 2 g/dL increase within their first 28 days on study, 
while 8 patients achieved a > 2 g/dL increase in hemoglobin through Day 85.      
Including all visits as of 10 March 2009 through Day 85, 9 out of 30 patients had a dose 
interruption due to a hemoglobin value of > 13 g/dL according to the dose modification rules 
defined in the protocol and 1 of the 9 patients, who had a history of hypertension, also had a dose 
interruption due to Grade 2 hypertension.  Three of the 9 patients that required a dose interruption 
due to a hemoglobin value of > 13 g/dL, as per protocol, had hemoglobin levels above 13 g/dL 
prior to their first dose.  Taken together, these data, suggest a beneficial pharmacodynamic effect 
of ACE-011 on erythropoiesis in a patient population with cancer chemotherapy induced anemia.  
No patients have had a dose reduction in ACE-011/placebo treatment or discontinued treatment.   
One SAE of prolonged hospitalization due to pneumonia, that was considered not related to 
ACE-011, was reported in a 
enrolled in the study.  On 
, four 
days after the first dose of ACE-011/placebo and the initial doses of melphalan, prednisolone and 
thalidomide (MPT), the patient presented with elevated temperatures up to 39º C, cough and 
fatigue.  Chest x-ray performed on 
 revealed a pneumonic infiltration in the lower  
 
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lobe of the left lung.  On 
 hospitalization of the patient was prolonged due to the 
event.  The patient was treated with moxifloxacin, doripenem, meropenem and fluconazole.   
On
 the pneumonic infiltration resolved, as confirmed by chest x-ray.  This SAE 
resolved upon discharge of the patient from the hospital on 
  
The investigator considered the event of pneumonia not related to ACE-011 and possibly related 
to MPT.  The Sponsor agreed with the Investigator’s assessment of causality.  Pneumonia is 
considered a labeled event per the current package insert for thalidomide.  The SAE was 
considered serious, related and expected with respect to thalidomide and unrelated to ACE-011. 
The A011-04 study has completed enrollment, while treatment, follow-up and data monitoring 
are ongoing.   
5.5. 
Potential Risks for Human Use 
The 1-month safety study in rats suggested that ACE-011 may affect sperm count and motility in 
a dose-dependent manner, although these findings appeared to be reversible upon drug 
discontinuation.  These reproductive effects are likely a result of the expected biological activity 
of activin inhibition.   
The 1-month safety study in rats also suggested that ACE-011 induces adrenocortical necrosis in 
rats.  At present, the mechanism by which ACE-011 has induced this lesion in rats and the basis 
for its apparent species specificity are unknown; the finding has not been observed in mice or 
cynomolgus monkeys at similar dose levels.  Adrenal cortical function was monitored in human 
subjects receiving ACE-011 by the evaluation of serum electrolytes including sodium and 
potassium levels and by the evaluation of cortisol response to ACTH stimulation in both the 
Phase 1a single dose and Phase 1b multiple dose healthy volunteer clinical studies.  These 
parameters were evaluated up to doses of 3.0 mg/kg IV and 1.0 mg/kg SC, and no clinically 
significant perturbations in adrenal function were observed.     
Laboratory findings from the Phase 1a single dose study showed elevations in hematology 
results, pancreas and liver enzymes, and uric acid.  The most commonly seen treatment-emergent 
adverse events in this study were headache, infusion site reaction, injection site hemorrhage, and 
toothache.  
Based on data from the Phase 1b study, the most notable AEs were increases in hematologic 
laboratory measures in the 1.0 mg/kg dose group: hematocrit, hemoglobin, and RBC count.  AEs 
of increased hemoglobin and/or hematocrit were reported for seven of the eight subjects in this 
dose group.  These events were reported as mild or moderate elevations; all were considered 
probably related to study drug treatment.  No erythroid lineage AEs were reported in the 0.1 or 
0.3 mg/kg treatment groups.  Hematologic parameters will be monitored carefully in this study.   
Headache was reported frequently in all treatment groups with no apparent dose response trend, 
though the reports in the higher dose groups were more often considered possibly related to 
treatment.  Most headaches were reported as mild (one headache was reported as moderate).  
Paresthesia and dizziness were reported more frequently in the ACE-011 groups, though the  
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events were generally not considered drug related.  Other frequently reported events (e.g. fatigue, 
upper respiratory infection) did not appear to increase with dose and were generally mild. 
In the Phase 1b multiple-dose healthy volunteer study, some subjects treated with ACE-011 
showed elevations in blood pressure.  One subject who had received two doses of ACE-011 at the 
1.0 mg/kg dose level had a serious adverse event.  The patient was hospitalized for further 
evaluation of increases in blood pressure and symptoms that may have been caused by the 
increase in blood pressure.  The symptoms that the subject experienced included headache, 
dizziness, nausea, vomiting, and elevated hematology values (increases in the number of red 
blood cells).  This serious adverse event was judged to be probably related to the study drug and 
resolved following discharge from hospital the following day. Throughout the course of the 
follow up period hematologic parameters were monitored frequently until the hemoglobin and 
hematocrit levels returned to within normal limits. Further details are outlined in the Investigator 
Brochure.  
As with all biologics there is the potential for anti-drug antibodies that can be associated with 
increased drug clearance and hypersensitivity reactions.  An immune response to ACE-011 has 
been seen in monkeys that received the drug for 1 month and longer.  Some of those animals 
developed kidney inflammation possibly related to that immune response.  Anti-drug antibody 
formation will be assessed in this study to examine the immunogenicity of ACE-011, and to 
monitor reversibility of any AEs over time.   
Please refer to the Investigator Brochure for more information. 
 
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6. 
TRIAL OBJECTIVES AND PURPOSE 
6.1. 
Primary objective  
1. To evaluate the proportion of patients in each ACE-011 dose regimen who achieve a 
hematopoietic response during the treatment period including up to 2 months after the last 
dose of ACE-011 treatment of chemotherapy induced anemia in patients with metastatic 
breast cancer. 
6.2. 
Secondary objectives 
1. To evaluate the safety and tolerability of ACE-011 for the treatment of chemotherapy 
induced anemia in patients with metastatic breast cancer.  
2. To evaluate the percentage of patients who achieve an increase in hemoglobin of ≥ 1 
g/dL, ≥ 2 g/dL and/or hemoglobin concentration ≥ 11 g/dL for a consecutive 28 day 
period during the treatment period including up to 2 months after the last dose of ACE-
011 in the absence of any RBC transfusions and/or ESAs.  
3. To estimate the duration of the hematopoietic response associated with each ACE-011 
dose regimen. 
4. To estimate the time to the hematopoietic response associated with each ACE-011 dose 
regimen. 
5. To estimate the proportion of patients receiving red blood cell (RBC) transfusions and/or 
ESAs within each cycle of ACE-011 with each dose regimen. 
6. To estimate the effect of each ACE-011 dose regimen on progression free survival (PFS) 
and objective response rate (ORR). 
6.3. 
Exploratory objectives  
1. To estimate the effect of each ACE-011 dose regimen on serum bone biomarkers (OC, 
BSAP, P1NP, CTX, TRACP-5b), urine bone biomarker (uNTX), bone mineral density 
(DXA scans of lumbar spine and hip) and incidence of skeletal related events (SREs). 
2. To evaluate the quality of life in relation to the treatment of chemotherapy induced 
anemia in patients with metastatic breast cancer during the study. 
.  
 
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7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design and Plan 
This is a Phase 2, double-blind, randomized, placebo-controlled study to evaluate the efficacy, 
safety, and tolerability of ACE-011 for the treatment of chemotherapy induced anemia in patients 
with metastatic breast cancer. A total of 105 patients will be enrolled. 
The Data Monitoring Committee (DMC) is responsible for reviewing safety. The DMC will be 
comprised of a minimum of 3 members.  The DMC will meet regularly during the study to 
review serious adverse events (SAEs), adverse events (AEs), laboratory results, and vital signs. 
Safety data will be reviewed throughout the study by the DMC, Medical Monitor and the 
Investigator. DMC responsibilities, membership, meeting frequencies and procedures will be 
outlined in the DMC charter.  
Patients will be evaluated for study inclusion/exclusion criteria by the Investigator. Patients who 
meet the study entry criteria will be enrolled within 14 days of the screening visit. Central lab 
values and local lab values for hemoglobin will be utilized for the evaluation of patient eligibility. 
Central labs will also be used in the evaluation of patient safety throughout the study. Local lab 
values for hemoglobin and hematocrit will be collected and reported from screening through the 
Day 281/Termination visit.  Three cohorts of 30 patients each are planned at the following doses 
of ACE-011: 0.1 mg/kg, 0.3 mg/kg and 0.5 mg/kg. Fifteen patients will be enrolled into the 
placebo cohort (as shown in Table 6). 
Table 6: 
Study Design    
 
Dose  
Number of  Patients 
0.1 mg/kg 
30 
0.3 mg/kg 
30 
0.5 mg/kg 
 
 
  
30 
 
Placebo 
15 
 
Total patients enrolled: 105 
 
 
Each eligible patient will be randomized to one of the four cohorts to receive a dose administered 
as a subcutaneous injection every 28 days for up to 4 doses. Dosing will be administered on days 
1, 29, 57, and 85. Concurrent treatment with a myelosuppressive chemotherapy regimen for 
metastatic breast cancer will also be administered per standard of care at the site. Patients will be 
stratified according to administration of either single agent weekly chemotherapy or less frequent 
chemotherapy regimens.  
Blood samples will be collected from approximately one-third of patients participating in the 
study at selected study sites for the evaluation of serum concentrations of ACE-011.  Pre-dose PK 
samples will be collected as specified in Appendix 5 (PK sampling schedule.) 
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Patients will be assessed for safety by monitoring adverse events, clinical laboratory tests, 
assessment of quality of life (FACT- Fatigue (17)), vital signs and physical examinations on an 
ongoing basis.  ECGs will be performed during screening, prior to dosing on the first cycle, 
during the first, second and third cycle, Day 113 (28 days after the last dose of ACE-011) and at 
Day 281/ Termination visit to monitor safety.  Blood pressure and lab values will be assessed at 
each study visit during the treatment and treatment follow up period. 
Local laboratory hemoglobin values and blood pressure values will be evaluated prior to dosing 
per the dose modification criteria, as applicable.  
Patients will be followed for a minimum of 7 months following their last dose of ACE-
011/placebo. Study participation for each patient is approximately 10.5 months (14 day screening 
period, 3 month treatment period with a 2 month treatment follow up period, and a 5 month post 
treatment follow-up period). If a patient discontinues the study due to progression of disease 
(metastatic breast cancer) and/or begins another chemotherapy regimen, the patient will 
discontinue ACE-011/placebo treatment, complete the Day 281/Termination visit procedures, and 
be followed for survival only (a minimum 7 months from the last dose of ACE-011/placebo).   
Anti-drug antibody testing will be performed at Day 281/Termination visit and if positive, the 
patient may be asked to return to the clinical site for additional monthly anti-drug antibody 
testing for up to 12 months, after their last dose. 
Back up (serum) blood samples will be collected for future testing for the evaluation of novel 
tumor markers, such as endoglin and ALK-1 (activin receptor-like kinase-1). The samples will 
the stored at the central lab until this evaluation is performed. 
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8.
8.1. 
SELECTION AND WITHDRAWAL OF PATIENTS 
Number of Patients
The study will include three dose levels of ACE-011 at 0.1 mg/kg, 0.3 mg/kg and 0.5 mg/kg and 
a placebo group. A total of 105 will be treated with ACE-011 or placebo. 
8.2. 
Entry Criteria 
8.2.1. 
Patient Inclusion Criteria 
1. Women > 18 years of age.
2. Histologically confirmed diagnosis of breast cancer documented by cytology or biopsy.
3. Evidence of metastatic breast cancer with a minimum of one measurable lesion or non
measurable lesion per RECIST criteria (Appendix 1).
4. Receiving a multicycle myelosuppressive chemotherapy regimen including one of the
following: anthracycline, taxane, gemcitabine or vinorelbine.
5. Planned treatment with the same myelosuppressive chemotherapy regimen for a
minimum of 9 weeks after Day 1 of ACE-011/placebo administration.
6. Hemoglobin value between ≥ 6.5 to < 11.0 g/dL (≥ 65 to < 110 g/L).
7. ≥ 30 days must have elapsed (from Day 1) since previous treatment with erythropoiesis-
stimulating agent (including concurrent treatment with IV iron) for chemotherapy
induced anemia.
8. ≥ 7 days have elapsed (from Day 1) since the last RBC blood transfusion and receipt of ≤
2 units of blood in the past 30 days.
9. ECOG Performance status of 0 – 2 (Appendix 2).
10. Adequate renal (creatinine ≤ 1.5 x ULN or creatinine clearance ≥ 40 mL/min) and hepatic
function (bilirubin < 1.5 x ULN; AST/ALT < 2.5 x ULN).
11. Females of childbearing potential  participating in the study are to use adequate birth
control measures (i.e. oral contraceptives or two forms of barrier method birth control)
during study participation. Females of childbearing potential must have a negative serum
pregnancy test within 3 days to ACE-011/placebo administration (Day 1). A female of
childbearing potential is a sexually mature woman who has not undergone a
hysterectomy or who has not been postmenopausal for at least 24 consecutive months
(i.e. who has had menses at some time in the preceding 24 months).
12. Life expectancy of ≥ 6 months.
13. Is willing to adhere to the study visit schedule, understand and comply with all protocol
requirements.
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14. Understand and sign a written informed consent. 
8.2.2. 
Patient Exclusion Criteria 
1. At the time of screening patients who have any grade > 3 toxicity (as per NCI CTCAE 
v3.0 (Appendix 3)) (except for the following disease related toxicities:  hematological 
events- anemia, thrombocytopenia or neutropenia or non hematological events- nausea, 
vomiting, fatigue, or muscle or bone/joint pain).  
2. Prior radiation therapy to > 20% of the whole skeleton. Use of palliative radiation if the 
area being treated is <15% of body surface area with no pelvic radiation or no more than 
10% of the bone marrow reserve is radiated is permitted during patient participation in 
the study, at the discretion of the investigator. 
3. Have received more than 5 prior chemotherapy treatment regimens for metastatic breast 
cancer.  
4. Concurrent use of bevacizumab with the chemotherapy regimen during study 
participation. 
5. Clinically significant pulmonary, endocrine, neurologic, gastrointestinal, hepatic or 
genitourinary disease unrelated to underlying hematologic disorder.  
6. Patients with heart failure as classified by the New York Heart Association (NYHA) 
classification of 3 or higher (Appendix 4). 
7. History of thrombosis, deep vein thrombosis (DVT), pulmonary emboli, or embolic 
stroke. 
8. Untreated CNS metastases (exception: CNS metastases treated with whole brain 
radiotherapy > 6 months prior to randomization). 
9. Diagnosis of a myeloid malignancy or known history of myelodysplasia.  
10. History of second malignancy within 5 years (except excised and cured basal cell 
carcinoma, squamous cell carcinoma of the skin or cervical carcinoma in situ).  
11. Patients with a recent history (within 14 days of Day 1) of administration of systemic (IV 
or oral) antibiotics. Patients should be free of infection at least 14 days after the last dose 
of systemic antibiotic treatment (from Day 1). 
12. Uncontrolled hypertension. If hypertension is considered clinically stable, systolic blood 
pressure (BP) must be < 150 mmHg and diastolic BP must be < 100 mmHg.  
13. Known history of hepatitis C antibody (HCV), hepatitis B surface antigen (HBsAg and 
HB core Ab), or human immunodeficiency virus (HIV) antibody.   
14. Deficiency in iron (serum ferritin < 100 ng/mL (< 224.7 pmol/L)), vitamin B12, or folate. 
15. History of anemia as a result of inherited hemoglobinopathy such as sickle cell anemia or 
thalassemia.  
16. History of autoimmune or hereditary hemolysis or gastrointestinal bleeding. 
17. Patient received treatment with another investigational drug or device within 1 month 
prior to Day 1, or if the half life of the previous product is known, within 5 times the half 
life prior to dosing, whichever may be longer.  
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18. Pregnant or lactating females. 
19. History of severe allergic or anaphylactic reactions or hypersensitivity to recombinant 
proteins or excipients in the investigational product.  
20. Major surgery within 30 days prior to Day 1 (patients must have completely recovered 
from any previous surgery prior to Day 1).   
8.3. 
Patient Withdrawal Criteria 
Patients will be informed that they have the right to withdraw from the study at any time for any 
reason without prejudice to their medical care.   
Patients must be withdrawn from the study for any of the following reasons:  
• Patient request 
• Patient is unwilling or unable to comply with the protocol 
• ESA administration during the treatment period 
• Medical reason, such as cancer or treatment related toxicity, or at the discretion of the 
Investigator and/or the Medical Monitor(s) 
The reasons for withdrawal must be recorded in the patient’s case report form (CRF).  The 
Investigator must notify the Medical Monitor and the contract research organization (CRO) 
immediately when a patient has been discontinued/withdrawn due to an AE.  All patients who 
are withdrawn from the study should complete the tests and evaluations scheduled for Day 
281/Termination at the time of withdrawal. Discontinued/withdrawn patients should be followed 
for survival only for 7 months after the last dose of ACE-011/placebo.  Patients who withdraw 
due to ESA administration during the treatment period or due to ACE-011 related toxicity should 
enter the treatment follow-up period.  
 
 
 
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9. 
TREATMENT OF PATIENTS 
9.1. 
Concomitant Medications 
9.1.1. 
General Concomitant Medication Usage 
During screening, and during the study, patients may take only stable doses of medications for 
chronic conditions that are not specifically excluded by the protocol (see Sections 8.2.1 Patient 
Inclusion Criteria and 8.2.2 Patient Exclusion Criteria).  The Medical Monitor should be 
consulted by the Investigator if there are any concerns about what constitutes a stable dose or 
what is a chronic condition.  Concomitant medications will be recorded in the CRF through 90 
days from the last dose of ACE-011/placebo.   
9.1.2. 
Concomitant treatment for anemia 
Concurrent therapy with a new prescription medication related to treatment of anemia during the 
course of the study must first be discussed with the Investigator and Medical Monitor prior to 
administration, unless appropriate medical care necessitates that medication should begin before 
the Medical Monitor can be consulted.  
9.1.2.1. 
Iron supplementation 
Iron supplementation within 7 days of Day 1 (besides an oral general multivitamin with iron) 
will not be allowed. If a patient becomes iron replete during study treatment (ferritin < 100 
ng/mL (< 224.7 pmol/L) or transferrin < 20%), treatment with iron supplementation is at the 
discretion of the investigator.  
9.1.2.2. 
Erythropoiesis-stimulating agents (ESAs) 
If concurrent treatment with erythropoiesis-stimulating agent is required in the opinion of the 
investigator, the erythropoiesis-stimulating agent label instructions are to be followed. The 
patient is to discontinue further treatment with ACE-011/placebo and enter the treatment follow- 
up period of the study. See Table 7 for Schedule of Events.  
9.1.2.3. 
RBC Transfusions 
Concurrent treatment for chemotherapy induced anemia with blood transfusions is recommended 
when hemoglobin value is < 8 g/dL or at investigator discretion if the hemoglobin value is above 
8 g/dL and associated with anemia symptoms such as hemodynamic or pulmonary compromise 
that require treatment. If a transfusion is given to a patient during the treatment period, ACE-
011/placebo should be administered no sooner than 7 days from the date of the transfusion.  
After the transfusion, the hemoglobin value should be assessed no later than 7 days from the date 
of the transfusion.  On the day of ACE-011/placebo administration, the hemoglobin value and 
blood pressure will be assessed. See Figure 1 for ACE-011/placebo dose modification rules.  
 
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9.2. 
Chemotherapy 
Chemotherapy treatment for metastatic breast cancer is to be given as per standard of care at the 
site.  ACE-011/placebo administration should be given prior to chemotherapy administration on 
ACE-011/placebo administration days.  Continuation of treatment with the same chemotherapy 
regimen through the treatment or post-treatment follow-up period of the study is at the discretion 
of the investigator. 
9.3. 
Treatment Compliance 
Each dose of ACE-011/placebo will be administered as a SC injection at the clinical site by the 
study staff and will be documented in the study record.  Monitoring for patient compliance with 
the treatment regimen is therefore unnecessary.  
9.4. 
Randomization  
Patients will be randomized to limit scientific bias within the study. Randomization assignments 
will be generated through a computerized system, provided by an Interactive Web/Voice 
Response System (IWRS/IVRS). Patients will be stratified according to frequency of the planned 
chemotherapy regimen (weekly chemotherapy vs. less frequent chemotherapy administration). 
9.4.1. 
Blinding 
The Investigators, patients, and sponsor or representative will remain blinded to the treatment 
arm assignment of each patient. The unblinded statistician will remain uninvolved in the study 
conduct until database lock and unblinding of the data has occurred.  
Safety parameters will be reviewed on an ongoing basis throughout the study including adverse 
events, serious adverse events, laboratory listings, and vital signs. If substantial toxicity trends 
are observed in one treatment group versus another, the DMC may request unblinding the 
treatment code assignment schema.  
9.4.2. 
Unblinding 
In the event of a medical emergency for an individual patient in which knowledge of the study 
medication is critical to the patient’s medical management, the investigator may break the blind 
for that patient. However, prior to breaking the blind, every effort must be made by the 
investigator to first discuss the need to break the blind with the sponsor or sponsor 
representative. Further, it must be determined by the investigator that breaking the treatment 
blind is necessary information for the medical management of that patient. If the blind is broken, 
the patient must withdraw from the study by completing the Day 281/Termination visit 
procedures and be followed for survival only. 
 
 
 
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9.5. 
Treatments Administered 
9.5.1. 
Selection of Doses in the Study 
Single dose administration of ACE-011 up to 3.0 mg/kg was previously demonstrated to be safe 
and to have durable effects on markers of bone formation and resorption as well as red blood 
cells following a single IV administration.  A dose-limiting pharmacodynamic effect of ACE-
011 with increases in hemoglobin, hematocrit and RBCs was established in healthy post-
menopausal women at the 1.0 mg/kg dose level following multiple SC administration.  This 
study will confirm the safety in following repeated SC administration of ACE-011 and further 
evaluate the potential efficacy in patients with chemotherapy induced anemia.  The safety and 
preliminary efficacy of ACE-011 following multiple doses up to 0.5 mg/kg will be assessed 
using a parallel randomization design. 
9.5.2. 
Selection and Timing of Dosing for Each Patient 
Patients will be enrolled and receive their assigned dose of ACE-011/placebo every 28 days (i.e. 
on Days 1, 29, 57, and 85). Patients will be receiving chemotherapy, concurrently for metastatic 
breast cancer. After completion of ACE-011/placebo treatment, patients will return to the site 
monthly for 3 follow-up assessments (i.e., Days 99, 113 and 141).  Subsequently, the patient will 
return to the site for 4 post treatment follow-up assessments (i.e. Days 169, 197, 225, and 253). 
The patient will return to the site for a termination visit approximately 1 month after the post 
treatment follow-up period (Day 281).  Patients will be discontinued from the ACE-011/placebo 
treatment for reasons listed in section 8.3 of the protocol, for unacceptable toxicity, if the 
chemotherapy regimen is discontinued or for disease progression that requires the initiation of 
another chemotherapy treatment. 
9.5.2.1. 
ACE-011 Treatment Related Toxicity  
Patients with grade ≥3 toxicity related to ACE-011 will be discontinued from ACE-011/placebo 
treatment except for the following.  Patients with grade 3 hypertension that decreases to grade 
≤ 1 within 7 days after treatment with anti-hypertensive therapy may continue on ACE-
011/placebo treatment.  Dose reduction rules will apply at the subsequent scheduled dosing 
day(s).  
Patients with a hemoglobin level above the upper limit of normal at any time during the study 
after Day 1 will be discontinued.  Patients who discontinue treatment with ACE-011/placebo will 
enter the treatment follow-up period. 
9.5.2.2. 
ACE-011 Dose Modification Rules 
Throughout the study blood pressure and hemoglobin values will be evaluated for patient safety. 
The local hemoglobin values and blood pressure values will be evaluated at each study visit and 
on each ACE-011/placebo dosing day.  The hemoglobin values from the previous 28 days 
between each ACE-011/placebo dosing day and blood pressure will be reviewed and evaluated   
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for dose modifications.  The parameters below outline rules for dosing modifications (Figure 1).  
Table 8 outlines the dose reduction levels of ACE-011.  
 
 
 
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10. 
STUDY PROCEDURES AND SCHEDULE 
10.1.1. 
Written Informed consent 
Patients will be required to sign an Institutional Review Board/Institutional Ethics Committee 
(IRB/IEC) approved informed consent form (ICF) prior to any study related procedures, 
including screening evaluations. 
Screen failure information will be maintained, including but not limited to, reason for failure.   
10.1.2. 
Screening (Within 14 days of dosing) 
The following will be collected within 14 days prior to the initial dosing Day 1.  Confirmatory 
labs for eligibility criteria must be drawn and resulted within 7 days of Day 1.: 
• Informed consent 
• Assessment of inclusion/exclusion criteria 
• Complete Medical History and Physical Examination 
• Vital signs including weight (kg), heart rate (beats/min), seated systolic and diastolic 
blood pressure (mmHg), temperature (°C) and height. 
• FACT-Fatigue survey 
• 12 lead Electrocardiogram (ECG) performed at two time intervals (approximately one 
hour apart) in triplicate at 3 minute intervals (±1 min) 
• Serum iron, total iron binding capacity (TIBC), transferrin and serum ferritin  
• Vitamin B12 and serum folate levels 
• Coagulation 
• Serum chemistry  
• Hematology 
• LH, FSH, testosterone, progesterone, and estradiol  
• Serum Pregnancy Test for females of childbearing potential- to be assessed within 7 
days of Day 1. 
• Urinalysis 
• Evaluation of transfusion frequency (including history of transfusion up to 8 weeks 
prior to Day 1) 
• Documentation of concomitant medications (any treatments taken 28 days prior to 
Day 1) 
 
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• Females of childbearing potential- collection of menstrual cycle information of the 
start and end date of the last menstruation. 
• CT/MRI scan: Head, neck, thoracic, abdominal, and pelvic scans are to be acquired.  
A CT/MRI scan acquired within 4 weeks of initiating the current chemotherapy 
regimen may be used for the screening assessment. One measurable or non-
measurable lesion per RECIST is to be identified by the scan.  
o Brain (head) CT only to be done to rule out CNS metastases in patients with 
suspicious clinical symptoms or prior history of CNS metastases.  
• Dual-energy X-ray absorptiometry (DXA) of  lumbar spine and hip 
• Bone scans (only for patients with bone metastases) acquired within 4 weeks of 
initiating the current chemotherapy regimen may be used for the screening 
assessment. 
10.1.3. 
Initial Dosing: Day 1  
Patients will be dosed on Day 1.  Results from screening evaluations must be reviewed prior to 
randomization to confirm patient eligibility.  A patient will be considered randomized once a 
multi-digit patient identification number has been assigned to the patient through the 
IVRS/IWRS.  After assignment of the patient identification number and the inclusion/exclusion 
criteria have been met, ACE-011/placebo administration may begin. 
Chemotherapy regimen will be administered per standard of care at the site. The following tests 
must be performed prior to ACE-011/placebo administration: 
• Confirm eligibility of patient by inclusion/exclusion criteria. The local hemoglobin 
value should be drawn prior to ACE-011/placebo administration.  
• Physical Examination 
• Vital signs including weight (kg), heart rate (beats/min), seated systolic and diastolic 
blood pressure (mmHg), and temperature (°C)  
• FACT-Fatigue survey 
• 12 lead Electrocardiogram (ECG) performed at two time intervals (approximately one 
hour apart) in triplicate at 3 minute interval (±1 min) 
• Serum iron, total iron binding capacity, transferrin and serum ferritin 
• Coagulation 
• Chemistry   
• Hematology 
• Serum erythropoietin marker  
 
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• LH, FSH, testosterone, progesterone, and estradiol  
• Anti-drug antibody test 
• Bone biomarkers- osteocalcin (OC), procollagen type 1 N-terminal propeptide 
(P1NP), serum bone specific alkaline phosphatase (BSAP), C-terminal type 1 
collagen telopeptide (CTX), tartrate-resistant acid phosphatase isoform-5b (TRACP-
5b), and urine N-telopeptide (uNTX).  
o Please refer to the Study Reference Guide, provided under separate cover, for 
the Bone Biomarker Collection and Handling Guidelines for instructions the 
on collection of serum and urine for the biomarkers.  
• Back-up blood sample to be drawn for future testing 
• Females of childbearing potential- Urine (dipstick) pregnancy test to be collected and 
resulted prior to ACE-011/placebo dosing 
• Urinalysis 
• Evaluation of transfusion frequency  
• Documentation of concomitant medications  
• Evaluation of adverse events (after ACE-011/placebo administration)  
• Females of childbearing potential-collection of menstrual cycle information of the 
start and end date of the last menstruation. 
• Patients will be administered ACE-011/placebo before the chemotherapy regimen 
begins during the study visits.  
After ACE-011/placebo and chemotherapy are administered, the patient may leave the clinic, 
based on the clinical judgment of the staff.   
10.1.4. 
ACE-011/placebo administration: Days 29, 57, and 85 (± 3 days)  
Chemotherapy regimen will be administered per standard of care at the site. ACE-011/placebo 
will be administered approximately every 28 days. The following procedures must be performed 
prior to ACE-011/placebo administration: 
• Physical Examination 
• Vital signs including weight (kg), heart rate (beats/min), seated systolic and diastolic 
blood pressure (mmHg), and temperature (°C)  
• FACT-Fatigue survey 
• Serum iron, total iron binding capacity, transferrin and serum ferritin  
• Coagulation 
• Serum chemistry  
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• Hematology 
• Serum erythropoietin marker  
• LH, FSH, testosterone, progesterone, and estradiol 
• Anti-drug antibody test 
• Bone biomarkers- OC, BSAP, P1NP, CTX, TRACP-5b, and uNTX 
o Please refer to the Study Reference Guide, provided under separate cover, for 
the Bone Biomarker Collection and Handling Guidelines for instructions the 
collection of serum and urine for the biomarkers.  
• Back-up blood sample to be drawn for future testing 
• Females of childbearing potential -Urine (dipstick) pregnancy test to be collected and 
resulted prior to ACE-011/placebo dosing 
• Urinalysis (Day 85 only) 
• Evaluation of transfusion frequency  
• Documentation of concomitant medications  
• Evaluation of adverse events  
• Females of childbearing potential- collection of menstrual cycle information of the 
start and end date of the last menstruation. 
Hemoglobin (HgB) and blood pressure (BP) measurement must be assessed prior to ACE-
011/placebo dose administration by review of local laboratory values.  
10.1.5. 
Additional visits during Treatment Period: Days 8, 15, 22, 36 (± 1 day), 43, 64 
and 71 (± 2 days) 
 
Chemotherapy regimen will be administered per standard of care at the site.  The following 
procedures are to be performed during the study visit:  
• Vital signs including weight (kg), heart rate (beats/min), seated systolic and diastolic 
blood pressure (mmHg), and temperature (°C)  
• 12 lead ECG (Days 8, 36, and 64 only- to be done in triplicate at 3 minute intervals 
(±1 min) 
• Serum folate (Day 36 only) 
• Coagulation 
• Serum chemistry  
 
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• Hematology  
• Back-up blood sample to be drawn for future testing 
• Evaluation of transfusion frequency  
• Documentation of concomitant medications 
• Evaluation of adverse events  
• CT/MRI scan (Day 64 only, +/- 5 day window).  Same modality as acquired for 
baseline should be used for follow up scans. Tumor response assessments to be 
evaluated by the investigator. 
• Bone scan (Day 64 only, +/- 5 day window). Follow-up scan to be acquired if 
performed at baseline. 
If patient terminates the treatment period early, prior to the Day 85 of ACE-011/placebo, the 
patient will enter the treatment period follow up. However, if patient terminates ACE-
011/placebo early and begins a new chemotherapy regimen, the patient should complete the Day 
281/Termination visit procedures and be followed for survival only. 
10.1.6. 
Treatment Period Follow-up visits : Days 99, 113 (± 3 days)  and 141 (± 7 days) 
Chemotherapy regimen will be administered per standard of care at the site.  The following 
procedures are to be performed during the study visit: 
• Physical Examination (Days 113 and 141 only) 
• Vital signs including weight (kg), heart rate (beats/min), seated systolic and diastolic 
blood pressure (mmHg), and temperature (°C)  
• 12 lead ECG-including (Day 113 only- to be done in triplicate at 3 minute intervals 
(±1 min) 
• Serum folate (Day 113 only) 
• Coagulation  
• Serum chemistry  
• Hematology   
• Serum erythropoietin marker  (Day 141 only) 
• LH, FSH, testosterone, progesterone, and estradiol (Days 113 and 141 only) 
• Anti-drug antibody test (Days 113 and 141 only) 
 
 
 
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• Bone biomarkers- OC, BSAP, P1NP, CTX, TRACP-5b, and uNTX (Days 113 and 
141 only) 
o Please refer to the Study Reference Guide, provided under separate cover, for 
the Bone Biomarker Collection and Handling Guidelines for instructions on  
the collection of serum and urine for the biomarkers. 
• Back-up blood sample to be drawn for future testing 
• Evaluation of transfusion frequency  
• Documentation of concomitant medications 
• Evaluation of adverse events  
• Females of childbearing potential- collection of menstrual cycle information of the 
start and end date of the last menstruation. (Days 113 and 141 only) 
• CT/MRI scan (Day 113 only, +/- 5 day window). Same modality as acquired for 
baseline should be used for follow up scans. Tumor response assessments to be 
evaluated by the investigator. 
• DXA of  lumbar spine and hip (Day 113 only) 
• Bone scan (Day 113 only, +/- 5 day window). Follow-up scan to be acquired if 
performed at baseline. 
10.1.7. 
Post Treatment Period Follow-up visits : Days 169, 197, 225, and 253 (± 7 days) 
If a CT/MRI and bone scan (if applicable) is performed as per standard of care during the post 
treatment period follow up, results may be collected within the CRF to capture the status of the 
disease. Chemotherapy regimen will be administered per standard of care at the site. The 
following procedures are to be performed during the study visit: 
• Hematology 
• Evaluation of transfusion frequency  
• Documentation of concomitant medications ( up to 90 days from the last dose of 
ACE-011/placebo) 
• Evaluation of adverse events  ( up to 90 days from the last dose of ACE-011/placebo) 
10.1.8. 
Termination Visit:  Day 281 (± 7 days) 
Day 281 is the final visit.  If a patient terminates the study early, the Day 281 procedures should 
be followed. Chemotherapy regimen will be administered per standard of care at the site. The 
following procedures are to be performed during the study visit: 
 
 
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• Physical Examination 
• Vital signs including weight (kg), heart rate (beats/min), seated systolic and diastolic 
blood pressure (mmHg), and temperature (°C)  
• FACT-Fatigue survey 
• 12 lead ECG (in triplicate at 3 minute intervals (±1 min) 
• Serum iron, total iron binding capacity, transferrin and serum ferritin  
• Serum folate 
• Coagulation 
• Serum chemistry  
• Hematology  
• Serum erythropoietin marker 
• Anti-drug antibody test 
• Bone biomarkers- OC, BSAP, P1NP, CTX, TRACP-5b, and uNTX  
o Please refer to the Study Reference Guide, provided under separate cover, for 
the Bone Biomarker Collection and Handling Guidelines for instructions on 
the collection of serum and urine for the biomarkers. 
• Back-up blood sample to be drawn for future testing 
• Females of childbearing potential -Urine (dipstick) pregnancy test  
• Urinalysis 
• Evaluation of transfusion frequency  
• Documentation of concomitant medications ( up to 90 days from the last dose of 
ACE-011/placebo) 
• Evaluation of adverse events ( up to 90 days from the last dose of ACE-011/placebo) 
• DXA of  lumbar spine and hip 
• Bone scan (Day 281, +/- 5 day window). Follow-up scan to be acquired if performed 
at baseline. 
If a patient has a positive anti-drug antibody result at Day 281/Termination visit, the patient may 
be asked to return to the clinical site for additional monthly anti-drug antibody testing, up to 12 
months after their last dose. 
 
 
 
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10.2. 
Discontinuation of study 
The Sponsor may terminate this study, after consultation with the Investigator, at any time for 
safety or administrative reasons.  The Sponsor may terminate the study if the occurrence of 
serious adverse events (SAEs) or other findings suggest unacceptable risk to the health of the 
patients.   
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11. 
INVESTIGATIONAL PRODUCT MATERIALS AND 
MANAGEMENT 
11.1. 
Reference Product 
The placebo (control agent) to be used in this study will be sterile normal saline (0.9% Sodium 
Chloride for Injection) administered as a SC injection.  Sterile, normal saline will be supplied by  
the investigational site’s pharmacy.  The manufacturer’s directions for placebo storage and 
handling are to be followed, as are standard clinical practices for ensuring sterility of the 
placebo. 
11.2. 
Investigational Product Packaging and Labeling 
ACE-011 will be supplied in 2 mL clear glass vials with gray stoppers and red flip-top seals that 
contain 1 mL of ACE-011.  The drug product consists of ACE-011 in PBS at a nominal 
concentration of approximately 50 mg/mL. 
11.3. 
Investigational Product Storage 
ACE-011 is recommended to be stored at ≤ -65°C. 
11.4. 
Investigational Product Preparation 
See Investigational Product Preparation Manual. 
11.5. 
Administration 
ACE-011/placebo will be administered by subcutaneous injection (SC). Subcutaneous injections 
will be given in the upper arm and/or thigh. Please refer to Investigational Product Handling and 
Administration document for further information. 
Dose modifications will be determined by the investigator after reference to the dose 
modification rules listed in Figure 1. In the case of a dose interruption or dose reduction of ACE-
011, the investigator or designee will notify the pharmacy staff, who is unblinded, of the 
treatment decision for appropriate preparation of the study drug to maintain the blind of the 
study.  
11.6. 
Drug Accountability 
Accountability for ACE-011/placebo is the responsibility of the Investigator.  Investigational 
clinical supplies must be received by a designated person at the clinical site and kept in a secured 
location.  The investigational site must maintain accurate records demonstrating dates and 
amounts of ACE-011/placebo received, to whom it was dispensed (patient-by-patient 
accounting), and accounts of any ACE-011/placebo accidentally or deliberately destroyed or 
returned.  Unless otherwise notified, all vials of ACE-011/placebo, both used and unused, must 
be saved for drug accountability.  The used vials may be discarded, per the institution’s standard  
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practice, after drug accountability has been completed by the monitor. The Investigator must 
return all unused vials of ACE-011 to the Sponsor at the end of the study, or the ACE-011 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. 
11.7. 
Investigational Product Handling and Disposal 
Please refer to the Study Reference Guide, provided under separate cover, for detailed drug 
handling, administration, and storage instructions.   
 
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12. 
ASSESSMENT OF EFFICACY 
Efficacy measurements will include assessments for hematopoietic response which is defined as 
an increase in hemoglobin of ≥ 0.5 g/dL, ≥ 1 g/dL, ≥ 2 g/dL and/or hemoglobin concentration ≥ 
11 g/dL above the study baseline value for 28 consecutive days during the treatment period 
including up to 2 months after the last dose of ACE-011, in the absence of any RBC transfusions 
and/or ESAs, at each dose level. The hematopoietic endpoints will be determined by the 
monitoring of hematologic laboratory values and RBC transfusion and/or ESA administration. 
Secondary endpoints associated with assessment of disease progression will be evaluated by 
CT/MRI scan and bone mineral density by DXA scans, respectively. Bone biomarkers and 
incidence of skeletal related events (SREs) will also be evaluated for all patients. SREs are 
defined as pathologic fracture, radiation therapy to bone, surgery to bone, or spinal cord 
compression. Quality of life assessment (FACT-Fatigue) will be evaluated for each patient.  
 
 
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13. 
ASSESSMENT OF SAFETY 
13.1. 
Safety Parameters 
13.1.1. 
Adverse Events 
All patients will be assessed for safety by monitoring adverse events, clinical laboratory tests, 
vital signs and physical examinations. AE information will be collected throughout the study. 
See Section 14 Adverse Events for a full description of AE definitions, AE and SAE reporting 
procedures, and emergency procedures. 
13.1.2. 
Clinical Laboratory Tests 
The following laboratory safety assessments will be drawn at the investigational site’s local 
laboratory according to the laboratory collection recommendations. The samples will then be 
sent to the central lab for value reporting. Please refer to Lab Reference Manual for further 
information. Hemoglobin and hematocrit lab tests will be drawn and evaluated by the local 
laboratory at screening and at each visit day throughout the study. The local hemoglobin 
laboratory value will be used in the evaluation of ACE-011/placebo dose modifications. The 
sponsor may request additional safety tests be performed based on ongoing data review during 
the study.  
• Iron studies: Serum iron, total iron binding capacity (TIBC), transferrin and serum ferritin on  
 
specified days. 
• 
Nutritional tests: Serum folate and vitamin B12 
• 
Coagulation (central lab only): prothrombin time (PT), partial thromboplastin time (PTT), 
and fibrinogen 
• 
Serum chemistry (central lab only): AST, ALT, lactate dehydrogenase (LDH), total bilirubin, 
indirect bilirubin, alkaline phosphatase, total protein, albumin, sodium, potassium, chloride, 
carbon dioxide, calcium, phosphorus, blood urea nitrogen (BUN), creatinine, uric acid, 
glucose, amylase, and lipase.  
• 
Hematology: complete blood count (CBC) with differential and platelet.  CBC includes red 
blood cells (RBC), white blood cells (WBC), hemoglobin, hematocrit, mean corpuscular 
volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin 
concentration (MCHC).  Reticulocyte percent, erythropoietin levels and peripheral blood 
smear will be collected on specified days.  
• 
Bone biomarkers: (serum) osteocalcin (OC), procollagen type 1 N-terminal propeptide 
(P1NP), serum bone specific alkaline phosphatase (BSAP), C-terminal type 1 collagen 
telopeptide (CTX), tartrate-resistant acid phosphatase isoform-5b (TRACP-5b), and urine N-
telopeptide (uNTX).  
• 
Pregnancy test for females of child bearing potential 
 
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• Urinalysis (central lab only): including determination of pH, specific gravity, protein, 
glucose, ketones, blood, leukocyte esterase and nitrite. Microscopy required only to follow-
up abnormal findings.  
13.1.3. 
Other Safety Assessments  
• Physical examinations 
• Vital signs: weight (kg), heart rate (beats/min), seated blood pressure (mmHg) and  
temperature (°C).  Height will be collected at screening only. 
• FACT-Fatigue survey 
• 12-lead ECG (done in triplicate) 
• LH, FSH, testosterone, progesterone, and estradiol 
• Anti-drug antibody test 
• CT/MRI scan   
• DXA 
• Bone scans (for those patients with baseline bone metastases) 
13.2. 
Pharmacokinetics 
 See Appendix 5 for further details regarding PK sampling.  
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14. 
ADVERSE EVENT 
Adverse Event 
An adverse event (AE) is any untoward medical occurrence in a patient administered a 
pharmaceutical product, which does not necessarily have a causal relationship with the treatment.  
An AE can be any unfavorable and unintended sign (e.g., including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of the study drug, whether or 
not it is considered to be study drug related.  This includes any newly occurring event or 
previous condition that has increased in severity or frequency since the administration of study 
drug (treatment-emergent). 
Serious Adverse Event 
A serious adverse event (SAE) is any AE, occurring at any dose level and regardless of causality 
that: 
• Results in death. 
• Is life-threatening:  Life-threatening means that the patient was at immediate risk of death 
from the reaction as it occurred, (i.e., it does not include a reaction which hypothetically 
might have caused death had it occurred in a more severe form). 
• Requires inpatient hospitalization or prolongation of existing hospitalization.  
• Results in persistent or significant disability/incapacity. 
• Is a congenital anomaly/birth defect. 
• Is an important medical event: an important medical event is an event that may not result 
in death, be life-threatening, or require hospitalization but may be considered an SAE 
when, based upon appropriate medical judgment, it may jeopardize the patient and may 
require medical or surgical intervention to prevent one of the outcomes listed in the 
definitions for SAEs.  Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, blood dyscrasias or 
convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse.   
• A hospitalization for an elective procedure will not be considered a SAE.  
SAEs will be captured throughout the patient participation in the study through Day 
281/Termination visit. SAEs will be captured up to 90 days from the last dose of ACE-
011/placebo for those patients who are followed for survival only. 
Unexpected Adverse Event 
An unexpected AE is an AE that is not reported in the Investigator Brochure or in the case of an 
AE already described, the severity of which is not described in the Investigator Brochure.  
 
 
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14.1. 
Adverse Event Classification 
The following classifications should be used when evaluating the relationship of AEs and SAEs 
to the investigational drug (study drug). 
None: 
No relationship between the experience and the administration of study 
drug; related to other etiologies such as concomitant medications or 
patient’s clinical state. 
Unlikely:  
 
 
The current state of knowledge indicates that a relationship is unlikely.   
Possibly: 
A reaction that follows a plausible temporal sequence from administration 
of the study drug and follows a known response pattern to the suspected 
study drug.  The reaction might have been produced by the patient’s 
clinical state or other modes of therapy administered to the patient. 
Probably: 
A reaction that follows a plausible temporal sequence from administration 
of the study drug and follows a known response pattern to the suspected 
study drug.  The reaction cannot be reasonably explained by the known 
characteristics of the patient’s clinical state or other modes of therapy 
administered to the patient. 
Definitely: 
A reaction that follows a plausible temporal sequence from administration 
of the study drug and follows a known response pattern to the suspected 
study drug and can be confirmed with a positive re-challenge test or 
supporting laboratory data. 
Severity of AEs will be graded by the investigator using the National Cancer Institute (NCI; US) 
Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 guidelines (Appendix 
3). 
14.2. 
Recording Adverse Events 
Patients will be evaluated and questioned generally for AEs during the course of the study, 
starting from baseline (Day 1).  The Medical History CRF should be comprehensive of patient’s 
medical history up to Day 1. All AEs occurring after ACE-011/placebo administration up to 90 
days from the last dose of ACE-011/placebo are to be documented on AE CRF. The specific 
disease or syndrome rather than individual associated signs and symptoms should be identified 
by the investigator and recorded on the CRF.  
Skeletal related event information is to be captured and reported for the duration of the patient 
participation in the study through Day 281/Terminiation visit. SREs will be captured up to 90 
days from the last dose of ACE-011/placebo for those patients who are followed for survival 
only. 
 
 
 
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Serious Adverse Events (SAEs) 
For SAEs, a SAE form must be completed with as much information as possible and submitted 
in the time frame described in Section 14.3.  
When new significant information is obtained as well as when the outcome of an event is known, 
the investigator should record the information on a new SAE form.  If the patient was 
hospitalized, a copy of the discharge summary must be included as part of the patient medical 
file.  In all instances, the investigator should follow up with patients until the outcome of the 
SAE is known. 
14.3. 
Reporting Adverse Events 
All AEs spontaneously reported by the patient and/or in response to an open question from study 
personnel or revealed by observation, physical examination or other diagnostic procedures will 
be recorded on the AE CRF.  Any clinically relevant change in laboratory assessments or other 
clinical findings is considered an AE and must be recorded on the AE CRF. Clinically significant 
laboratory abnormalities are those that are identified as such by the investigator and/or those that 
require intervention. All AEs are to be followed until the event resolves or the clinical course is 
stabilized.  
Serious Adverse Events 
For SAEs, a SAE form must be completed with as much information as possible and submitted 
in the time frame described below. 
All SAEs that occur during the course of the study (from the signing of the ICF and throughout 
patient participation in the study procedures) must be reported by the Investigator to PPD and 
Sponsor by faxing the SAE form within 24 hours from the point in time when the Investigator 
becomes aware of the SAE.  All SAEs and deaths must be reported whether or not considered 
causally related to the study drug.   
SAE Reporting: 
PPD Medical Monitor 
PPD Inc. 
If there are serious, unexpected AEs associated with the use of the study drug, the Sponsor will 
notify the appropriate regulatory agency(ies) and all appropriate parties on an expedited basis.  It 
is the responsibility of the Investigator to promptly notify the Institutional Review Board (IRB) 
of all unexpected SAEs involving risk to human patients. 
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14.4. 
Emergency Sponsor Contact 
In the event of a medical emergency (i.e., an event that requires immediate attention regarding 
the treatment of a patient, operation of the clinical study, and/or the use of investigational drug), 
investigational site personnel must immediately contact the Medical Monitor. 
 
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15. 
STATISTICS 
Statistics Analysis Overview 
The study will be considered complete with regard to the primary endpoint once all eligible 
subjects have completed up to 2 months after the last dose of ACE-011. Patients will be 
randomized to one of three ACE-011 treatment groups (0.1, 0.3 and 0.5 mg/kg) or placebo with a 
ratio of 2:2:2:1.  Patients will be stratified according to administration of either single agent 
weekly chemotherapy or less frequent chemotherapy regimens.  
15.1. 
Determination of Sample Size 
With an anticipated dropout rate of 20%, a sample size of 30 patients per dose level is estimated 
to achieve at least 80% power with 2 sided significance level of 0.05 to differentiate targeted 
response rate of p1=0.45 from null hypothesis p0=0.20. An additional 15 patients will be 
enrolled to the placebo group for safety comparison. A total of 105 patients will be randomized 
to three ACE-011 dose groups (0.1, 0.3, and 0.5 mg/kg) and placebo with a ratio of 2:2:2:1.  
15.2. 
Analysis Populations 
For this study, the following populations will be defined and used in the analysis and 
presentation of the data. 
Modified Intent-to-Treat (MITT) population: The MITT population is defined as all patients 
randomized who received at least one dose of ACE-011/placebo. 
Per-Protocol (PP) population: The PP population is defined as all patients randomized who have 
confirmed chemotherapy induced anemia, received at least one dose of ACE-011 and on study 
(treatment) for at least 2 months (57 days). 
Safety population: The safety population is defined as all patients who received at least one dose 
of ACE-011 or placebo. 
15.3. 
Background and Demographic Characteristics 
Summary statistics (mean, standard deviation, median, minimum and maximum) will be 
provided for those variables measured on a continuous scale.  The frequency distribution 
(number and percentage) will be provided for those variables measured on a nominal scale. 
15.3.1. 
Patient Disposition 
Patient disposition (analysis population allocation, entered, discontinued, along with primary 
reason for discontinuation) will be summarized using frequency and percent for each dose group.  
A summary of patients enrolled by site will be provided.  
 
 
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15.3.2. 
ACE-011 
ACE-011 treatment exposure (total dosage received) will be summarized for each dose group as 
well as for each cycle for each dose level.  Listings for dose adjustment will be provided. 
15.3.3. 
Concomitant Therapy 
By-patient listings will be provided for all concomitant medications and therapies taken during 
the study.  All concomitant medications will be coded and categorized by the WHO drug coding 
system.  Usage frequency of each coded concomitant medications will be summarized by each 
dose group. 
15.4. 
Efficacy Evaluation 
15.4.1. 
Primary Efficacy Analysis 
The primary efficacy endpoint is the hematopoietic response rate at each dose level.  It is defined 
as the proportion of patients who have a hematopoietic response of an increase in hemoglobin of 
≥ 0.5 g/dL for 28 consecutive days during the treatment period including up to 2 months after the 
last dose of ACE-011, in the absence of any RBC transfusions and/or ESAs. The ACE-011 
treatment period is defined as from the time of first ACE-011 dose to up to 2 months after the 
last dose of ACE-011 treatment.  To be considered as a responder, all hemoglobin measurements 
during a 28 consecutive day period or longer must have an increase of ≥ 0.5 g/dL from baseline. 
If RBC transfusions and/or ESAs are required, no hemoglobin measurements within 28 days will 
be used to determine the hemoglobin response. Primary efficacy analysis will be based on PP 
population.  Primary efficacy analysis will also be conducted on MITT population as supportive 
to the PP based analysis.  Patients who do not receive ACE-011 will be excluded from primary 
efficacy analysis.  Patients who discontinue the ACE-011 treatment prematurely will be counted 
as non-responder in the calculation of response rate.     
A 95% confidence interval (CI) for the response rate for each dose level will be provided to 
assess whether 95% CI of response rate contains null hypothesis response rate, p0=0.20.  The 
response rate and 95% CI will also be provided for patients with chemotherapy on weekly basis 
versus those with chemotherapy on a less frequent basis for each dose level as well as overall (all 
three doses levels analyzed together).  
An exploratory analysis with the Kaplan Meier approach will be considered to account for those 
patients who discontinue the ACE-011 treatment prematurely if the drop out rate is greater than 
20%.  Exploratory analysis of comparing hematopoietic response rates between active and 
placebo will be performed using Fisher’s exact test.  Due to the nature of the study (phase 2 dose 
determination study), no multiplicity adjustment will made for the multiple comparisons.  
 
 
 
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15.4.2. 
Secondary Efficacy Analyses 
The secondary efficacy endpoints include: 
• Proportion of patients achieving an increase in hemoglobin of ≥ 1 g/dL, ≥ 2 g/dL and/or 
hemoglobin concentration ≥ 11 g/dL for 28 consecutive days during the treatment period 
and up to 2 months after the last dose of ACE-011 in the absence of any RBC 
transfusions and/or ESAs.   
• Duration of hematopoietic response (days) defined as the first time hemoglobin increases 
at least 0.5 g/dL, ≥ 1 g/dL, ≥ 2 g/dL and/or hemoglobin concentration ≥ 11 g/dL from 
baseline to the last time there is hemoglobin ≥ 0.5 g/dL, ≥ 1 g/dL, ≥ 2 g/dL and/or 
hemoglobin concentration ≥ 11 g/dL increase from baseline.  Duration of response is only 
calculated for a responder and will be at least 28 days.  The duration of response will be 
at least 28 days is only calculated for a patient who meets the primary efficacy endpoint.  
• Time to achieve hematopoietic response (days) defined as time from first dose of ACE-
011 to the first time a hemoglobin result at least 0.5 g/dL, ≥ 1 g/dL, ≥ 2 g/dL and/or 
hemoglobin concentration ≥ 11 g/dL increase from baseline and maintained for a period 
of at least 28 consecutive days. 
• Proportion of patients receiving red blood cell (RBC) transfusions and/or ESAs in each 
dose group as well as within each cycle of each ACE-011 dose level. 
• Objective tumor response rate for each dose level using RECIST criteria. 
• Progression-Free Survival is defined as the time from randomization into the study to the 
first observation of documented disease progression or death due to any cause.  If the 
subject has not progressed or died at the time of final analysis, PFS will be censored at 
the time of last tumor assessment.   
The statistical analysis for binary endpoints will be similar to the primary efficacy analysis.  For 
time to event endpoints, the Kaplan-Meier method will be used to estimate the survival curve and 
median time to event.  These analyses will be performed for each dose group and all ACE-011 
groups combined.   
15.5. 
Safety Evaluation 
Safety variables will be tabulated and presented for all patients who receive ACE-011.  Adverse 
events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA).  
Incidence of treatment-emergent adverse events will be presented by system organ class (SOC) 
and preferred term.  Adverse events will also be presented by severity, and relationship to study 
drug.  Change from baseline in clinical laboratory parameters and vital signs will be summarized 
across time.  Shift tables will be presented for selected laboratory parameters.  Physical 
examination results will be presented in listings.  
 
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Data from all patients who receive one or more doses of ACE-011/placebo will be included in 
the safety analyses. To assess clinical safety, adverse events, vital sign measurements and 
clinical laboratory information will be summarized by visit. Adverse events and laboratory 
results will also be summarized by severity grade (NCI CTCAE v3.0). Descriptive statistics will 
be generated and shift tables provided as appropriate.  
15.6. 
Pharmacokinetic Evaluation 
Listing of individual patient serum ACE-011 concentrations, actual blood sampling times and 
graphs of concentration vs. time will be prepared for each dose group.  Summaries of PK 
parameters will be summarized by dose group. The trough concentrations will be summarized for 
all patients who provide pharmacokinetic samples by dose group. Exploratory analyses will be 
performed to correlate trough concentrations with efficacy, bone biomarker data, and safety data, 
however these analyses will be data-driven and only conducted if warranted by the data.  
15.6.1. 
Anti-drug Antibody Data 
The results of anti-drug and neutralizing antibodies will be presented over time.  Exploratory 
analysis will be performed on the potential effect of anti-drug antibody on ACE-011 PK and 
drug exposure if anti-drug antibody tests are deemed positive. 
15.7. 
Interim Analysis  
There is no planned interim analysis for this study.   
15.8. 
Deviation from Original Analysis Plan 
Deviations from the statistical analyses outlined in this protocol will be indicated in the statistical 
analysis plan; any further modifications will be noted in the final clinical study report. 
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16. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
16.1. 
Study Monitoring 
The Clinical Monitor will arrange to visit the Investigator sites at regular intervals during the 
study.  The monitoring visits must be conducted according to the applicable ICH and GCP 
guidelines to ensure protocol adherence, quality of data, drug accountability, compliance with 
regulatory requirements, and continued adequacy of the investigational site and its facilities.  
During these visits, CRFs and other data related to the study will be reviewed and any 
discrepancies or omissions will be resolved.  The Clinical Monitor will be given access to study 
relevant source documents (including medical records) for purposes of source data verification. 
During and/or after completion of the study, quality assurance officers named by the Sponsor or 
the regulatory authorities may wish to perform on-site audits.  The Investigator is expected to 
cooperate with any audit and provide assistance and documentation (including source data) as 
requested. 
16.2. 
Audits and Inspections 
The Investigators and clinical sites will permit trial related monitoring, audits, IRB review, and 
regulatory inspections as requested by FDA, the Sponsor or designee, including direct access to 
source data/documents (i.e., original medical records, laboratory reports, hospital documents, 
progress reports, signed ICFs, etc.) in addition to CRFs. 
 
 
 
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17. 
QUALITY CONTROL AND QUALITY ASSURANCE 
17.1. 
Data Quality Control and Quality Assurance 
17.1.1. 
Investigator responsibility 
The investigator is responsible for ensuring the study is conducted according to the protocol, 
Code of Federal Regulations (CFR), GCP, and any other applicable regulatory requirements. The 
investigator responsibilities are outlined in these documents along with ensuring that 
documentation of a signed informed consent, is obtained prior to patient participation in the 
study.  
17.1.2. 
Protocol modifications 
The investigator may not modify the protocol without agreement from the Sponsor and prior 
review or approval by the IRB. Any deviations from the protocol should be documented by the 
investigator or designee.  
17.2. 
Financing and Insurance 
Financing and insurance are addressed in a separate document. 
17.3. 
Confidentiality 
To maintain patient privacy, all CRFs, study drug accountability records, study reports and 
communications will identify the patient by the assigned patient identification number.  The 
Investigator will grant monitor(s) and auditor(s) from the Sponsor or designee and regulatory 
authority(ies) access to the patient’s original medical records for verification of data gathered on 
the CRFs and to audit the data collection process.  The patient’s confidentiality will be 
maintained and will not be made publicly available to the extent permitted by the applicable laws 
and regulations. 
All information regarding the investigational product supplied by the Sponsor to the Investigator 
is privileged and confidential information.  The Investigator agrees to use this information to 
accomplish the study and will not use it for other purposes without consent from the Sponsor.  It 
is understood that there is an obligation to provide the Sponsor with complete data obtained 
during the study.  The information obtained from the clinical study will be used towards the 
development of the investigational product and may be disclosed to regulatory authority(ies), 
other Investigators, corporate partners, or consultants as required. 
17.4. 
Publication Policy 
All information concerning ACE-011 is considered confidential and shall remain the sole 
property of the Sponsor.  The Investigator agrees to use this information only in conducting the 
study and shall not use it for any other purposes without the Sponsor’s written approval.  The 
Investigator agrees not to disclose the Sponsor’s confidential information to anyone except to  
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people involved in the study that need such information to assist in conducting the study, and 
then only on like terms of confidentiality and nonuse. 
It is understood by the Investigator that the information developed from this clinical study will 
be used by the Sponsor in connection with the development of ACE-011, and therefore may be 
disclosed as required to regulatory agencies.  To allow for the use of the information derived 
from clinical studies, it is understood that there is an obligation to provide the Sponsor with 
complete test results and all data developed in the study. 
No publication or disclosure of study results will be permitted except as specified in a separate, 
written, agreement between the Sponsor and the Investigator. 
17.5. 
Protocol Amendments 
Protocol amendments that impact patient safety change the scope of the investigation, or affect 
the scientific quality of the study must be approved by the IRB and submitted to the appropriate 
regulatory authorities before implementation of such modifications to the study. 
In the event that the protocol needs to be modified immediately to eliminate an apparent hazard 
to a patient, the Sponsor will amend and implement the protocol change and subsequently notify 
the regulatory authorities and/or the IRB, as appropriate. 
 
 
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18. 
ETHICS 
18.1. 
Institutional Review Board or Independent Ethics Committee 
The Investigator must obtain written IRB approval of the protocol, approval for relevant 
supporting information and all types of patient recruitment and advertisement and ICF prior to 
starting the study.  The IRB will meet all Food and Drug Administration (FDA) requirements 
governing IRBs (Code of Federal Regulations, Title 21, Part 56). 
The Sponsor or designee must approve the ICF submitted to the investigational site’s IRB. All 
patient recruitment and advertisements must be submitted to the Sponsor or designee prior to 
submission to the IRB, for review. 
18.2. 
Ethical Conduct of the Study 
The Sponsor and the Investigator must comply with all instructions, regulations, and agreements 
in this protocol and in the applicable International Conference on Harmonisation (ICH) and GCP 
guidelines, and must also conduct the study in accordance with local regulations.   
18.3. 
Written Informed Consent 
18.3.1. 
Informed Consent 
Informed written consent is required from each patient prior to any testing under this protocol, 
including screening tests and evaluations.  The consent form, as specified by the clinical site’s 
IRB, must follow the Protection of Human Patients regulations listed in the Code of Federal 
Regulations, Title 21, Part 50.   
The background of the proposed study and the benefits and risks of the procedures and study 
must be explained to the patients.  It is the responsibility of the Investigator to obtain consent and 
to provide the patient with a copy of the signed and dated ICF.  Confirmation of a patient’s 
informed consent must also be documented in the patient’s medical record prior to any testing 
under this protocol, including screening tests and evaluations. 
All ICFs used in this study must be approved by the appropriate IRB and by the Sponsor or 
designee.  The ICF must not be altered without the prior agreement of the relevant IRB and the 
Sponsor.   
18.3.2. 
Patient Data Protection 
Prior to any testing under this protocol, including screening tests and evaluations, patients must 
authorize the release and use of protected health information (PHI), as required by local law. 
The patient will not be identified by name in the CRF or in any study reports.  These reports will 
be used for research purposes only.  The Sponsor, its designee, and various government health 
agencies may inspect the records of this study.  Every effort will be made to keep the patient’s 
personal medical data confidential. 
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19. 
DATA HANDLING AND RECORDKEEPING 
19.1. 
Case Report Form Completion 
CRFs will be completed for each randomized patient.  It is the Investigator’s responsibility to 
ensure the accuracy, completeness, and timeliness of the data reported in the patient’s CRF.  
Source documentation supporting the CRF data should indicate the patient’s participation in the 
study and should document the dates and details of study procedures, AEs, and patient status. 
Investigators will maintain copies of the CRFs at the clinical site.  For patients who discontinue 
or terminate from the study, the CRFs will be completed as much as possible, and the reason for 
the discontinuation or termination clearly and concisely specified on the appropriate CRF. 
19.2. 
Retention of Records 
The Investigator will maintain all study records according to ICH-GCP and applicable regulatory 
requirements.  Records will be retained for at least 2 years after the last marketing application 
approval or 2 years after formal discontinuation of the clinical development of the investigational 
product or according to applicable regulatory requirements.  If the Investigator withdraws from 
the responsibility of keeping the study records, custody must be transferred to a person willing to 
accept the responsibility.  The Sponsor must be notified in writing if a custodial change occurs. 
 
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20. 
REFERENCES 
 
      1.   Groopman JE, Itri LM. (1999). Chemotherapy-Induced Anemia in Adults: Incidence and  
 
   Treatment. Journal of the National Cancer Institute 91, 1616-1634.  
2. NCCN Clinical Practice Guidelines in Oncology: Cancer and Chemotherapy Induced 
Anemia, V.3. 2009 http://www.nccn.org/professionals/physician_gls/PDF/anemia.pdf; 
2008. 
3. Ying S-Y. (1988). Inhibins, activins, and follistatins: gonadal proteins modulating the 
secretion of follicle-stimulating hormone. Endocrine Rev 9, 267-93. 
4. Woodruff TK. (1998). Regulation of cellular and system function by activin. Biochem 
Pharmacol 55, 953-63. 
5. Perrien DS, Akel NS, Edwards PK, Carver AA, Bendre MS, Swain FL, Skinner RA, 
Hoque WR, Nicks KM, Pierson TM, Suva LJ, and Gaddy D. (2007). Inhibin A is an 
endocrine stimulator of bone mass and strength. Endocrinology 148, 1654-65. 
6. Rivier J, Spiess J, McClintock R, Vaughan J and Vale W. (1985). Purification and partial 
characterization of inhibin from porcine follicular fluid. Biochem Biophys Res Commun 
133, 120-7. 
7. Murata M, Onomichi K, Eto Y, Shibai H, and Muramatsu M. (1988). Expression of 
erythroid differentiation factor (EDF) in Chinese hamster ovary cells.  Biochem Biophys 
Res Commun 151, 230-5. 
8. Shiozaki M, Sakai R, Tabuchi M, Nakamura T, Sugino K, Sugino H, and Eto Y. (1992). 
Evidence for the participation of endogenous activin A/erythroid differentiation factor in 
the regulation of erythropoiesis.  Proc Natl Acad Sci USA 89, 1553-6. 
9. Shiozaki M, Sakai R, Tabuchi M, Eto Y, Kosaka M, and Shibai H. (1989). In vivo 
treatment with erythroid differentiation factor (EDF/activin A) increases erythroid 
precursors (CFU-E and BFU-E) in mice. Biochem Biophys Res Commun 165, 1155-61. 
10. Nakao K, Kosaka M and Saito S. (1991). Effects of erythroid differentiation factor (EDF) 
on proliferation and differentiation of human hematopoietic progenitors. Exp Hematol 19, 
1090-5 
11. Chen Y-G, Lui HM, Lin S-L, Lee JM, and Ying S-Y. (2002). Regulation of cell 
proliferation, apoptosis, and carcinogenesis by activin. Exp Biol Med 227, 75-87. 
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12. Mathews LS. (1994). Activin receptors and cellular signaling by the receptor serine 
kinase family. Endocr Rev 15, 310-25. 
13. Chantry A, Heath D, Mulivor A, Coulton L, Evans H, Abdul N, Werner ED, Bouxsein 
ML, Pearsall RS, Seehra J, Vanderkerken K, and Croucher PI. (2008). Inhibiting activin-
A signalling stimulates bone formation, prevents tumor-induced osteolytic bone 
destruction and blocks bone metastasis. Submitted 2008. 
14. Pearsall RS, Canalis E, Cornwall-Brady M, Underwood KW, Haigis B, Ucran J, Kumar 
R, Pobre E, Grinberg A, Werner ED, Glatt V, Stadmeyer L, Smith D, Seehra J, and 
Bouxsein ML. (2008). A soluble activin type IIA receptor induces bone formation and 
improves skeletal integrity. Proc Natl Acad Sci USA 105, 7082-7 
15. Lotinun S, Fajardo RJ, Pearsall RS, Bouxsein ML, and Baron R. (2008). A soluble 
activin receptor type IIA fusion protein, ACE-011, increases bone mass by stimulating 
bone formation and inhibiting bone resorption in cynomolgus monkeys. ASBMR 30th 
annual meeting, 2008. 
16. Ruckle J, Jacobs M, Kramer W, Pearsall AE, Kumar R, Underwood KW, Seehra J, Yang 
Y, Condon CH, Sherman ML. (2008).  A single-dose, randomized, double-blind, 
placebo-controlled study of ACE-011 (ActRIIA-IgG1) in postmenopausal women.  J 
Bone Miner Res: 1-42.  Posted online on 2 Dec 2008. 
17. Functional Assessment of Chronic Illness, FACT-Fatigue Version 4. 
http://www.facit.org/qview/qlist.aspx. 2003. 
 
 
 
 
 
 
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21. 
APPENDICES 
Appendix 1: Response Evaluation Criteria in Solid Tumors 
 
 
Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 
  
Terms 
Definition 
Measurable disease  
 The presence of at least one measurable lesion by CT or MRI. If the 
measurable disease is restricted to a solitary lesion, its neoplastic nature 
should be confirmed by cytology/histology. 
All measurements should be taken and recorded in metric notation, using a 
ruler or calipers. All baseline evaluations should be performed as closely as 
possible to the beginning of treatment and never more than 4 weeks before 
the beginning of the treatment.  
Measurable lesions 
Lesions that can be accurately measured in least one dimension by CT scan 
with longest diameter > 10 mm (CT scan thickness no greater than 5 mm). 
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during 
follow-up.  
Non-measurable lesion 
All other lesions, including small lesions (longest diameter <10mm or 
pathological lymph nodes with P10 to <15mm short axis) as well as truly 
non-measurable lesions. Lesions considered truly non-measurable include: 
leptomeningeal disease, ascites, pleural or pericardial effusion, 
inflammatory breast disease, lymphangitic involvement of skin or lung, 
abdominal masses/abdominal organomegaly identified by physical exam 
that is not measurable by reproducible imaging techniques. 
 
 
 
 
 
 
 
 
 
 
 
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RECIST Criteria-Response Evaluation 
Evaluation of target lesions 
  
  
Complete Response (CR) 
 Disappearance of all target lesions. 
Any pathological lymph nodes (whether target or non-target) 
must have reduction in short axis to <10 mm. 
Partial Response (PR): 
At least a 30% decrease in the sum of diameters of target lesions, 
taking as reference the baseline sum diameters. 
Stable Disease (SD):   
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum 
diameters while on study. 
Progressive Disease (PD):  
At least a 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest sum on study (this includes the 
baseline sum if that is the smallest on study). In addition to 
the relative increase of 20%, the sum must also demonstrate 
an absolute increase of at least 5 mm.  
(Note: the appearance of one or more new lesions is also 
considered progression). 
 
 
 
 
Evaluation of non-target 
lesions 
  
  
Complete Response (CR):  
Disappearance of all non-target lesions and normalisation of 
tumour marker level. All lymph nodes must be non-pathological 
in size (<10mm short axis). 
 
Non-CR/Non-PD 
 
Persistence of one or more non-target lesion(s) and/or 
maintenance of tumour marker level above the normal limits. 
Progressive Disease (PD):  
Unequivocal progression (see comments below) of existing non-
target lesions.  
(Note: the appearance of one or more new lesions is also 
considered progression). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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RECIST Criteria-Response 
Evaluation cont- 
 
 
 
 
 
 
Evaluation of best overall 
response 
The best overall response is the best response recorded 
from the start of the treatment until disease 
progression/recurrence (taking as reference for PD the 
smallest measurements recorded since the treatment 
started). In general, the patient's best response assignment 
will depend on the achievement of both measurement and 
confirmation criteria. 
 
Patients with a global deterioration of health status 
requiring discontinuation of treatment without objective 
evidence of disease progression at that time should be 
classified as having “symptomatic deterioration”. Every 
effort should be made to document the objective 
progression even after discontinuation of treatment.  
 
In some circumstances it may be difficult to distinguish 
residual disease from normal tissue. When the evaluation of 
complete response depends on this determination, it is 
recommended that the residual lesion be investigated (fine 
needle aspirate/biopsy) to confirm the complete response 
status.  
 
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R,  Dancey J, Arbuck S, Gwyther S, Mooney M, 
Rubinstein L, Shankar L, Dodd L, Kaplan R,  Lacombe D, Verweij J.New response evaluation criteria in solid tumours: Revised 
RECIST guideline (version 1.1)  (2009). European Journal of Cancer 45, 228-247. 
 
 
 
 
 
 
 
 
 
 
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Appendix 2: ECOG Performance Status 
The ECOG scale is used to assess a patient’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 
patient.  
 
Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., Carbone, P.P. (1982) Toxicity And Response 
Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Onco 5:649-655. 
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, e.g., 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 
 
 
 
 
 
 
 
 
 
 
 
 
 
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                                               Acceleron Pharma 
 
 
 
Appendix 3:  National Cancer Institute (NCI) Common Terminology Criteria 
for Adverse Events (CTCAE) Version 3.0 
 
See http://ctep.cancer.gov/reporting/ctc.html  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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ocol A011-08                                                                                                                                        Confidential    
evision 2.0 
 
09                                                             
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 National Heart, Lung, and Blood Institute, National Institutes of Health. New York Heart Association Classification. 2008. 
Appendix 4: New York Heart Association- Classification of heart failure 
Class 1 - Class 1 heart failure - no limitation of activities. No symptoms from ordinary activities. 
Class 2 - Class 2 heart failure- mild limitation of activity. Comfortable with rest or mild exertion. 
Class 3 - Class 3 heart failure- marked limitation of activity and be comfortable only at rest. 
Class 4 –Class 4 heart failure- complete rest, confined to bed or chair; any physical activity brings on  
discomfort and symptoms occur at rest. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Protocol A011-08                                                                                                                           Confidential                                      
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07Oct09                                                        
                                      Acceleron Pharma 
 
 
Protocol Amendment – Summary of Changes 
CLINICAL STUDY PROTOCOL 
A Phase 2, Double-Blind, Randomized, Placebo-Controlled 
Study of ACE-011 for the Treatment of Chemotherapy 
Induced Anemia in Patients with Metastatic Breast Cancer 
 
 
STUDY DRUG: 
 
 
ACE-011 
 
PROTOCOL NUMBER: 
 
 
A011-08 
 
SPONSOR: 
 
           Acceleron Pharma, Inc. 
                       128 Sidney Street 
                       Cambridge, MA 02139  
 
                     
                     
 
MEDICAL MONITOR: 
                 PPD Inc. 
 
                
 
                                                          
 
 
 
 
 
          
 
 
 
 
 
          
 
 
      
 
 
PROTOCOL DATE: 
                 13 March 2009 
AMENDMENT #1: 
                 22 April 2009 
AMENDMENT #2:  
 
           21 May 2009 
AMENDMENT #3: 
 
           07 October 2009 
 
 
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Criteria for evaluation 
o Amended the primary endpoint language defining the hematopoietic 
value from > 0.5 g/dL to > 1.0 g/dL. 
o Amended the secondary endpoint language based on the changes to 
the primary endpoint.  
o Statistical methods- Efficacy 
o Amended the primary endpoint language defining the hematopoietic 
value from > 0.5 g/dL to > 1.0 g/dL. 
Section 2. Schedule of 
events 
Table 7: Schedule of 
events 
o Formatting. 
o Deletion of timepoints for acquiring a bone scan on days 64 and 
113.  
o Addition of the following text “Refer to Imaging Acquisition 
Guidelines for 
o guidelines regarding washout period for contrast ( if used) for 
radiological 
o images, prior to collection of DXA” to the footnote for DXA scans.  
o Amended language regarding the baseline CT/MRI scans from 4 
weeks to 6 weeks.  
o Addition of the following text “Follow up bone scan, when the 
baseline bone scan was abnormal.” to the footnote for acquiring 
follow up bone scans.  
o Addition of text “All study visit day dates (inclusive of windows) 
are calculated from Day 1(day of initial ACE-011/placebo 
administration). 
Section 5: Introduction 
 Section 5.4 Clinical Experience 
o Additional text added to update the SAE information for the A011-
04 study.  
Section 6. Trial Objectives 
and Purpose 
 
Section 6.1: Primary Objective  
o Amended the primary endpoint language defining the hematopoietic 
value from > 0.5 g/dL to > 1.0 g/dL. 
Section 6.2: Secondary Objectives  
o Amended the secondary endpoint language based on the changes to 
the primary endpoint.  
 
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Section 7. Investigational 
Plan 
o Additional text added regarding central and local lab values.  
 
 Section 8. Selection  
Section 8.2.1 Patient inclusion criteria 
o Added “cytologically” and removed “documented by cytology or 
biopsy” from inclusion criteria “Histologically confirmed diagnosis 
of breast cancer documented by cytology or biopsy.”  
o Added version number to RECIST text with the inclusion criteria.  
o Added “anticipated” instead of “planned” for treatment with a 
myelosuppressive chemotherapy criteria. 
Section 8.2.2 Patient exclusion criteria 
o Deletion of “Concurrent use of bevacizumab with the chemotherapy 
regimen during study participation. 
o Addition of text “active gastrointestinal bleed (within the last 12 
months as compared to Day 1)  
Section 9. Treatment of 
Patients 
o Formatting. 
o Addition of “Rescreening” section.  
o Table 8 Amended.  
Section 10. Study 
Procedures 
Formatting. 
Section 10.1.2 Screening ( within 14 days of Day 1) 
o Amended the following language (in bold): A CT/MRI scan 
acquired within 6 weeks of initiating the current chemotherapy 
regimen may be used for the screening assessment. One measurable 
or non-measurable lesion per RECIST v1.1 is to be identified by the 
scan.  
o Added text – “Scans of the anatomical areas of head ( if applicable), 
neck, thoracic, abdominal, and pelvic are to be available for 
evaluation. If one of the anatomical areas listed has not be acquired, 
prior to screening, then a CT/MRI must be done, during screening 
for this study,  to ensure a scan of the  head (if applicable), neck, 
thoracic, abdominal, and pelvic is available.” 
o Added text- “Refer to Imaging Acquisition Guidelines for guidelines 
regarding washout period for contrast (if used) for radiological 
images, prior to acquiring DXA scan.” 
Section 10.1.4 ACE-011/placebo administration: Days 29, 57, and 85 (± 3 
days) 
o Added text- “Local Hgb must be done within 1 day prior to the 
ACE-011/placebo dosing day.” 
 
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Section 10.1.5 Additional visits during the Treatment Period: Days 8, 15, 
22, 36 (± 1 day), 43, 64 and 71 (± 2 days) 
o Added text- “anatomical areas” to the following section:  CT/MRI 
scan (Day 64 only, +/- 5 day window).  Same modality and 
anatomical areas as acquired prior to enrollment should be used for 
follow up scans. Tumor response assessments to be evaluated by the 
investigator. 
o Deletion of bone scan text.  
Section 10.1.6 Treatment Period Follow-up visits : Days 99, 113(± 3 days) 
and 141(± 7 days) 
o Added text- “anatomical areas” to the following section:  CT/MRI 
scan (Day 113 only, +/- 5 day window).  Same modality and 
anatomical areas as acquired prior to enrollment should be used for 
follow up scans. Tumor response assessments to be evaluated by the 
investigator. 
o Deletion of text for bone scan. 
o Added text- “Refer to Imaging Acquisition Guidelines for guidelines 
regarding washout period for contrast (if used) for radiological 
images, prior to acquiring DXA scan.” 
Section 10.1.8 Termination Visit: Day 281 (± 7 days) 
o Added text- “Refer to Imaging Acquisition Guidelines for guidelines 
regarding washout period for contrast (if used) for radiological 
images, prior to acquiring DXA scan.” 
o Added text- “and the scan was abnormal” to the following: Bone 
scan (Day 281, +/- 5 day window). Follow-up scan to be acquired if 
performed at baseline. 
 
 
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Section 11. Investigational 
Product Materials and 
Management 
o Added text: ACE-011 Handling and Administration Guidelines 
through out the section.  
Section 14. Adverse Event 
o Formatting. 
o Amended text “study drug” to investigational drug” throughout the 
section. 
Section 15. Statistics 
Section 15.4.1 Primary Efficacy Analysis 
o Amended the primary endpoint language defining the hematopoietic 
value from > 0.5 g/dL to > 1.0 g/dL. 
o Added text “with no sufficient hemoglobin measurement” 
Section 15.4.2 Secondary Efficacy Analysis 
o Amended the secondary endpoint language based on the changes to 
the primary endpoint.  
o Added the following language to the Progression Free Survival 
section- “the start date of current chemotherapy regimen” 
 
 
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                                 CLINICAL STUDY PROTOCOL 
A Phase 2, Double-Blind, Randomized, Placebo-Controlled 
Study of ACE-011 for the Treatment of Chemotherapy Induced 
Anemia in Patients with Metastatic Breast Cancer 
 
 
STUDY DRUG: 
 
 
ACE-011 
 
PROTOCOL NUMBER: 
 
 
A011-08 
 
SPONSOR: 
 
      Acceleron Pharma, Inc. 
            128 Sidney Street 
            Cambridge, MA 02139  
 
          
          
 
MEDICAL MONITOR: 
      PPD Inc. 
 
     
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
     
 
 
 
 
 
 
 
 
 
 
  
 
      
 
 
PROTOCOL DATE: 
     13 March 2009 
AMENDMENT #1 : 
     22 April 2009 
AMENDMENT #2 : 
     21 May 2009 
AMENDMENT #3 : 
     07 October 2009 
 
 
Confidentiality Statement 
This confidential information in this document is provided to you as an investigator or consultant for review by you, your staff, 
and the applicable institutional Review Board/Independent Ethics Committee.  Your acceptance of this document constitutes 
agreement that you will not disclose the information contained herein to others without written authorization from the Sponsor. 
 
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PROCEDURES IN CASE OF EMERGENCY 
 
Table 1: 
Emergency Contact Information 
Role in Study 
Name 
Address and Telephone number 
PPD Medical Monitor 
PPD Inc. 
1800 Perimeter Park Drive,  Suite 275 
Morrisville, NC 27560-7200 USA 
Clinical Trial Manager 
Acceleron Pharma, Inc. 
128 Sidney Street  
Cambridge, MA 02139 USA  
 
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2. 
PROTOCOL SYNOPSIS 
Name of Sponsor/Company:  Acceleron Pharma, Inc. 
 
 
 
 
                          128 Sidney Street 
 
 
 
 
                          Cambridge, MA 02139 
Name of Investigational Product: ACE-011 
Name of Active Ingredient:   
ACE-011 is a fully human fusion protein consisting of the extracellular domain (ECD) of the 
activin receptor IIA (ActRIIA) linked to the human IgG1 Fc domain.  
Mechanism of Action: ACE-011 is a disulfide-linked, glycosylated, dimeric protein. ACE-011 
competes with the activin receptor IIA that binds a number of TGF-β superfamily ligands 
including activin, myostatin (growth differentiation factor [GDF]-8), and GDF-11. 
Title of Study:  A Phase 2, Double-Blind, Randomized, Placebo-Controlled Study of ACE-011 
for the Treatment of Chemotherapy Induced Anemia in Patients with Metastatic Breast 
Cancer. 
Study center(s): approximately 25-35 centers  
Phase of development: 2 
Objectives 
Primary:  
1. To evaluate the proportion of patients in each ACE-011 dose regimen who achieve a 
hematopoietic response during the treatment period including up to 2 months after the 
last dose of ACE-011 treatment of chemotherapy induced anemia in patients with 
metastatic breast cancer. Hematopoietic response is defined as an increase in 
hemoglobin of ≥ 1.0 g/dL above the study baseline value for 28 consecutive days 
during the treatment period including up to 2 months after the last dose of ACE-011, in 
the absence of any RBC transfusions and/or ESAs. 
Secondary: 
1. To evaluate the safety and tolerability of ACE-011 for the treatment of chemotherapy 
induced anemia in patients with metastatic breast cancer.  
2. To evaluate the percentage of patients who achieve an increase in hemoglobin of, ≥ 2 
g/dL and/or hemoglobin concentration ≥ 11 g/dL for 28 consecutive days during the 
treatment period including up to 2 months after the last dose of ACE-011 in the 
absence of any RBC transfusions and/or ESAs.   
3. To estimate the duration of the hematopoietic response associated with each ACE-011 
dose regimen. 
4. To estimate the time to the hematopoietic response associated with each ACE-011 dose 
regimen. 
 
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5. To estimate the proportion of patients receiving red blood cell (RBC) transfusions 
and/or ESAs within each cycle of ACE-011 with each dose regimen. 
6. To estimate the effect of each ACE-011 dose regimen on progression free survival 
(PFS) and objective response rate (ORR). 
Exploratory objectives: 
1. To estimate the effect of each ACE-011 dose regimen on serum bone biomarkers (OC, 
BSAP, P1NP, CTX, TRACP-5b), urine bone biomarker (uNTX), bone mineral density 
(DXA scans of lumbar spine and hip) and incidence of skeletal related events (SREs). 
2. To evaluate the quality of life in relation to the treatment of chemotherapy induced 
anemia in patients with metastatic breast cancer during the study. 
Methodology: This is a Phase 2, double-blind, randomized, placebo-controlled study to 
evaluate the efficacy, safety, and tolerability of ACE-011 for the treatment of chemotherapy 
induced anemia in patients with metastatic breast cancer. Patients will be randomized to one of 
three treatment arms or placebo: 
 
1. ACE-011 0.1 mg/kg subcutaneously (SC) every 28 days for up to 4 doses. 
2. ACE-011 0.3 mg/kg SC every 28 days for up to 4 doses.  
3. ACE-011 0.5 mg/kg SC every 28 days for up to 4 doses. 
4. Placebo SC every 28 days for up to 4 doses. 
 
  
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Number of patients (planned): 105 patients 
Diagnosis and main criteria for inclusion 
 
Inclusion Criteria: 
1. Women > 18 years of age. 
2. Histologically or cytologically confirmed diagnosis of breast cancer. 
3. Evidence of metastatic breast cancer with a minimum of one measurable lesion or non 
measurable lesion per RECIST 1.1 criteria (Appendix 1). 
4. Receiving a multicycle myelosuppressive chemotherapy regimen including one of the 
following: anthracycline, taxane, gemcitabine or vinorelbine. 
5. Anticipated treatment with the same myelosuppressive chemotherapy regimen for a 
minimum of 9 weeks after Day 1 of ACE-011/placebo administration.  
6. Hemoglobin value between ≥ 6.5 to < 11.0 g/dL (≥ 65 to < 110 g/L).  
7. ≥ 30 days must have elapsed (from Day 1) since previous treatment with erythropoiesis-
stimulating agent (including concurrent treatment with IV iron) for chemotherapy induced 
anemia.  
8. ≥ 7 days have elapsed (from Day 1) since the last RBC blood transfusion and receipt of ≤ 2 
units of blood in the past 30 days.  
9. ECOG Performance status of 0 – 2 (Appendix 2). 
10. Adequate renal (creatinine ≤ 1.5 x ULN or creatinine clearance ≥ 40 mL/min) and hepatic 
function (bilirubin < 1.5 x ULN; AST/ALT < 2.5 x ULN). 
11. Females of childbearing potential  participating in the study are to use adequate birth 
control measures (i.e. oral contraceptives or two forms of barrier method birth control) 
during study participation. Females of childbearing potential must have a negative serum 
pregnancy test within 7 days to ACE-011/placebo administration (Day 1). A female of 
childbearing potential is a sexually mature woman who has not undergone a hysterectomy 
or who has not been postmenopausal for at least 24 consecutive months (i.e. who has had 
menses at some time in the preceding 24 months). 
12. Life expectancy of ≥ 6 months. 
13. Is willing to adhere to the study visit schedule, understand and comply with all protocol 
requirements. 
14. Understand and sign a written informed consent. 
 
 
 
 
 
 
 
 
 
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Exclusion Criteria: 
1. At the time of screening patients who have any grade > 3 toxicity (as per NCI CTCAE 
v3.0 (Appendix 3)) (except for the following disease related toxicities:  hematological 
events- anemia, thrombocytopenia or neutropenia or non hematological events- nausea, 
vomiting, fatigue, or muscle or bone/joint pain).  
2. Prior radiation therapy to > 20% of the whole skeleton. Use of palliative radiation if the 
area being treated is <15% of body surface area with no pelvic radiation or no more than 
10% of the bone marrow reserve is radiated is permitted during patient participation in the 
study, at the discretion of the investigator. 
3. Have received more than 5 prior chemotherapy treatment regimens for metastatic breast 
cancer.  
4. Clinically significant pulmonary, endocrine, neurologic, gastrointestinal, hepatic or 
genitourinary disease unrelated to underlying hematologic disorder.  
5. Patients with heart failure as classified by the New York Heart Association (NYHA) 
classification of 3 or higher (Appendix 4). 
6. History of thrombosis, deep vein thrombosis (DVT), pulmonary emboli, or embolic stroke. 
7. Untreated CNS metastases (exception: CNS metastases treated with whole brain 
radiotherapy > 6 months prior to randomization). 
8. Diagnosis of a myeloid malignancy or known history of myelodysplasia.  
9. History of second malignancy within 5 years (except excised and cured basal cell 
carcinoma, squamous cell carcinoma of the skin or cervical carcinoma in situ).  
10. Patients with a recent history (within 14 days of Day 1) of administration of systemic (IV 
or oral) antibiotics. Patients should be free of infection at least 14 days after the last dose 
of systemic antibiotic treatment (from Day 1). 
11. Uncontrolled hypertension. If hypertension is considered clinically stable, systolic blood 
pressure (BP) must be < 150 mmHg and diastolic BP must be < 100 mmHg.  
12. Known history of hepatitis C antibody (HCV), hepatitis B surface antigen (HBsAg and HB 
core Ab), or human immunodeficiency virus (HIV) antibody.   
13. Deficiency in iron (serum ferritin < 100 ng/mL (< 224.7 pmol/L)), vitamin B12, or folate. 
14. History of anemia as a result of inherited hemoglobinopathy such as sickle cell anemia or 
thalassemia.  
15. History of autoimmune or hereditary hemolysis or active gastrointestinal bleeding (within 
the previous 12 months as compared to Day 1). 
16. Patient received treatment with another investigational drug or device within 1 month prior 
to Day 1, or if the half life of the previous product is known, within 5 times the half life 
prior to dosing, whichever may be longer.  
17. Pregnant or lactating females. 
18. History of severe allergic or anaphylactic reactions or hypersensitivity to recombinant 
proteins or excipients in the investigational product.    
19. Major surgery within 30 days prior to Day 1 (patients must have completely recovered 
from any previous surgery prior to Day 1). 
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Investigational product, dosage and mode of administration:  
ACE-011/placebo will be administered as a SC injection, approximately every 28 days, on 
days 1, 29, 57, and 85 of the treatment period.  Each patient will be randomized to one of three 
treatment arms or placebo: 
 
 
 
 
 
 
 
 
Patients with grade ≥ 3 toxicity related to ACE-011 will be discontinued from ACE-011/ 
placebo treatment except for the following: Patients with grade 3 hypertension that decreases 
to grade ≤ 1 within 7 days after treatment with anti-hypertensive therapy may continue on 
ACE-011/placebo treatment.  Dose reduction rules will apply at the subsequent scheduled 
dosing day(s).  Patients with a hemoglobin level above the upper limit of normal at any time 
during the study after Day 1 will be discontinued.   
ACE-011/placebo dose modification rules are based on hemoglobin values and blood pressure 
measurements during each treatment cycle. ACE-011/placebo dose interruption and dose 
reduction rules will be implemented for those patients with hemoglobin of ≥ 11 g/dL, an 
increase of ≥ 2 g/dL/ 28 days, or hypertension ≥ Grade 2 within each cycle (see Figure 1). 
Dose  
Number of  Patients 
0.1 mg/kg 
30 
0.3 mg/kg 
30 
0.5 mg/kg 
30 
Placebo 
15 
Total patients enrolled: 105 
Duration of study: Patients will be followed for a minimum of 7 months following their last 
dose of ACE-011/placebo. Study participation for each patient is approximately 10.5 months 
(14 day screening period, 3 month treatment period with a 2 month treatment follow up period, 
and a 5 month post treatment follow-up period). The start date of the chemotherapy regimen 
used in this protocol to treat metastatic breast cancer will be recorded. If a patient begins a new 
chemotherapy regimen during the study, the patient will discontinue further ACE-011/placebo 
treatment, complete the Day 281/Termination visit procedures and be followed for survival 
only. If a patient has a positive anti-drug antibody result at the Day 281/Termination visit, they 
may be asked to return to the clinical site for additional monthly repeat anti-drug antibody 
testing for up to 12 months, following the last dose of ACE-011/placebo.  The study is 
complete when the last patient enrolled has completed the last protocol required follow up 
visit. 
Criteria for evaluation 
Efficacy: The primary endpoint is to establish the proportion of patients who have a 
hematopoietic response of an increase in hemoglobin of ≥ 1.0 g/dL above the study baseline 
value for 28 consecutive days during the treatment period including up to 2 months after the 
last dose of ACE-011, in the absence of any RBC transfusions and/or ESAs.   
The proportion of patients with an increase in hemoglobin of ≥ 2 g/dL and/or hemoglobin 
concentration ≥ 11 g/dL for 28 consecutive days during the treatment period up to 2 months 
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after the last dose of ACE-011 in the absence of any RBC transfusions and/or ESAs will be 
evaluated as a secondary efficacy endpoint. 
The hematopoietic endpoints will be determined by the monitoring of hematologic laboratory 
values, RBC transfusion and/or ESAs administration. The evaluation of response will be from 
the first dose of ACE-011 through 2 months after the last dose (for each patient).  Additional 
endpoints will be evaluated with the assessment of disease progression by CT/MRI and bone 
scan and bone mineral density by DXA scans.  Bone biomarkers will be evaluated in all 
patients and incidence of SREs will be recorded, as applicable. SREs are defined as pathologic 
fracture, radiation therapy to bone, surgery to bone, or spinal cord compression. 
Safety: Throughout the study, safety will be evaluated by the sponsor, medical monitor and 
principal investigator.  Additionally, the DMC will review safety parameters for patients 
enrolled in the study. All patients will be assessed for safety by monitoring adverse events, 
clinical laboratory tests, assessment of quality of life, vital signs and physical examinations on 
an ongoing basis.  ECGs will also be performed during screening, prior to dosing on the first 
cycle, during the first, second and third cycle, Day 113 (28 days after the last dose of ACE-
011) and at Day 281/Termination visit to monitor safety.  Blood pressure and lab values will 
be assessed at each study visit during the treatment and treatment follow up period.  
Pharmacokinetics: The blood samples will be collected at selected study sites from 
approximately one-third of patients for the evaluation of serum concentrations of ACE-011.  
Pre-dose PK samples will be collected on Day 1.  See Appendix 5 for PK sampling schedule. 
Statistical methods  
Sample size determination: With an anticipated dropout rate of 20%, a sample size of 30 
patients per dose level is planned to achieve at least 80% power with 2 sided significance level 
of 0.05 to differentiate targeted response rate of p1=0.45 from null hypothesis p0=0.20. An 
additional 15 patients will be enrolled into the placebo group for safety comparison. A total of 
105 patients will be randomized to three ACE-011 dose groups or placebo with a ratio of 
2:2:2:1. 
Efficacy analysis: The primary endpoint is the proportion of patients who have a 
hematopoietic response of an increase in hemoglobin of ≥ 1.0 g/dL above the study baseline 
value for 28 consecutive days during the treatment period including up to 2 months after the 
last dose of ACE-011, in the absence of any RBC transfusions and/or ESAs. The proportion of 
responders will be determined together with 95% confidence interval.  
For binary endpoints, the proportion of responders and 95% confidence interval will be 
calculated. For time to event endpoints, the Kaplan-Meier method will be used to estimate the 
survival curve and median time to event.  Due to the nature of the study, no multiplicity 
adjustment will be made for efficacy analysis. 
Safety analysis: Data from all patients who receive at least one dose of ACE-011/placebo will 
be included in the safety analyses. To assess clinical safety, adverse events, vital sign 
measurements and clinical laboratory information will be summarized. Adverse events and 
laboratory results will also be summarized by severity grade (NCI CTCAE v3.0). Changes 
from baseline clinical laboratory values and vital signs will be summarized over time. 
Descriptive statistics and shift tables will be generated as appropriate.  
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3. 
TABLE OF CONTENTS, LIST OF TABLES AND LIST OF 
FIGURES  
TABLE OF CONTENTS 
1. 
TITLE PAGE..............................................................................................................1 
2. 
PROTOCOL SYNOPSIS .............................................................................................4 
3. 
TABLE OF CONTENTS, LIST OF TABLES AND LIST OF FIGURES................12 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................18 
5. 
INTRODUCTION......................................................................................................21 
5.1. 
Indication and Rationale.............................................................................................21 
5.2. 
Description of ACE-011.............................................................................................21 
5.3. 
Activin Biology ..........................................................................................................22 
5.3.1. 
Pharmacology Studies ................................................................................................22 
5.3.2. 
Toxicology..................................................................................................................24 
5.4. 
Summary of Clinical Experience................................................................................25 
5.4.1. 
A011-01: A Phase 1a Study in Healthy Postmenopausal Women .............................25 
5.4.2. 
A011-02: A Phase 1b Study in Healthy Postmenopausal Women.............................26 
5.4.3. 
A011-04: A Phase 2a Study in Patients with Osteolytic Lesions of Multiple 
Myeloma.....................................................................................................................29 
5.5. 
Potential Risks for Human Use...................................................................................31 
6. 
TRIAL OBJECTIVES AND PURPOSE....................................................................33 
6.1. 
Primary objective........................................................................................................33 
6.2. 
Secondary objectives ..................................................................................................33 
6.3. 
Exploratory objectives................................................................................................33 
7. 
INVESTIGATIONAL PLAN.....................................................................................34 
7.1. 
Overall Study Design and Plan...................................................................................34 
8. 
SELECTION AND WITHDRAWL OF PATIENTS.................................................38 
8.1. 
Number of Patients .....................................................................................................38 
8.2. 
Entry Criteria ..............................................................................................................38 
8.2.1. 
Patient Inclusion Criteria............................................................................................38 
8.2.2. 
Patient Exclusion Criteria...........................................................................................39 
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8.3. 
Patient Withdrawal Criteria........................................................................................40 
9. 
TREATMENT OF PATIENTS..................................................................................41 
9.1. 
Concomitant Medications...........................................................................................41 
9.1.1. 
General Concomitant Medication Usage....................................................................41 
9.1.2. 
Concomitant treatment for anemia .............................................................................41 
9.1.2.1. 
Iron supplementation ..................................................................................................41 
9.1.2.2. 
Erythropoiesis-stimulating agents (ESAs)..................................................................41 
9.1.2.3. 
RBC Transfusions.......................................................................................................41 
9.2. 
Chemotherapy.............................................................................................................42 
9.3. 
Treatment Compliance................................................................................................42 
9.4. 
Rescreening.................................................................................................................42 
9.5. 
Randomization............................................................................................................42 
9.5.1. 
Blinding ......................................................................................................................42 
9.5.2. 
Unblinding..................................................................................................................43 
9.6. 
Treatments Administered............................................................................................43 
9.6.1. 
Selection of Doses in the Study..................................................................................43 
9.6.2. 
Selection and Timing of Dosing for Each Patient ......................................................43 
9.6.2.1. 
ACE-011 Treatment Related Toxicity........................................................................43 
9.6.2.2. 
ACE-011 Dose Modification Rules............................................................................44 
10. 
STUDY PROCEDURES AND SCHEDULE ............................................................47 
10.1.1. 
Written Informed consent...........................................................................................47 
10.1.2. 
Screening (Within 14 days of dosing) ........................................................................47 
10.1.3. 
Initial Dosing: Day 1 ..................................................................................................48 
10.1.4. 
ACE-011/placebo administration: Days 29, 57, and 85 (± 3 days)............................49 
10.1.5. 
Additional visits during Treatment Period: Days 8, 15, 22, 36 (± 1 day), 43, 
64 and 71 (± 2 days) ...................................................................................................50 
10.1.6. 
Treatment Period Follow-up visits : Days 99, 113 (± 3 days)  and 141 (± 7 
days)............................................................................................................................51 
10.1.7. 
Post Treatment Period Follow-up visits : Days 169, 197, 225, and 253 (± 7 
days)............................................................................................................................52 
10.1.8. 
Termination Visit:  Day 281 (± 7 days)......................................................................53 
10.2. 
Discontinuation of study.............................................................................................54 
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11. 
INVESTIGATIONAL PRODUCT MATERIALS AND MANAGEMENT.............55 
11.1. 
Reference Product.......................................................................................................55 
11.2. 
Investigational Product Packaging and Labeling .......................................................55 
11.3. 
Investigational Product Storage..................................................................................55 
11.4. 
Investigational Product Preparation............................................................................55 
11.5. 
Administration............................................................................................................55 
11.6. 
Drug Accountability ...................................................................................................55 
11.7. 
Investigational Product Handling and Disposal .........................................................56 
12. 
ASSESSMENT OF EFFICACY ................................................................................57 
13. 
ASSESSMENT OF SAFETY.....................................................................................58 
13.1. 
Safety Parameters .......................................................................................................58 
13.1.1. 
Adverse Events...........................................................................................................58 
13.1.2. 
Clinical Laboratory Tests ...........................................................................................58 
13.1.3. 
Other Safety Assessments...........................................................................................59 
13.2. 
Pharmacokinetics........................................................................................................59 
14. 
ADVERSE EVENT....................................................................................................60 
14.1. 
Adverse Event Classification......................................................................................61 
14.2. 
Recording Adverse Events .........................................................................................61 
14.3. 
Reporting Adverse Events..........................................................................................62 
14.4. 
Emergency Sponsor Contact.......................................................................................63 
15. 
STATISTICS..............................................................................................................64 
15.1. 
Determination of Sample Size....................................................................................64 
15.2. 
Analysis Populations ..................................................................................................64 
15.3. 
Background and Demographic Characteristics ..........................................................64 
15.3.1. 
Patient Disposition......................................................................................................64 
15.3.2. 
ACE-011.....................................................................................................................65 
15.3.3. 
Concomitant Therapy .................................................................................................65 
15.4. 
Efficacy Evaluation ....................................................................................................65 
15.4.1. 
Primary Efficacy Analysis..........................................................................................65 
15.4.2. 
Secondary Efficacy Analyses .....................................................................................66 
15.5. 
Safety Evaluation........................................................................................................66 
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15.6. 
Pharmacokinetic Evaluation.......................................................................................67 
15.6.1. 
Anti-drug Antibody Data............................................................................................67 
15.7. 
Interim Analysis..........................................................................................................67 
15.8. 
Deviation from Original Analysis Plan ......................................................................67 
16. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................68 
16.1. 
Study Monitoring........................................................................................................68 
16.2. 
Audits and Inspections................................................................................................68 
17. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................69 
17.1. 
Data Quality Control and Quality Assurance.............................................................69 
17.1.1. 
Investigator responsibility ..........................................................................................69 
17.1.2. 
Protocol modifications................................................................................................69 
17.2. 
Financing and Insurance.............................................................................................69 
17.3. 
Confidentiality............................................................................................................69 
17.4. 
Publication Policy.......................................................................................................69 
17.5. 
Protocol Amendments ................................................................................................70 
18. 
ETHICS ......................................................................................................................71 
18.1. 
Institutional Review Board or Independent Ethics Committee ..................................71 
18.2. 
Ethical Conduct of the Study......................................................................................71 
18.3. 
Written Informed Consent..........................................................................................71 
18.3.1. 
Informed Consent .......................................................................................................71 
18.3.2. 
Patient Data Protection ...............................................................................................71 
19. 
DATA HANDLING AND RECORDKEEPING.......................................................72 
19.1. 
Case Report Form Completion...................................................................................72 
19.2. 
Retention of Records ..................................................................................................72 
20. 
REFERENCES ...........................................................................................................73 
21. 
APPENDICES............................................................................................................75 
Appendix 1: Response Evaluation Criteria in Solid Tumors.........................................................75 
Appendix 2: ECOG Performance Status........................................................................................78 
Appendix 3:  National Cancer Institute (NCI) Common Terminology Criteria for 
Adverse Events (CTCAE) Version 3.0.......................................................................79 
Appendix 4: New York Heart Association- Classification of heart failure...................................80 
Appendix 5- Pharmacokinetic Sampling .......................................................................................81 
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LIST OF TABLES 
 
Table 1: 
Emergency Contact Information...................................................................................3 
Table 2: 
Abbreviations and Specialist Terms ...........................................................................18 
Table 3: 
A011-02: A Phase 1b Study in Healthy Postmenopausal Women: 
Hemoglobin Evaluation..............................................................................................27 
Table 4: 
A011-02: Incidence of Most Common Adverse Events.............................................28 
Table 5: 
A011-02: A Phase 1b Study in Healthy Postmenopausal Women: BMD..................29 
Table 6: 
Study Design...............................................................................................................34 
Table 7: 
Schedule of Events .....................................................................................................36 
Table 8: 
ACE-011/Placebo Dose Reduction Levels.................................................................46 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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LIST OF FIGURES 
Figure 1: 
ACE-011/placebo Dose Modification Rules (after initial dose of ACE-
011/placebo) ...............................................................................................................45 
 
 
 
 
 
 
 
 
 
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4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
The following abbreviations and specialist terms are used in this study protocol. 
Table 2: 
Abbreviations and Specialist Terms   
Term 
Definition 
ACTH 
Adrenocorticotropic hormone 
ActRIIA 
Activin receptor IIA  
AE 
Adverse event 
ALT 
Alanine aminotransferase  
AST 
Aspartate aminotransferase  
AUC 
Area under the plasma concentration - time curve 
AUC(0-last) 
AUC from time 0 to time of last quantifiable sample  
AUC(0-∞) 
AUC extrapolated to infinity  
BMD 
Bone mineral density 
BP 
Blood pressure 
BSAP 
Bone specific alkaline phosphatase 
BUN 
Blood urea nitrogen 
CBC 
Complete Blood Count 
CFR 
Code of Federal Regulations (US) 
CH 
Constant domain 
CI 
Confidence interval 
CIA 
Chemotherapy induced anemia 
CL 
Clearance 
CL/F 
Total clearance 
Cmax 
Maximum observed concentration  
CNS 
Central nervous system 
CO2 
Carbon dioxide 
CRF 
Case report form 
CRO 
Clinical research organization 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTX 
Serum C-terminal type I collagen telopeptide 
DLT 
Dose-limiting toxicity 
DXA 
Dual-energy x-ray absorptiometry 
DMC 
Data Monitoring Committee 
DVT 
Deep vein thrombosis 
ECD 
Extracellular domain 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EDF 
Erythroid differentiation factor  
ESA 
Erythropoiesis-stimulating agents 
F 
Bioavailability (absolute) 
FACT 
Functional Assessment of Chronic Illness 
FDA 
Food and Drug Administration  
FSH 
Follicle-stimulating hormone 
GCP 
Good Clinical Practices 
GH 
Growth hormone 
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Term 
Definition 
HBV 
Hepatitis B virus 
Hct 
Hematocrit 
HCV 
Hepatitis C virus 
Hgb 
Hemoglobin 
HIV 
Human immunodeficiency virus 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug 
IP 
Intraperitoneal 
IRB 
Institutional Review Board 
IV 
Intravenous 
IVRS 
Interactive Voice Response System 
Kd 
Binding coefficient 
λz 
Elimination rate constant 
LDH 
Lactate dehydrogenase 
LH 
Luteinizing hormone 
MCH 
Mean corpuscular hemoglobin 
MCHC 
Mean corpuscular hemoglobin concentration 
MCV 
Mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MITT 
Modified Intent to Treat (population) 
MRI 
Magnetic resonance imaging 
NOAEL 
No adverse events level  
NYHA 
New York Heart Association 
OC 
Osteocalcin 
ORR 
Objective response rate 
OVX 
Ovariectomized 
PD 
Progressive disease 
PFS 
Progression free survival 
PHI 
Protected health information 
P1NP 
Serum intact procollagen type I N terminal propeptide 
PK 
Pharmacokinetic 
PP 
Per-protocol (population) 
PT 
Prothrombin time 
PTH 
Parathyroid hormone 
PTT 
Partial thromboplastin time 
RAP-011 
Murine version of ACE-011, ActRIIA mFc 
RBC 
Red blood cell (count) 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SC 
Subcutaneous 
SERM 
Selective estrogen receptor modulator 
SHAM 
Sham-operated 
SPEP 
Serum protein electrophoresis 
SRE 
Skeletal-related event 
T1/2 
Elimination half-life  
TIBC 
Total iron binding capacity 
Tmax 
Time to Cmax 
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Term 
Definition 
TRACP-5b 
Serum tartrate-resistant acid phosphatase isoform-5b 
ULN 
Upper limit of normal 
Vz/F 
Volume of distribution 
WBC 
White blood cell (count) 
 
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5. 
INTRODUCTION 
5.1. 
Indication and Rationale 
This study is designed to evaluate the efficacy, safety, and tolerability of ACE-011 for the 
treatment of chemotherapy induced anemia in patients with metastatic breast cancer. 
Treatment of patients with metastatic breast cancer with myelosuppressive chemotherapy is 
frequently associated with anemia. Chemotherapy induced anemia (CIA) is a significant problem 
for patients with cancer, causing fatigue and reduced quality of life (1).  Patients with CIA are 
currently treated with blood transfusion and/or erythropoiesis-stimulating agents (2). However, 
with these treatment options CIA is still an area of unmet medical need. Erythropoiesis-
stimulating agents (ESAs) can successfully mitigate transfusion need in a proportion of these 
patients, but concerns have emerged regarding apparent negative effects on survival and/or tumor 
progression in certain patient populations. The murine surrogate to ACE-011, RAP-011, has been 
tested as a single agent in breast cancer cell lines MDA-MB-231 and MCF-7 and no effect on 
enhanced proliferation of these cell lines has been observed in vitro. Therefore, treatment with 
ACE-011 may provide a distinct benefit/risk profile to patients with chemotherapy induced 
anemia.  
In both a Phase 1 single dose and multiple dose study of ACE-011 in postmenopausal women, 
increases in hemoglobin and hematocrit were observed following ACE-011 treatment and 
remained elevated over the course of study.  The observed hemoglobin and hematocrit effects of 
ACE-011 were dose and time dependent.  Please refer to the Investigator Brochure for further 
information.  
Based on the effect of ACE-011 on hematopoiesis and consistent biological phenomena observed 
in both non clinical and clinical studies, it is hypothesized that the blockade of ActRIIA receptor 
signaling impedes the terminal differentiation step in erythropoiesis to allow additional rounds of 
cell replication before cells enter the final differentiation phase. The result is a substantial 
increase in mature erythrocytes released into the circulation.  Since this proposed mechanism is 
different to that of known ESAs, ACE-011 may provide a different clinical profile in the 
treatment of CIA.  
This study will provide information on the pharmacodynamics (PD) properties regarding the 
ability of ACE-011 to increase hemoglobin in patients with CIA. 
5.2. 
Description of ACE-011 
ACE-011 (ActRIIA-IgG1) is a fully human fusion protein consisting of the extracellular domain 
(ECD) of activin receptor IIA (ActRIIA) linked to the human IgG1 Fc domain, which includes 
the heavy chain hinge and constant domains, CH2 and CH3.  ACE-011 avidly binds to activin A 
with a binding coefficient (Kd) approximately 8.9 pM and prevents its binding to endogenous 
receptors, thereby inhibiting biological effects of activin.   
 
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5.3. 
Activin Biology 
Activin A was initially identified as a gonadal differentiation factor involved in modulating 
follicle stimulating hormone (FSH) secretion from the pituitary (3). Subsequently, the pleiotropic 
nature of activin A has become more apparent (4).   There is a growing body of data suggesting a 
role for activin A in bone remodeling, specifically as a negative regulator of bone growth (5).  
Before the two molecules were shown to be identical (6), activin A was also described as 
erythroid differentiation factor (EDF), effecting red blood cells in the later stages of maturation 
(7).  The mechanism(s) by which activin A influences erythropoiesis remain under investigation 
and, in fact, there are data from studies in vitro and in animals that support erythropoiesis-
stimulatory (8,9) and -inhibitory effects (10).   
At the cellular level, activin A binds initially to the high-affinity Type II receptor (ActRIIA).  The 
ligand-bound ActRIIA then recruits the low-affinity Type I receptor (ActRIA or ALK-4).  The 
receptor heterocomplex, through its cytoplasmic protein kinase activity, then activates the Smad 
signal cascade to eventually influence nuclear transcriptional factors (11, 12).  The competitive 
binding of activin A in the blood by the ACE-011 soluble fusion protein can result in inhibition 
of ActRIIA receptor signaling pathway by impeding biological processes attributed to activin A.  
Activin has also been attributed to erythroid differentiation and has been reported to have 
proerythrocytic effects and to induce terminal differentiation of RBCs.  Inhibition of activin may 
lead to increases in proliferation of the erythroid lineage.  Based on its pharmacologic effects, 
ACE-011 (ActRIIA-IgG1) is being developed for the treatment of bone loss associated with 
various disease states (e.g., osteoporosis and treatment of osteolytic lesions in patients with 
multiple myeloma), and treatment of anemia associated with a variety of disorders, such as 
chemotherapy induced anemia. 
The extracellular domain sequence of ActRIIA is completely conserved among numerous species 
including mouse, rat, cynomolgus monkey and humans, thus ACE-011 is active in these animals.  
However, in order to reduce the potential immunogenicity of the fully human molecule, ACE-
011, in mice and to maximize the opportunity to maintain exposures in chronic models, a murine 
surrogate molecule was constructed by exchanging the human immunoglobulin Fc sequence 
portion of ACE-011 with its murine IgG2a homolog.  The resultant construct is referred to as 
RAP-011 (ActRIIA-mIgG2aFc).   
5.3.1. 
Pharmacology Studies 
RAP-011 was evaluated in a broad range of animal pharmacology studies to assess the effects of 
inhibition of activin A on the biological processes attributed to that regulatory protein.  RAP-011 
has been shown to have significant effects on the red cell compartment.  RAP-011 treatment of 
mice at 10, 30 and 50 mg/kg by intraperitoneal injection (IP) twice per week for 3 months 
resulted in a 16-26% increase in red blood cell (RBC) counts compared to control animals.  Rats 
treated with RAP-011 at 0.3, 3 and 30 mg/kg once per week for 3 months showed RBC count 
increases of 6-15% over control animals.  Finally, in cynomolgus monkeys treated with 10, 30 or  
 
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50 mg/kg of ACE-011 twice per month for 3 months there was a 21- 24% increase in RBC counts 
compared to controls animals.  In this study, the RBC count increase was apparent as early as 2 
weeks following the initial dose of ACE-011.   
While the mechanism(s) underlying the stimulation effect of ACE-011 on erythropoiesis are not 
yet fully understood, it is hypothesized that a blockade of ActRIIA receptor signaling impedes the 
terminal differentiation step in erythropoiesis to allow additional rounds of erythroid cell 
replication before cells enter the terminal differentiation phase.  The result is a substantial 
increase in mature erythrocytes released into circulation.   
RAP-011 administered at 10 mg/kg to mice three days prior to administration of paclitaxel at 30 
mg/kg was sufficient to prevent decreases in red blood cell parameters seen three days later.  
Mice receiving paclitaxel alone had decreased hematocrit from 43% to 38% three days later.  
RAP-011 administered 3 days prior to paclitaxel injection was sufficient to keep the hematocrit 
above 42% at three days and up to two weeks after paclitaxel administration.  Therefore 
prophylactic treatment with RAP-011 was able to prevent paclitaxel induced anemia in mice. 
RAP-011 has also been shown to significantly increase bone mineral density and strength in 
normal animals and in a variety of animal models of bone loss (13, 14, 15).  In a murine 
ovariectomy (OVX)-induced model of osteopenia, RAP-011 (10 mg/kg IV, twice per week x 12 
weeks) increased trabecular BMD > 25% in 6-12 weeks compared to the phosphate buffered 
saline (PBS)-treated controls (p<0.002).  RAP-011 treatment was able to reverse the accelerated 
bone loss associated with ovariectomy.  As expected sham-operated (SHAM) mice (i.e., intact 
ovaries) started the study with a greater trabecular BMD than OVX mice.  PBS-treated SHAM 
mice showed a 10% decrease in trabecular BMD after 12 weeks of treatment compared to 
baseline, while SHAM-RAP-011 mice had a 32% increase in trabecular BMD over the same 
period.  These data demonstrate that RAP-011 is able to increase trabecular BMD in both the 
normal state and in a model of established bone loss.  The femurs of both the RAP-011 treated 
OVX and SHAM mice showed statistically significant increases in all measured parameters of 
bone strength (i.e., maximum load, stiffness, energy, ultimate strength, and elastic modulus).  In 
summary, treatment with RAP-011 produced bone of superior quality consistent with an anabolic 
agent. 
RAP-011 was evaluated in a mouse model of skeletal metastasis using luciferase-tagged, human 
MDA-MB-231 breast cancer cells (estrogen receptor negative).  Mice were pretreated for 2 
weeks with RAP-011 (10 mg/kg, biweekly, SC) prior to intracardiac injection of tumor cells.  
Treatment with RAP-011 was continued for an additional 5 weeks following tumor implantation. 
A parallel study was conducted to examine the effect of RAP-011 treatment, as described above, 
on survival of MDA-MB-231 bearing mice. 
The data demonstrate that RAP-011 treatment acts to inhibit MDA-MB-231 metastasis to bone 
and may also play a role in inhibiting tumor growth in soft tissue.  Furthermore, in the presence 
of tumor cells, RAP-011 is able to prevent lytic disease through an anabolic mechanism of bone 
formation.  Lastly, inhibition of tumor growth and metastasis with RAP-011 leads to a greater 
than 25% survival benefit in this model.  
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The efficacy of RAP-011 was examined in an orthotopic model of breast cancer using luciferase-
tagged human MCF-7 breast cancer cells (estrogen receptor positive). Mice were pretreated for 2 
weeks with RAP-011 (10 mg/kg, biweekly, SC) prior to the implantation of tumor cells into the 
mammary fat pad of female nude mice. Treatment with RAP-011 was continued for an additional 
7 weeks following tumor implantation at which time mice were sacrificed and assessed for tumor 
burden. RAP-011 effectively lowered the tumor burden in mice as detected by bio-luminescence. 
In addition, a 60% reduction in tumor weight was observed in the RAP-011 treated mice.  
The ability of RAP-011 to repair osteolytic lesions caused by metastatic disease was investigated 
in mice.  In this model athymic nude mice received an intratibial injection of MDA-MB-231-Luc 
cells to mimic bone metastasis.  Mice were treated with a chemotherapy regimen of paclitaxel (20 
mg/kg, IP, every three days) starting seven days after tumor injection and continuing for the 
duration of the study.  On study day 42 mice with a detectable tumor burden by bioluminescent 
imaging were divided into two groups and began treatment with RAP-011 (10 mg/kg, SC, 
biweekly) or vehicle.  Prior to dosing, μCT scans of the tumor bearing tibia were conducted to 
identify osteolytic lesions.  RAP-011 treatment continued for four weeks (to study day 70) and a 
final μCT scan of the tibia was performed.  On study day 70 osteolytic lesions remained the same 
or had progressed further when compared to study day 42 in the vehicle treated mice.  While 
some mice showed progression of osteolytic lesions (most likely related to tumor burden) on 
study day 70, a majority of mice treated with RAP-011 demonstrated repair of the osteolytic 
lesions seen on study day 42.  Therefore treatment with RAP-011 has the ability to repair 
osteolytic lesions caused by tumors and after cytoxic chemotherapy with paclitaxel. 
5.3.2. 
Toxicology 
ACE-011 has been evaluated for toxicological effects in two species, Sprague-Dawley rats and 
cynomolgus monkeys.  The dose levels ranged from 0.3 to 30 mg/kg in rats and from 1 to 50 
mg/kg in monkeys.  These dose ranges were designed to support Phase 1a single-dose levels of 
0.01 to 3.0 mg/kg IV and Phase 1b multiple doses of 0.1 to 2 mg/kg (monthly, SC).  Weekly 
dosing in animals was designed to provide continuous, but fluctuating serum concentrations of 
ACE-011, which would be mimicked by a one-month dosing interval in humans. 
Initial studies utilized IV dosing to identify target organs while longer-term studies (3 months in 
rats; 3 and 6 months in monkeys) utilized SC dosing to mimic the intended dosing regimen for 
patients.  The expected pharmacologic effect, increased red blood cells (RBCs), hemoglobin 
(Hb), hematocrit (HCT) and reticulocytes, was observed in all studies, presumably based on the 
ability of ACE-011 to inhibit activin.  A second expected pharmacologic effect of ACE-011, 
based on inhibition of activin, was the reversible reduction in sperm production and testicular 
tubular damage in rats.  Since male cynomolgus monkeys were sexually immature in these 
studies, it was not possible to monitor this effect in this species. 
Effects on the adrenal gland were only seen in rats and were more pronounced in female rats. 
This toxicological observation may not be relevant for predicting effects in humans since adrenal 
toxicity was not seen in cynomolgus monkeys.  Dose-limiting toxicity and no observable adverse 
effect levels (NOAELs) were primarily based on renal toxicity in both rats and monkeys.  There  
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was some indication that kidney toxicity was an indirect effect, based on the formation of 
antibody/antigen complexes, but since these studies were not designed to investigate 
toxicological mechanisms, a definitive cause of renal impairment and renal damage was not 
determined.  Development of antibodies to ACE-011 was noted in all of these studies, which is 
an expected immune reaction in rats and monkeys dosed with a human protein.  
The no observable adverse effect level (NOAELs) from the 3 month SC studies was 3 and 30 
mg/kg in rats and monkeys, respectively. Because the kidney findings were observed at all dose 
levels, the NOAEL from the 6 month monkey study is < 10 mg/kg.  
5.4. 
Summary of Clinical Experience 
5.4.1. 
A011-01: A Phase 1a Study in Healthy Postmenopausal Women  
ACE-011 was first studied in a randomized, Phase 1a, single dose, dose escalation study in 
healthy, post-menopausal females (16).  ACE-011 was diluted in normal saline administered as 
an IV infusion (over approximately 1 hour) or as a SC injection on Day 1.  Dose levels were 0.01, 
0.03, 0.1, 0.3, 1.0, and 3.0 mg/kg IV and 0.03 and 0.1 mg/kg SC.  A total of 48 subjects were 
enrolled; 5 active and 1 placebo at each of the IV and SC dose levels.  All subjects were followed 
for 4 months following a single dose administration. 
The pharmacokinetics of ACE-011 was linear for all IV and SC doses.  Across IV doses ranging 
from 0.1 through 3.0 mg/kg, the mean clearance (CL) ranged from 0.092 to 0.128 mL/h/kg, the 
volume of distribution ranged from 73.7 to 110 mL/kg, and the mean T1/2 ranged from 23.7 to 
31.8 days, with no apparent dependence on dose.  After SC administration of 0.03 and 0.1 mg/kg, 
ACE-011 was completely absorbed, and the mean T1/2 was approximately 30 days, with no 
apparent dependence on dose.   
The most commonly occurring treatment-emergent adverse events (AEs; i.e., those occurring in 
more than 1 subject in any treatment group) were headache, infusion site reaction, injection site 
hemorrhage, and toothache.  The majority of the injection site reactions and injection site 
hemorrhages were in the first IV cohort and were related to infiltration of the IV site.  The 
majority of treatment-emergent AEs were mild in severity and were judged to be unrelated to 
ACE-011.  No deaths, serious AEs (SAEs), or AEs leading to discontinuation were reported.  
Changes in red blood cells (RBCs), hemoglobin, reticulocytes, liver function tests, glucose, uric 
acid, amylase and lipase occurred in some subjects; however, none of these laboratory results 
were reported as adverse events.  Mild, transient elevations in pancreas enzymes, liver enzymes, 
or glucose were reported as AEs in five patients.  There were no clinically significant changes 
from baseline in vital signs, physical examination, endocrine function, or electrocardiogram 
(ECG) data.  Preservation of adrenal cortical function was monitored through evaluation of serum 
electrolytes (sodium and potassium levels) and through cortisol response to adrenocorticotropic 
hormone (ACTH) stimulation.  No clinically significant findings were observed at doses up to 3.0 
mg/kg IV, and ACE-011 was well tolerated in healthy, post-menopausal female volunteers in 
single dose levels up to 0.1 mg/kg SC and 3.0 mg/kg IV, the highest dose levels tested in this 
study. 
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5.4.2. 
A011-02: A Phase 1b Study in Healthy Postmenopausal Women  
ACE-011 was studied in a Phase 1b, single-center, randomized, double-blind, placebo-controlled, 
multi-dose, dose-escalating study to evaluate the safety, tolerability and pharmacodynamics of 
ACE-011 in healthy postmenopausal women.  Four cohorts of 10 subjects each were planned at 
the following dose levels: 0.1, 0.3, 1.0, and 2.0 mg/kg administered subcutaneously.  Within each 
cohort, subjects were to be randomized to either active or placebo treatment in an 8:2 ratio. 
Subjects were to receive one SC injection of ACE-011 or placebo every 28 days for a total of 4 
doses. All subjects were to be followed for 12 weeks after the last dose. 
The treatment phase of the study was terminated early after a dose-limiting pharmacodynamic 
effect was observed.  While on study, one subject in the 1.0 mg/kg cohort experienced a Serious 
Adverse Event (SAE) of progressive and persistent hypertension that was attributed to a rapid 
and significant rise in hemoglobin and hematocrit levels.  Due to symptoms of headaches, nausea, 
eye pain, dizziness and vomiting approximately 1 week following the second dose, the subject 
was hospitalized for monitoring and evaluation of her hypertension.  The head MRI, fundoscopy, 
and ECG performed were reported as normal and headache symptoms resolved following 
therapeutic phlebotomy. The SAE resolved and the subject was discharged from the hospital the 
following day.  The hypertension was monitored closely and managed initially with 
antihypertensive medication.  The hypertension resolved by the end of the study without need of 
any antihypertensive medication. The subject received aspirin prophylactically until the end of 
the study and continued taking ibuprofen as needed for headaches.  Further details can be found 
in the Investigator Brochure.  
Based on the magnitude of the hematopoietic response, the Sponsor suspended dose escalation to 
the 2.0 mg/kg dose level and further dosing in all cohorts as a result of this dose-limiting 
pharmacodynamic effect at the 1.0 mg/kg dose level.  In total, 31 subjects were enrolled and 
treated.  Dose levels of ACE-011 administered included 0.1, 0.3, and 1.0 mg/kg (Cohorts 1, 2, 
and 3 respectively).  All subjects randomized to active treatment in Cohort 1 received all 4 
planned doses of ACE-011.  Due to early discontinuation of study drug, subjects randomized to 
active treatment in Cohort 2 received 3 doses of ACE-011, and subjects randomized to active 
treatment in Cohort 3 received 2 doses of ACE-011.  Subjects randomized to placebo treatment 
received between 1 and 4 doses of study treatment.   
In the analysis of the unblinded data, after the administration of the first dose, a dose and time 
dependent increase in hemoglobin values was observed (see Table 3 below): 
 
 
 
 
 
 
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Table 3: 
A011-02: A Phase 1b Study in Healthy Postmenopausal Women: Hemoglobin 
Evaluation 
       
*The number of placebo subjects with data decreases over time as a result of the early discontinuation of the study (i.e., there were placebo 
subjects in each dosing cohort).  There were seven placebo subjects with data at baseline, Days 8, 15, and 36; six subjects with data at Days 29, 
43, 57, and 85; five subjects with data on Days 71 and 113; four subjects with data on Day 64; three subjects with data on Day 141; two subjects 
with data on Day 99; and one subject with data on Days 92 and 169. 
** Number of doses administered per treatment group: 0.1 mg/kg 4 doses; 0.3 mg/kg 3 doses; 1.0 mg/kg 2 doses.  Data beyond this study day are 
considered follow-up results. 
***n=1 
No severe or life-threatening events were reported. The incidence of the most common treatment-
emergent AEs (i.e., occurring in more than one subject in any treatment group) is presented 
below (see Table 4). The most notable AEs were those related to increases in hematologic 
laboratory measures in the 1.0 mg/kg dose group: hematocrit, hemoglobin, and RBC count.  AEs 
of increased hemoglobin and/or hematocrit were reported for seven of the eight subjects in this 
dose group.  These events were reported as mild or moderate elevations; all were considered 
probably related to study drug treatment. Three of the subjects in the 1.0 mg/kg group with 
elevated hemoglobin levels underwent phlebotomies and all hemoglobin elevations were resolved 
by the end of the follow-up period. No erythroid lineage AEs were reported in the 0.1 or 0.3 
mg/kg treatment groups.   
 
Mean Change from Baseline (g/dL) 
Evaluation Time Point 
Placebo 
 
N=7* 
ACE-011 
0.1 mg/kg 
N=8 
ACE-011 
0.3 mg/kg 
N=8 
ACE-011 
1.0 mg/kg 
N=8 
Baseline Mean, pre-Dose 1 
13.20 
13.11 
13.30 
12.71 
Day 8 
0.17 
0.68 
0.85 
1.21 
Day 15 
-0.27 
0.43 
0.44 
1.75 
Day 29 
0.27 
0.61 
1.21 
    2.68** 
Day 36 
0.56 
0.64 
1.89 
2.96 
Day 43 
-0.02 
0.89 
1.21 
2.85 
Day 57 
0.27 
1.28 
    1.64** 
2.09 
Day 64 
0.53 
1.11 
2.49 
2.21 
Day 71 
-0.10 
1.34 
2.09 
1.66 
Day 85 
0.38 
    1.18** 
2.55 
1.86 
Day 92 
      0.00*** 
1.04 
      1.60*** 
      3.80*** 
Day 99 
-0.20 
1.21 
      3.20*** 
      1.28*** 
Day 113 
-0.02 
1.30 
1.29 
1.04 
Day 141 
 0.30 
0.95 
0.34 
2.30 
Day 169 
       0.20*** 
0.06 
 
      2.00*** 
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Headache was reported frequently in all treatment groups with no apparent dose response trend, 
though the reports in the higher dose groups were more often considered possibly related to 
treatment.  Most headaches were reported as mild (one headache was reported as moderate).  
Paresthesia and dizziness were reported more frequently in the ACE-011 groups, though the 
events were generally not considered drug related.  Other frequently reported events (e.g. fatigue, 
upper respiratory infection) did not appear to increase with dose and were generally mild.  
 
Table 4: 
A011-02: Incidence of Most Common Adverse Events    
Dose Group 
System Organ Class and Preferred Term 
Placebo 
N=7 
n (%) 
0.1 mg/kg 
N=8 
n (%) 
0.3 mg/kg 
N=8 
n (%) 
1.0 mg/kg 
N=8 
n (%) 
GASTROINTESTINAL DISORDERS 
     Diarrhea 
0 (0.0%) 
2 (25.0%) 
0 (0.0%) 
0 (0.0%) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
     Asthenia 
0 (0.0%) 
1 (12.5%) 
2 (25.0%) 
0 (0.0%) 
     Fatigue 
2 (28.6%) 
0 (0.0%) 
1 (12.5%) 
2 (25.0%) 
INFECTIONS AND INFESTATIONS 
     Viral upper respiratory tract infection 
0 (0.0%) 
4 (50.0%) 
0 (0.0%) 
0 (0.0%) 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
     Limb injury 
0 (0.0%) 
1 (12.5%) 
0 (0.0%) 
2 (25.0%) 
INVESTIGATIONS 
     Hematocrit increased 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
6 (75.0%) 
     Hemoglobin increased 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
7 (87.5%) 
     Red blood cell count increased 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
3 (37.5%) 
METABOLISM AND NUTRITION DISORDERS 
     Decreased Appetite 
1 (14.3%) 
0 (0.0%) 
2 (25.0%) 
0 (0.0%) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
     Arthralgia 
2 (28.6%) 
0 (0.0%) 
2 (25.0%) 
0 (0.0%) 
     Muscle spasms 
0 (0.0%) 
1 (12.5%) 
0 (0.0%) 
2 (25.0%) 
NERVOUS SYSTEM DISORDERS 
     Dizziness 
0 (0.0%) 
0 (0.0%) 
2 (25.0%) 
2 (25.0%) 
     Headache 
2 (28.6%) 
4 (50.0%) 
3 (37.5%) 
2 (25.0%) 
     Paresthesia 
1 (14.3%) 
0 (0.0%) 
0 (0.0%) 
3 (37.5%) 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
     Oropharyngeal pain 
2 (28.6%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
VASCULAR DISORDERS 
     Hot flush 
0 (0.0%) 
2 (25.0%) 
0 (0.0%) 
1 (12.5%) 
Note: Table presents AEs reported in more than one subject in any treatment group. 
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Hemoglobin levels for all subjects with elevations had returned to within normal limits by the end 
of the study.   
Adrenal cortical function was monitored through evaluation of serum electrolytes (sodium and 
potassium levels) and through cortisol response to adrenocorticotropic hormone (ACTH) 
stimulation. All ACTH simulation test results were normal. 
PK results confirmed that the PK of ACE-011 is linear following the first SC doses of all three 
dose levels tested, 0.1, 0.3, and 1.0 mg/kg. The terminal half life (T1/2) of ACE-011 following the 
last dose in all three dose groups was identical, with mean T1/2 being approximately 23 days. The 
mean CL/F ranged from 3.05 to 3.90 mL/d/kg, the mean Vz/F ranged from 97.47 to 103.03 
mL/kg, and the mean T1/2 ranged from 20.92 to 23.34 days in all 3 dose levels, with no apparent 
dependence on dose.  
Bone mineral density was assessed by dual-energy X-ray absorptiometry (DXA).  Mean change 
and mean percent change in BMD results from baseline to study end are summarized in the table 
below.  A dose-dependent increase in the BMD of the total hip from baseline to end of study was 
observed, with a significant and rapid increase of 2.4% in the 1.0 mg/kg dose group, compared to 
a 0.7% decrease in the placebo group.  BMD results for lumbar spine showed slight increases of 
0.4% to 1.0% from baseline to study end in all active treatment groups, compared with a 0.5% 
decrease in the placebo group (see Table 5 below): 
Table 5: 
A011-02: A Phase 1b Study in Healthy Postmenopausal Women: BMD 
 
5.4.3. 
A011-04: A Phase 2a Study in Patients with Osteolytic Lesions of Multiple 
Myeloma  
Study A011-04 is an ongoing, non-IND, Phase 2a, multi-center, randomized, multiple-dose study 
to evaluate the safety, tolerability and efficacy of ACE-011 in patients with osteolytic lesions of 
multiple myeloma.  Safety evaluations include adverse events (AEs), clinical laboratory tests, 
standard 12-lead electrocardiogram (ECG), vital signs, Eastern Cooperative Oncology Group  
Treatment Group 
Placebo 
 
N=7 
ACE-011 
0.1 mg/kg 
N=8 
ACE-011 
0.3 mg/kg 
N=8 
ACE-011 
1.0 mg/kg 
N=8 
 
Mean 
Change 
Mean Percent 
Change 
Mean 
Change 
Mean Percent 
Change 
Mean 
Change 
Mean Percent 
Change 
Mean 
Change 
Mean Percent 
Change 
Lumbar Spine 
(g/cm2) 
-0.0020 
-0.5% 
0.0099 
0.7% 
0.0082 
1.0% 
0.0051 
0.4% 
Total Hip 
(g/cm2) 
-0.0062 
-0.7% 
0.0050 
0.6% 
0.0075 
0.9% 
0.0220 
2.4% 
Number of doses administered and day of last dose per treatment group: 0.1 mg/kg 4 doses (Day 85); 0.3 mg/kg 3 doses (Day 57); 1.0 mg/kg 2 
doses (Day 29).  Data beyond this study day are considered follow-up results. 
 
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Phase 1a single dose and Phase 1b multiple dose healthy volunteer clinical studies.  These 
parameters were evaluated up to doses of 3.0 mg/kg IV and 1.0 mg/kg SC, and no clinically 
significant perturbations in adrenal function were observed.     
Laboratory findings from the Phase 1a single dose study showed elevations in hematology 
results, pancreas and liver enzymes, and uric acid.  The most commonly seen treatment-emergent 
adverse events in this study were headache, infusion site reaction, injection site hemorrhage, and 
toothache.  
Based on data from the Phase 1b study, the most notable AEs were increases in hematologic 
laboratory measures in the 1.0 mg/kg dose group: hematocrit, hemoglobin, and RBC count.  AEs 
of increased hemoglobin and/or hematocrit were reported for seven of the eight subjects in this 
dose group.  These events were reported as mild or moderate elevations; all were considered 
probably related to study drug treatment.  No erythroid lineage AEs were reported in the 0.1 or 
0.3 mg/kg treatment groups.  Hematologic parameters will be monitored carefully in this study.   
Headache was reported frequently in all treatment groups with no apparent dose response trend, 
though the reports in the higher dose groups were more often considered possibly related to 
treatment.  Most headaches were reported as mild (one headache was reported as moderate).  
Paresthesia and dizziness were reported more frequently in the ACE-011 groups, though the 
events were generally not considered drug related.  Other frequently reported events (e.g. fatigue, 
upper respiratory infection) did not appear to increase with dose and were generally mild. 
In the Phase 1b multiple-dose healthy volunteer study, some subjects treated with ACE-011 
showed elevations in blood pressure.  One subject who had received two doses of ACE-011 at the 
1.0 mg/kg dose level had a serious adverse event.  The patient was hospitalized for further 
evaluation of increases in blood pressure and symptoms that may have been caused by the 
increase in blood pressure.  The symptoms that the subject experienced included headache, 
dizziness, nausea, vomiting, and elevated hematology values (increases in the number of red 
blood cells).  This serious adverse event was judged to be probably related to the study drug and 
resolved following discharge from hospital the following day. Throughout the course of the 
follow up period hematologic parameters were monitored frequently until the hemoglobin and 
hematocrit levels returned to within normal limits. Further details are outlined in the Investigator 
Brochure.  
As with all biologics there is the potential for anti-drug antibodies that can be associated with 
increased drug clearance and hypersensitivity reactions.  An immune response to ACE-011 has 
been seen in monkeys that received the drug for 1 month and longer.  Some of those animals 
developed kidney inflammation possibly related to that immune response.  Anti-drug antibody 
formation will be assessed in this study to examine the immunogenicity of ACE-011, and to 
monitor reversibility of any AEs over time.   
Please refer to the Investigator Brochure for more information. 
 
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6. 
TRIAL OBJECTIVES AND PURPOSE 
6.1. 
Primary objective  
1. To evaluate the proportion of patients in each ACE-011 dose regimen who achieve a 
hematopoietic response during the treatment period including up to 2 months after the last 
dose of ACE-011 treatment of chemotherapy induced anemia in patients with metastatic 
breast cancer. Hematopoietic response is defined as an increase in hemoglobin of ≥ 1.0 
g/dL above the study baseline value for 28 consecutive days during the treatment period 
including up to 2 months after the last dose of ACE-011, in the absence of any RBC 
transfusions and/or ESAs. 
6.2. 
Secondary objectives 
1. To evaluate the safety and tolerability of ACE-011 for the treatment of chemotherapy 
induced anemia in patients with metastatic breast cancer.  
2. To evaluate the percentage of patients who achieve an increase in hemoglobin of  ≥ 2 
g/dL and/or hemoglobin concentration ≥ 11 g/dL for a consecutive 28 day period during 
the treatment period including up to 2 months after the last dose of ACE-011 in the 
absence of any RBC transfusions and/or ESAs.  
3. To estimate the duration of the hematopoietic response associated with each ACE-011 
dose regimen. 
4. To estimate the time to the hematopoietic response associated with each ACE-011 dose 
regimen. 
5. To estimate the proportion of patients receiving red blood cell (RBC) transfusions and/or 
ESAs within each cycle of ACE-011 with each dose regimen. 
6. To estimate the effect of each ACE-011 dose regimen on progression free survival (PFS) 
and objective response rate (ORR). 
6.3. 
Exploratory objectives  
1. To estimate the effect of each ACE-011 dose regimen on serum bone biomarkers (OC, 
BSAP, P1NP, CTX, TRACP-5b), urine bone biomarker (uNTX), bone mineral density 
(DXA scans of lumbar spine and hip) and incidence of skeletal related events (SREs). 
2. To evaluate the quality of life in relation to the treatment of chemotherapy induced 
anemia in patients with metastatic breast cancer during the study. 
.  
 
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7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design and Plan 
This is a Phase 2, double-blind, randomized, placebo-controlled study to evaluate the efficacy, 
safety, and tolerability of ACE-011 for the treatment of chemotherapy induced anemia in patients 
with metastatic breast cancer. A total of 105 patients will be enrolled. 
The Data Monitoring Committee (DMC) is responsible for reviewing safety. The DMC will be 
comprised of a minimum of 3 members.  The DMC will meet regularly during the study to 
review serious adverse events (SAEs), adverse events (AEs), laboratory results, and vital signs. 
Safety data will be reviewed throughout the study by the DMC, Medical Monitor and the 
Investigator. DMC responsibilities, membership, meeting frequencies and procedures will be 
outlined in the DMC charter.  
Patients will be evaluated for study inclusion/exclusion criteria by the Investigator. Patients who 
meet the study entry criteria will be enrolled within 14 days of the screening visit. Local lab 
values for hemoglobin and central lab values will be utilized for the evaluation of patient 
eligibility. Central labs will also be used in the evaluation of patient safety throughout the study. 
Local lab values for hemoglobin and hematocrit will be collected and reported from screening 
(for eligibility) through the Day 281/Termination visit.  Three cohorts of 30 patients each are 
planned at the following doses of ACE-011: 0.1 mg/kg, 0.3 mg/kg and 0.5 mg/kg. Fifteen 
patients will be enrolled into the placebo cohort (as shown in Table 6). 
Table 6: 
Study Design    
 
 
 
  
 
 
 
 
Each eligible patient will be randomized to one of the four cohorts to receive a dose administered 
as a subcutaneous injection every 28 days for up to 4 doses. Dosing will be administered on days 
1, 29, 57, and 85. Concurrent treatment with a myelosuppressive chemotherapy regimen for 
metastatic breast cancer will also be administered per standard of care at the site. Patients will be 
stratified according to administration of either single agent weekly chemotherapy or less frequent 
chemotherapy regimens.  
Blood samples will be collected from approximately one-third of patients participating in the 
study at selected study sites for the evaluation of serum concentrations of ACE-011.  Pre-dose PK 
samples will be collected as specified in Appendix 5 (PK sampling schedule.) 
Dose  
Number of  Patients 
0.1 mg/kg 
30 
0.3 mg/kg 
30 
0.5 mg/kg 
30 
Placebo 
15 
Total patients enrolled: 105 
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Patients will be assessed for safety by monitoring adverse events, clinical laboratory tests, 
assessment of quality of life (FACT- Fatigue (17)), vital signs and physical examinations on an 
ongoing basis.  ECGs will be performed during screening, prior to dosing on the first cycle, 
during the first, second and third cycle, Day 113 (28 days after the last dose of ACE-011) and at 
Day 281/ Termination visit to monitor safety.  Blood pressure and lab values will be assessed at 
each study visit during the treatment and treatment follow up period. 
Local laboratory hemoglobin values and blood pressure values will be evaluated prior to dosing 
per the dose modification criteria, as applicable.  
Patients will be followed for a minimum of 7 months following their last dose of ACE-
011/placebo. Study participation for each patient is approximately 10.5 months (14 day screening 
period, 3 month treatment period with a 2 month treatment follow up period, and a 5 month post 
treatment follow-up period). If a patient discontinues the study due to progression of disease 
(metastatic breast cancer) and/or begins another chemotherapy regimen, the patient will 
discontinue ACE-011/placebo treatment, complete the Day 281/Termination visit procedures, and 
be followed for survival only (a minimum 7 months from the last dose of ACE-011/placebo).   
Anti-drug antibody testing will be performed at Day 281/Termination visit and if positive, the 
patient may be asked to return to the clinical site for additional monthly anti-drug antibody 
testing for up to 12 months, after their last dose. 
Back up (serum) blood samples will be collected for future testing for the evaluation of novel 
tumor markers, such as endoglin and ALK-1 (activin receptor-like kinase-1). The samples will 
the stored at the central lab until this evaluation is performed. 
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8. 
SELECTION AND WITHDRAWL OF PATIENTS 
8.1. 
Number of Patients 
The study will include three dose levels of ACE-011 at 0.1 mg/kg, 0.3 mg/kg and 0.5 mg/kg and 
a placebo group. A total of 105 will be treated with ACE-011 or placebo. 
8.2. 
Entry Criteria 
8.2.1. 
Patient Inclusion Criteria 
1. Women > 18 years of age. 
2. Histologically confirmed diagnosis of breast cancer documented by cytology or biopsy. 
3. Evidence of metastatic breast cancer with a minimum of one measurable lesion or non 
measurable lesion per RECIST criteria (Appendix 1). 
4. Receiving a multicycle myelosuppressive chemotherapy regimen including one of the 
following: anthracycline, taxane, gemcitabine or vinorelbine. 
5. Anticipated treatment with the same myelosuppressive chemotherapy regimen for a 
minimum of 9 weeks after Day 1 of ACE-011/placebo administration.  
6. Hemoglobin value between ≥ 6.5 to < 11.0 g/dL (≥ 65 to < 110 g/L).  
7. ≥ 30 days must have elapsed (from Day 1) since previous treatment with erythropoiesis-
stimulating agent (including concurrent treatment with IV iron) for chemotherapy 
induced anemia.  
8. ≥ 7 days have elapsed (from Day 1) since the last RBC blood transfusion and receipt of ≤ 
2 units of blood in the past 30 days.  
9. ECOG Performance status of 0 – 2 (Appendix 2). 
10. Adequate renal (creatinine ≤ 1.5 x ULN or creatinine clearance ≥ 40 mL/min) and hepatic 
function (bilirubin < 1.5 x ULN; AST/ALT < 2.5 x ULN). 
11. Females of childbearing potential  participating in the study are to use adequate birth 
control measures (i.e. oral contraceptives or two forms of barrier method birth control) 
during study participation. Females of childbearing potential must have a negative serum 
pregnancy test within 7 days to ACE-011/placebo administration (Day 1). A female of 
childbearing potential is a sexually mature woman who has not undergone a 
hysterectomy or who has not been postmenopausal for at least 24 consecutive months 
(i.e. who has had menses at some time in the preceding 24 months). 
12. Life expectancy of ≥ 6 months. 
13. Is willing to adhere to the study visit schedule, understand and comply with all protocol 
requirements. 
14. Understand and sign a written informed consent. 
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8.2.2. 
Patient Exclusion Criteria 
1. At the time of screening patients who have any grade > 3 toxicity (as per NCI CTCAE 
v3.0 (Appendix 3)) (except for the following disease related toxicities:  hematological 
events- anemia, thrombocytopenia or neutropenia or non hematological events- nausea, 
vomiting, fatigue, or muscle or bone/joint pain).  
2. Prior radiation therapy to > 20% of the whole skeleton. Use of palliative radiation if the 
area being treated is <15% of body surface area with no pelvic radiation or no more than 
10% of the bone marrow reserve is radiated is permitted during patient participation in 
the study, at the discretion of the investigator. 
3. Have received more than 5 prior chemotherapy treatment regimens for metastatic breast 
cancer.  
4. Clinically significant pulmonary, endocrine, neurologic, gastrointestinal, hepatic or 
genitourinary disease unrelated to underlying hematologic disorder.  
5. Patients with heart failure as classified by the New York Heart Association (NYHA) 
classification of 3 or higher (Appendix 4). 
6. History of thrombosis, deep vein thrombosis (DVT), pulmonary emboli, or embolic 
stroke. 
7. Untreated CNS metastases (exception: CNS metastases treated with whole brain 
radiotherapy > 6 months prior to randomization). 
8. Diagnosis of a myeloid malignancy or known history of myelodysplasia.  
9. History of second malignancy within 5 years (except excised and cured basal cell 
carcinoma, squamous cell carcinoma of the skin or cervical carcinoma in situ).  
10. Patients with a recent history (within 14 days of Day 1) of administration of systemic (IV 
or oral) antibiotics. Patients should be free of infection at least 14 days after the last dose 
of systemic antibiotic treatment (from Day 1). 
11. Uncontrolled hypertension. If hypertension is considered clinically stable, systolic blood 
pressure (BP) must be < 150 mmHg and diastolic BP must be < 100 mmHg.  
12. Known history of hepatitis C antibody (HCV), hepatitis B surface antigen (HBsAg and 
HB core Ab), or human immunodeficiency virus (HIV) antibody.   
13. Deficiency in iron (serum ferritin < 100 ng/mL (< 224.7 pmol/L)), vitamin B12, or folate. 
14. History of anemia as a result of inherited hemoglobinopathy such as sickle cell anemia or 
thalassemia.  
15. History of autoimmune or hereditary hemolysis or active gastrointestinal bleeding 
(within the previous 12 months as compared to Day 1). 
16. Patient received treatment with another investigational drug or device within 1 month 
prior to Day 1, or if the half life of the previous product is known, within 5 times the half 
life prior to dosing, whichever may be longer.  
17. Pregnant or lactating females. 
18. History of severe allergic or anaphylactic reactions or hypersensitivity to recombinant 
proteins or excipients in the investigational product. 
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19. Major surgery within 30 days prior to Day 1 (patients must have completely recovered 
from any previous surgery prior to Day 1).   
8.3. 
Patient Withdrawal Criteria 
Patients will be informed that they have the right to withdraw from the study at any time for any 
reason without prejudice to their medical care.   
Patients must be withdrawn from the study for any of the following reasons:  
• Patient request 
• Patient is unwilling or unable to comply with the protocol 
• ESA administration during the treatment period 
• Medical reason, such as cancer or treatment related toxicity, or at the discretion of the 
Investigator and/or the Medical Monitor(s) 
The reasons for withdrawal must be recorded in the patient’s case report form (CRF).  The 
Investigator must notify the Medical Monitor and the contract research organization (CRO) 
immediately when a patient has been discontinued/withdrawn due to an AE.  All patients who 
are withdrawn from the study should complete the tests and evaluations scheduled for Day 
281/Termination at the time of withdrawal. Discontinued/withdrawn patients should be followed 
for survival only for 7 months after the last dose of ACE-011/placebo.  Patients who withdraw 
due to ESA administration during the treatment period or due to ACE-011 related toxicity should 
enter the treatment follow-up period.  
 
 
 
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9. 
TREATMENT OF PATIENTS 
9.1. 
Concomitant Medications 
9.1.1. 
General Concomitant Medication Usage 
During screening, and during the study, patients may take only stable doses of medications for 
chronic conditions that are not specifically excluded by the protocol (see Sections 8.2.1 Patient 
Inclusion Criteria and 8.2.2 Patient Exclusion Criteria).  The Medical Monitor should be 
consulted by the Investigator if there are any concerns about what constitutes a stable dose or 
what is a chronic condition.  Concomitant medications will be recorded in the CRF through 90 
days from the last dose of ACE-011/placebo.   
9.1.2. 
Concomitant treatment for anemia 
Concurrent therapy with a new prescription medication related to treatment of anemia during the 
course of the study must first be discussed with the Investigator and Medical Monitor prior to 
administration, unless appropriate medical care necessitates that medication should begin before 
the Medical Monitor can be consulted.  
9.1.2.1. 
Iron supplementation 
Iron supplementation within 7 days of Day 1 (besides an oral general multivitamin with iron) 
will not be allowed. If a patient becomes iron replete during study treatment (ferritin < 100 
ng/mL (< 224.7 pmol/L) or transferrin < 20%), treatment with iron supplementation is at the 
discretion of the investigator.  
9.1.2.2. 
Erythropoiesis-stimulating agents (ESAs) 
If concurrent treatment with erythropoiesis-stimulating agent is required in the opinion of the 
investigator, the erythropoiesis-stimulating agent label instructions are to be followed. The 
patient is to discontinue further treatment with ACE-011/placebo and enter the treatment follow- 
up period of the study. See Table 7 for Schedule of Events.  
9.1.2.3. 
RBC Transfusions 
Concurrent treatment for chemotherapy induced anemia with blood transfusions is recommended 
when hemoglobin value is < 8 g/dL or at investigator discretion if the hemoglobin value is above 
8 g/dL and associated with anemia symptoms such as hemodynamic or pulmonary compromise 
that require treatment. If a transfusion is given to a patient during the treatment period, ACE-
011/placebo should be administered no sooner than 7 days from the date of the transfusion.  
After the transfusion, the hemoglobin value should be assessed no later than 7 days from the date 
of the transfusion.  On the day of ACE-011/placebo administration, the hemoglobin value and 
blood pressure will be assessed. See Figure 1 for ACE-011/placebo dose modification rules.  
 
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9.2. 
Chemotherapy 
Chemotherapy treatment for metastatic breast cancer is to be given as per standard of care at the 
site.  ACE-011/placebo administration should be given prior to chemotherapy administration on 
ACE-011/placebo administration days.  Continuation of treatment with the same chemotherapy 
regimen through the treatment or post-treatment follow-up period of the study is at the discretion 
of the investigator. 
9.3. 
Treatment Compliance 
Each dose of ACE-011/placebo will be administered as a SC injection at the clinical site by the 
study staff and will be documented in the study record.  Monitoring for patient compliance with 
the treatment regimen is therefore unnecessary.  
9.4. 
Rescreening 
If a patient receives a screening number through Interactive Web/Voice Response System 
(IVRS/IWRS) and does not continue to meet eligibility criteria (prior to randomization), the 
patient may be re-screened once during the enrollment period of the study. Evaluation and 
decision to re-screen a patient will be done by the site, Medical Monitor, and Acceleron (as 
needed). All screening procedures are to be re-performed to verify patient eligibility. The 
screening DXA scan is to be re-done if more than 45 days has elapsed since the initial screening 
DXA scan. Informed consent must be signed by the patient if more than 14 days has elapsed 
since initially signing consent.  
Patients who have been randomized but have not received the first dose of ACE-011/placebo and 
no longer meet eligibility criteria will require further evaluation by the site, Medical Monitor, 
and Acceleron (as needed) for continued participation in the study. 
9.5. 
Randomization  
Patients will be randomized to limit scientific bias within the study. Randomization assignments 
will be generated through a computerized system, provided by an Interactive Web/Voice 
Response System (IWRS/IVRS). Patients will be stratified according to frequency of the planned 
chemotherapy regimen (weekly chemotherapy vs. less frequent chemotherapy administration). 
9.5.1. 
Blinding 
The Investigators, patients, and sponsor or representative will remain blinded to the treatment 
arm assignment of each patient. The unblinded statistician will remain uninvolved in the study 
conduct until database lock and unblinding of the data has occurred.  
Safety parameters will be reviewed on an ongoing basis throughout the study including adverse 
events, serious adverse events, laboratory listings, and vital signs. If substantial toxicity trends 
are observed in one treatment group versus another, the DMC may request unblinding the 
treatment code assignment schema.  
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9.5.2. 
Unblinding 
In the event of a medical emergency for an individual patient in which knowledge of the study 
medication is critical to the patient’s medical management, the investigator may break the blind 
for that patient. However, prior to breaking the blind, every effort must be made by the 
investigator to first discuss the need to break the blind with the sponsor or sponsor 
representative. Further, it must be determined by the investigator that breaking the treatment 
blind is necessary information for the medical management of that patient. If the blind is broken, 
the patient must withdraw from the study by completing the Day 281/Termination visit 
procedures and be followed for survival only 
9.6. 
Treatments Administered 
9.6.1. 
Selection of Doses in the Study 
Single dose administration of ACE-011 up to 3.0 mg/kg was previously demonstrated to be safe 
and to have durable effects on markers of bone formation and resorption as well as red blood 
cells following a single IV administration.  A dose-limiting pharmacodynamic effect of ACE-
011 with increases in hemoglobin, hematocrit and RBCs was established in healthy post-
menopausal women at the 1.0 mg/kg dose level following multiple SC administration.  This 
study will confirm the safety in following repeated SC administration of ACE-011 and further 
evaluate the potential efficacy in patients with chemotherapy induced anemia.  The safety and 
preliminary efficacy of ACE-011 following multiple doses up to 0.5 mg/kg will be assessed 
using a parallel randomization design. 
9.6.2. 
Selection and Timing of Dosing for Each Patient 
Patients will be enrolled and receive their assigned dose of ACE-011/placebo every 28 days (i.e. 
on Days 1, 29, 57, and 85). Patients will be receiving chemotherapy, concurrently for metastatic 
breast cancer. After completion of ACE-011/placebo treatment, patients will return to the site 
monthly for 3 follow-up assessments (i.e., Days 99, 113 and 141).  Subsequently, the patient will 
return to the site for 4 post treatment follow-up assessments (i.e. Days 169, 197, 225, and 253). 
The patient will return to the site for a termination visit approximately 1 month after the post 
treatment follow-up period (Day 281).  Patients will be discontinued from the ACE-011/placebo 
treatment for reasons listed in section 8.3 of the protocol, for unacceptable toxicity, if the 
chemotherapy regimen is discontinued or for disease progression that requires the initiation of 
another chemotherapy treatment. 
9.6.2.1. 
ACE-011 Treatment Related Toxicity  
Patients with grade ≥3 toxicity related to ACE-011 will be discontinued from ACE-011/placebo 
treatment except for the following.  Patients with grade 3 hypertension that decreases to grade 
≤ 1 within 7 days after treatment with anti-hypertensive therapy may continue on ACE-
011/placebo treatment.  Dose reduction rules will apply at the subsequent scheduled dosing 
day(s). Patients with a hemoglobin level above the upper limit of normal at any time during the 
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study after Day 1 will be discontinued.  Patients who discontinue treatment with ACE-
011/placebo will enter the treatment follow-up period. 
9.6.2.2. 
ACE-011 Dose Modification Rules 
Throughout the study blood pressure and hemoglobin values will be evaluated for patient safety. 
The local hemoglobin values and blood pressure values will be evaluated at each study visit and 
on each ACE-011/placebo dosing day.  The hemoglobin values from the previous 28 days 
between each ACE-011/placebo dosing day and blood pressure will be reviewed and evaluated 
for dose modifications.  The parameters below outline rules for dosing modifications (Figure 1).  
Table 8 outlines the dose reduction levels of ACE-011.  
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10. 
STUDY PROCEDURES AND SCHEDULE 
10.1.1. 
Written Informed consent 
Patients will be required to sign an Institutional Review Board/Institutional Ethics Committee 
(IRB/IEC) approved informed consent form (ICF) prior to any study related procedures, 
including screening evaluations. 
Screen failure information will be maintained, including but not limited to, reason for failure.   
10.1.2. 
Screening (Within 14 days of dosing) 
The following will be collected within 14 days prior to the initial dosing Day 1.  Confirmatory 
labs for eligibility criteria must be drawn and resulted within 7 days of Day 1: 
• Informed consent 
• Assessment of inclusion/exclusion criteria 
• Complete Medical History and Physical Examination 
• Vital signs including weight (kg), heart rate (beats/min), seated systolic and diastolic 
blood pressure (mmHg), temperature (°C) and height. 
• FACT-Fatigue survey 
• 12 lead Electrocardiogram (ECG) performed at two time intervals (approximately one 
hour apart) in triplicate at 3 minute intervals (±1 min) 
• Serum iron, total iron binding capacity (TIBC), transferrin and serum ferritin  
• Vitamin B12 and serum folate levels 
• Coagulation 
• Serum chemistry  
• Hematology 
• LH, FSH, testosterone, progesterone, and estradiol  
• Serum Pregnancy Test for females of childbearing potential- to be assessed within 7 
days of Day 1. 
• Urinalysis 
• Evaluation of transfusion frequency (including history of transfusion up to 8 weeks 
prior to Day 1) 
• Documentation of concomitant medications (any treatments taken 28 days prior to 
Day 1) 
 
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• Females of childbearing potential- collection of menstrual cycle information of the 
start and end date of the last menstruation. 
• CT/MRI scan:  A CT/MRI scan acquired within 6 weeks of initiating the current 
chemotherapy regimen may be used for the screening assessment. One measurable or 
non-measurable lesion per RECIST v1.1 is to be identified by the scan.  
o Scans of the anatomical areas of  head ( if applicable), neck, thoracic, 
abdominal, and pelvic are to be available for evaluation. If one of the 
anatomical areas listed has not be acquired, prior to screening, then a CT/MRI 
must be done, during screening for this study,  to ensure a scan of the  head (if 
applicable), neck, thoracic, abdominal, and pelvic is available.  
 Brain (head) CT only to be done to rule out CNS metastases in patients 
with suspicious clinical symptoms or prior history of CNS metastases.  
• Dual-energy X-ray absorptiometry (DXA) of  lumbar spine and hip 
o Refer to Imaging Acquisition Guidelines for guidelines regarding washout 
period for contrast ( if used) for radiological images, prior to acquiring DXA 
scan. 
• Bone scans (only for patients with bone metastases) acquired within 4 weeks of 
initiating the current chemotherapy regimen may be used for the screening 
assessment. 
10.1.3. 
Initial Dosing: Day 1  
Patients will be dosed on Day 1.  Results from screening evaluations must be reviewed prior to 
randomization to confirm patient eligibility.  A patient will be considered randomized once a 
multi-digit patient identification number has been assigned to the patient through the 
IVRS/IWRS.  After assignment of the patient identification number and the inclusion/exclusion 
criteria have been met, ACE-011/placebo administration may begin. 
Chemotherapy regimen will be administered per standard of care at the site. The following tests 
must be performed prior to ACE-011/placebo administration: 
• Confirm eligibility of patient by inclusion/exclusion criteria (local lab hemoglobin 
value and central lab values). The local hemoglobin value should be drawn prior to 
ACE-011/placebo administration (up to 1 day prior to Day 1).  
• Physical Examination 
• Vital signs including weight (kg), heart rate (beats/min), seated systolic and diastolic 
blood pressure (mmHg), and temperature (°C)  
• FACT-Fatigue survey 
• 12 lead Electrocardiogram (ECG) performed at two time intervals (approximately one 
hour apart) in triplicate at 3 minute interval (±1 min) 
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• Serum iron, total iron binding capacity, transferrin and serum ferritin 
• Coagulation 
• Chemistry   
• Hematology 
• Serum erythropoietin marker  
• LH, FSH, testosterone, progesterone, and estradiol  
• Anti-drug antibody test 
• Bone biomarkers- osteocalcin (OC), procollagen type 1 N-terminal propeptide 
(P1NP), serum bone specific alkaline phosphatase (BSAP), C-terminal type 1 
collagen telopeptide (CTX), tartrate-resistant acid phosphatase isoform-5b (TRACP-
5b), and urine N-telopeptide (uNTX).  
o Please refer to the Study Reference Guide, provided under separate cover, for 
the Bone Biomarker Collection and Handling Guidelines for instructions the 
on collection of serum and urine for the biomarkers.  
• Back-up blood sample to be drawn for future testing 
• Females of childbearing potential- Urine (dipstick) pregnancy test to be collected and 
resulted prior to ACE-011/placebo dosing 
• Urinalysis 
• Evaluation of transfusion frequency  
• Documentation of concomitant medications  
• Evaluation of adverse events (after ACE-011/placebo administration)  
• Females of childbearing potential-collection of menstrual cycle information of the 
start and end date of the last menstruation. 
• Patients will be administered ACE-011/placebo before the chemotherapy regimen 
begins during the study visits.  
After ACE-011/placebo and chemotherapy are administered, the patient may leave the clinic, 
based on the clinical judgment of the staff.   
All study visit day dates (inclusive of windows) are calculated from Day 1(day of initial ACE-
011/placebo administration). 
10.1.4. 
ACE-011/placebo administration: Days 29, 57, and 85 (± 3 days)  
Chemotherapy regimen will be administered per standard of care at the site. ACE-011/placebo 
will be administered approximately every 28 days. The following procedures must be performed 
prior to ACE-011/placebo administration: 
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• Physical Examination 
• Vital signs including weight (kg), heart rate (beats/min), seated systolic and diastolic 
blood pressure (mmHg), and temperature (°C)  
• FACT-Fatigue survey 
• Serum iron, total iron binding capacity, transferrin and serum ferritin  
• Coagulation 
• Serum chemistry  
• Hematology 
• Serum erythropoietin marker  
• LH, FSH, testosterone, progesterone, and estradiol 
• Anti-drug antibody test 
• Bone biomarkers- OC, BSAP, P1NP, CTX, TRACP-5b, and uNTX 
o Please refer to the Study Reference Guide, provided under separate cover, for 
the Bone Biomarker Collection and Handling Guidelines for instructions the 
collection of serum and urine for the biomarkers.  
• Back-up blood sample to be drawn for future testing 
• Females of childbearing potential -Urine (dipstick) pregnancy test to be collected and 
resulted prior to ACE-011/placebo dosing 
• Urinalysis (Day 85 only) 
• Evaluation of transfusion frequency  
• Documentation of concomitant medications  
• Evaluation of adverse events  
• Females of childbearing potential- collection of menstrual cycle information of the 
start and end date of the last menstruation. 
Hemoglobin (HgB) (by review of local lab values) and blood pressure (BP) measurement must 
be assessed prior to ACE-011/placebo dose administration. Local Hgb must be done within 1 day 
prior to the ACE-011/placebo dosing day. 
10.1.5. 
Additional visits during Treatment Period: Days 8, 15, 22, 36 (± 1 day), 43, 64 
and 71 (± 2 days) 
 
Chemotherapy regimen will be administered per standard of care at the site.  The following 
procedures are to be performed during the study visit:  
 
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• Vital signs including weight (kg), heart rate (beats/min), seated systolic and diastolic 
blood pressure (mmHg), and temperature (°C)  
• 12 lead ECG (Days 8, 36, and 64 only- to be done in triplicate at 3 minute intervals 
(±1 min) 
• Serum folate (Day 36 only) 
• Coagulation 
• Serum chemistry  
• Hematology  
• Back-up blood sample to be drawn for future testing 
• Evaluation of transfusion frequency  
• Documentation of concomitant medications 
• Evaluation of adverse events  
• CT/MRI scan (Day 64 only, +/- 5 day window).  Same modality and anatomical areas 
as acquired prior to enrollment should be used for follow up scans. Tumor response 
assessments to be evaluated by the investigator. 
If patient terminates the treatment period early, prior to the Day 85 of ACE-011/placebo, the 
patient will enter the treatment period follow up. However, if patient terminates ACE-
011/placebo early and begins a new chemotherapy regimen, the patient should complete the Day 
281/Termination visit procedures and be followed for survival only. 
10.1.6. 
Treatment Period Follow-up visits : Days 99, 113 (± 3 days)  and 141 (± 7 days) 
Chemotherapy regimen will be administered per standard of care at the site.  The following 
procedures are to be performed during the study visit: 
• Physical Examination (Days 113 and 141 only) 
• Vital signs including weight (kg), heart rate (beats/min), seated systolic and diastolic 
blood pressure (mmHg), and temperature (°C)  
• 12 lead ECG-including (Day 113 only- to be done in triplicate at 3 minute intervals 
(±1 min) 
• Serum folate (Day 113 only) 
• Coagulation  
• Serum chemistry  
• Hematology   
• Serum erythropoietin marker  (Day 141 only) 
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• LH, FSH, testosterone, progesterone, and estradiol (Days 113 and 141 only) 
• Anti-drug antibody test (Days 113 and 141 only) 
• Bone biomarkers- OC, BSAP, P1NP, CTX, TRACP-5b, and uNTX (Days 113 and 
141 only) 
o Please refer to the Study Reference Guide, provided under separate cover, for 
the Bone Biomarker Collection and Handling Guidelines for instructions on  
the collection of serum and urine for the biomarkers. 
• Back-up blood sample to be drawn for future testing 
• Evaluation of transfusion frequency  
• Documentation of concomitant medications 
• Evaluation of adverse events  
• Females of childbearing potential- collection of menstrual cycle information of the 
start and end date of the last menstruation. (Days 113 and 141 only) 
• CT/MRI scan (Day 113 only, +/- 5 day window). Same modality and anatomical 
areas as acquired prior to enrollment should be used for follow up scans. Tumor 
response assessments to be evaluated by the investigator. 
• DXA of  lumbar spine and hip (Day 113 only) 
o Refer to Imaging Acquisition Guidelines for guidelines regarding washout 
period for contrast ( if used) for radiological images, prior to acquiring DXA 
scan. 
10.1.7. 
Post Treatment Period Follow-up visits : Days 169, 197, 225, and 253 (± 7 days) 
If a CT/MRI and bone scan (if applicable) is performed as per standard of care during the post 
treatment period follow up, results may be collected within the CRF to capture the status of the 
disease. Chemotherapy regimen will be administered per standard of care at the site. The 
following procedures are to be performed during the study visit: 
• Hematology 
• Evaluation of transfusion frequency  
• Documentation of concomitant medications ( up to 90 days from the last dose of 
ACE-011/placebo) 
• Evaluation of adverse events  ( up to 90 days from the last dose of ACE-011/placebo) 
 
 
 
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10.1.8. 
Termination Visit:  Day 281 (± 7 days) 
Day 281 is the final visit.  If a patient terminates the study early, the Day 281 procedures should 
be followed. Chemotherapy regimen will be administered per standard of care at the site. The 
following procedures are to be performed during the study visit: 
• Physical Examination 
• Vital signs including weight (kg), heart rate (beats/min), seated systolic and diastolic 
blood pressure (mmHg), and temperature (°C)  
• FACT-Fatigue survey 
• 12 lead ECG (in triplicate at 3 minute intervals (±1 min) 
• Serum iron, total iron binding capacity, transferrin and serum ferritin  
• Serum folate 
• Coagulation 
• Serum chemistry  
• Hematology  
• Serum erythropoietin marker 
• Anti-drug antibody test 
• Bone biomarkers- OC, BSAP, P1NP, CTX, TRACP-5b, and uNTX  
o Please refer to the Study Reference Guide, provided under separate cover, for 
the Bone Biomarker Collection and Handling Guidelines for instructions on 
the collection of serum and urine for the biomarkers. 
• Back-up blood sample to be drawn for future testing 
• Females of childbearing potential -Urine (dipstick) pregnancy test  
• Urinalysis 
• Evaluation of transfusion frequency  
• Documentation of concomitant medications ( up to 90 days from the last dose of 
ACE-011/placebo) 
• Evaluation of adverse events ( up to 90 days from the last dose of ACE-011/placebo) 
• DXA of  lumbar spine and hip 
o Refer to Imaging Acquisition Guidelines for guidelines regarding washout 
period for contrast ( if used) for radiological images, prior to acquiring DXA 
scan. 
 
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• Bone scan (Day 281, +/- 5 day window). Follow-up scan to be acquired if performed 
at baseline and the scan was abnormal. 
If a patient has a positive anti-drug antibody result at Day 281/Termination visit, the patient may 
be asked to return to the clinical site for additional monthly anti-drug antibody testing, up to 12 
months after their last dose. 
 
10.2. 
Discontinuation of study 
The Sponsor may terminate this study, after consultation with the Investigator, at any time for 
safety or administrative reasons.  The Sponsor may terminate the study if the occurrence of 
serious adverse events (SAEs) or other findings suggest unacceptable risk to the health of the 
patients.   
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11. 
INVESTIGATIONAL PRODUCT MATERIALS AND 
MANAGEMENT 
11.1. 
Reference Product 
The placebo (control agent) to be used in this study will be sterile normal saline (0.9% Sodium 
Chloride for Injection) administered as a SC injection.  Sterile, normal saline will be supplied by  
the investigational site’s pharmacy, as applicable.  The manufacturer’s directions for placebo 
storage and handling are to be followed, as are standard clinical practices for ensuring sterility of 
the placebo. 
11.2. 
Investigational Product Packaging and Labeling 
ACE-011 will be supplied in 2 mL clear glass vials with gray stoppers and red flip-top seals that 
contain 1 mL of ACE-011.  The investigational drug product consists of ACE-011 in PBS at a 
nominal concentration of approximately 50 mg/mL. 
11.3. 
Investigational Product Storage 
ACE-011 is recommended to be stored at ≤ -65°C. 
11.4. 
Investigational Product Preparation 
See ACE-011 Handling and Administration Guidelines. 
11.5. 
Administration 
ACE-011/placebo will be administered by subcutaneous injection (SC). Subcutaneous injections 
will be given in the upper arm and/or thigh. Please refer to ACE-011 Handling and 
Administration Guidelines document for further information. 
Dose modifications will be determined by the investigator after reference to the dose 
modification rules listed in Figure 1. In the case of a dose interruption or dose reduction of ACE-
011, the investigator or designee will notify the pharmacy staff, who is unblinded, of the 
treatment decision for appropriate preparation of the investigational drug to maintain the blind of 
the study.  
11.6. 
Drug Accountability 
Accountability for ACE-011/placebo is the responsibility of the Investigator.  Investigational 
clinical supplies must be received by a designated person at the clinical site and kept in a secured 
location.  The investigational site must maintain accurate records demonstrating dates and 
amounts of ACE-011/placebo received, to whom it was dispensed (patient-by-patient 
accounting), and accounts of any ACE-011/placebo accidentally or deliberately destroyed or 
returned.  Unless otherwise notified, all vials of ACE-011/placebo, both used and unused, must 
be saved for drug accountability.  The used vials may be discarded, per the institution’s standard  
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practice, after drug accountability has been completed by the monitor. The Investigator must 
return all unused vials of ACE-011 to the Sponsor at the end of the study, or the ACE-011 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. 
11.7. 
Investigational Product Handling and Disposal 
Please refer to the ACE-011 Handling and Administration Guidelines, provided under separate 
cover, for detailed drug handling, administration, and storage instructions.   
 
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12. 
ASSESSMENT OF EFFICACY 
Efficacy measurements will include assessments for hematopoietic response which is defined as 
an increase in hemoglobin of  ≥ 1 g/dL, ≥ 2 g/dL and/or hemoglobin concentration ≥ 11 g/dL 
above the study baseline value for 28 consecutive days during the treatment period including up 
to 2 months after the last dose of ACE-011, in the absence of any RBC transfusions and/or 
ESAs, at each dose level. The hematopoietic endpoints will be determined by the monitoring of 
hematologic laboratory values and RBC transfusion and/or ESA administration. Secondary 
endpoints associated with assessment of disease progression will be evaluated by CT/MRI scan 
and bone mineral density by DXA scans, respectively. Bone biomarkers and incidence of 
skeletal related events (SREs) will also be evaluated for all patients. SREs are defined as 
pathologic fracture, radiation therapy to bone, surgery to bone, or spinal cord compression. 
Quality of life assessment (FACT-Fatigue) will be evaluated for each patient.  
 
 
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13. 
ASSESSMENT OF SAFETY 
13.1. 
Safety Parameters 
13.1.1. 
Adverse Events 
All patients will be assessed for safety by monitoring adverse events, clinical laboratory tests, 
vital signs and physical examinations. AE information will be collected throughout the study. 
See Section 14 Adverse Events for a full description of AE definitions, AE and SAE reporting 
procedures, and emergency procedures. 
13.1.2. 
Clinical Laboratory Tests 
The following laboratory safety assessments will be drawn at the investigational site’s local 
laboratory according to the laboratory collection recommendations. The samples will then be 
sent to the central lab for value reporting. Please refer to Lab Reference Manual for further 
information. Hemoglobin and hematocrit lab tests will be drawn and evaluated by the local 
laboratory at screening and at each visit day throughout the study. The local hemoglobin 
laboratory value will be used in the evaluation of ACE-011/placebo dose modifications. The 
sponsor may request additional safety tests be performed based on ongoing data review during 
the study.  
• Iron studies: Serum iron, total iron binding capacity (TIBC), transferrin and serum ferritin on  
 
specified days. 
• 
Nutritional tests: Serum folate and vitamin B12 
• 
Coagulation (central lab only): prothrombin time (PT), partial thromboplastin time (PTT), 
and fibrinogen 
• 
Serum chemistry (central lab only): AST, ALT, lactate dehydrogenase (LDH), total bilirubin, 
indirect bilirubin, alkaline phosphatase, total protein, albumin, sodium, potassium, chloride, 
carbon dioxide, calcium, phosphorus, blood urea nitrogen (BUN), creatinine, uric acid, 
glucose, amylase, and lipase.  
• 
Hematology: complete blood count (CBC) with differential and platelet.  CBC includes red 
blood cells (RBC), white blood cells (WBC), hemoglobin, hematocrit, mean corpuscular 
volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin 
concentration (MCHC).  Reticulocyte percent, erythropoietin levels and peripheral blood 
smear will be collected on specified days.  
• 
Bone biomarkers: (serum) osteocalcin (OC), procollagen type 1 N-terminal propeptide 
(P1NP), serum bone specific alkaline phosphatase (BSAP), C-terminal type 1 collagen 
telopeptide (CTX), tartrate-resistant acid phosphatase isoform-5b (TRACP-5b), and urine N-
telopeptide (uNTX).  
• 
Pregnancy test for females of child bearing potential 
 
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• Urinalysis (central lab only): including determination of pH, specific gravity, protein, 
glucose, ketones, blood, leukocyte esterase and nitrite. Microscopy required only to follow-
up abnormal findings.  
13.1.3. 
Other Safety Assessments  
• Physical examinations 
• Vital signs: weight (kg), heart rate (beats/min), seated blood pressure (mmHg) and  
temperature (°C).  Height will be collected at screening only. 
• FACT-Fatigue survey 
• 12-lead ECG (done in triplicate) 
• LH, FSH, testosterone, progesterone, and estradiol 
• Anti-drug antibody test 
• CT/MRI scan   
• DXA 
• Bone scans (for those patients with baseline bone metastases) 
13.2. 
Pharmacokinetics 
 See Appendix 5 for further details regarding PK sampling.  
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14. 
ADVERSE EVENT 
Adverse Event 
An adverse event (AE) is any untoward medical occurrence in a patient administered a 
pharmaceutical product, which does not necessarily have a causal relationship with the treatment.  
An AE can be any unfavorable and unintended sign (e.g., including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of the investigational drug, 
whether or not it is considered to be investigational drug related.  This includes any newly 
occurring event or previous condition that has increased in severity or frequency since the 
administration of investigational drug (treatment-emergent). 
Serious Adverse Event 
A serious adverse event (SAE) is any AE, occurring at any dose level and regardless of causality 
that: 
• Results in death. 
• Is life-threatening:  Life-threatening means that the patient was at immediate risk of death 
from the reaction as it occurred, (i.e., it does not include a reaction which hypothetically 
might have caused death had it occurred in a more severe form). 
• Requires inpatient hospitalization or prolongation of existing hospitalization.  
• Results in persistent or significant disability/incapacity. 
• Is a congenital anomaly/birth defect. 
• Is an important medical event: an important medical event is an event that may not result 
in death, be life-threatening, or require hospitalization but may be considered an SAE 
when, based upon appropriate medical judgment, it may jeopardize the patient and may 
require medical or surgical intervention to prevent one of the outcomes listed in the 
definitions for SAEs.  Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, blood dyscrasias or 
convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse.   
• A hospitalization for an elective procedure will not be considered a SAE.  
SAEs will be captured throughout the patient participation in the study through Day 
281/Termination visit. SAEs will be captured up to 90 days from the last dose of ACE-
011/placebo for those patients who are followed for survival only. 
Unexpected Adverse Event 
An unexpected AE is an AE that is not reported in the Investigator Brochure or in the case of an 
AE already described, the severity of which is not consistent with that described in the 
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14.1. 
Adverse Event Classification 
The following classifications should be used when evaluating the relationship of AEs and SAEs 
to the investigational drug. 
None: 
No relationship between the experience and the administration of 
investigational drug; related to other etiologies such as concomitant 
medications or patient’s clinical state. 
Unlikely:  
 
 
The current state of knowledge indicates that a relationship is unlikely.   
Possibly: 
A reaction that follows a plausible temporal sequence from administration 
of the investigational drug and follows a known response pattern to the 
suspected investigational drug.  The reaction might have been produced by 
the patient’s clinical state or other modes of therapy administered to the 
patient. 
Probably: 
A reaction that follows a plausible temporal sequence from administration 
of the investigational drug and follows a known response pattern to the 
suspected investigational drug.  The reaction cannot be reasonably 
explained by the known characteristics of the patient’s clinical state or 
other modes of therapy administered to the patient. 
Definitely: 
A reaction that follows a plausible temporal sequence from administration 
of the investigational drug and follows a known response pattern to the 
suspected investigational drug and can be confirmed with a positive re-
challenge test or supporting laboratory data. 
Severity of AEs will be graded by the investigator using the National Cancer Institute (NCI; US) 
Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 guidelines (Appendix 
3). 
14.2. 
Recording Adverse Events 
Patients will be evaluated and questioned generally for AEs during the course of the study, 
starting from baseline (Day 1).  The Medical History CRF should be comprehensive of patient’s 
medical history up to Day 1. All AEs occurring after ACE-011/placebo administration up to 90 
days from the last dose of ACE-011/placebo are to be documented on AE CRF. The specific 
disease or syndrome rather than individual associated signs and symptoms should be identified 
by the investigator and recorded on the CRF.  
Specifically, skeletal related event information is to be captured and reported for the duration of 
the patient participation in the study through Day 281/Terminiation visit. SREs will be captured 
up to 90 days from the last dose of ACE-011/placebo for those patients who are followed for 
survival only. 
 
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Serious Adverse Events (SAEs) 
For SAEs, a SAE form must be completed with as much information as possible and submitted 
in the time frame described in Section 14.3.  
When new significant information is obtained as well as when the outcome of an event is known, 
the investigator should record the information on a new SAE form.  If the patient was 
hospitalized, a copy of the discharge summary must be included as part of the patient medical 
file.  In all instances, the investigator should follow up with patients until the outcome of the 
SAE is known. 
14.3. 
Reporting Adverse Events 
All AEs spontaneously reported by the patient and/or in response to an open question from study 
personnel or revealed by observation, physical examination or other diagnostic procedures will 
be recorded on the AE CRF.  Any clinically relevant change in laboratory assessments or other 
clinical findings is considered an AE and must be recorded on the AE CRF. Clinically significant 
laboratory abnormalities are those that are identified as such by the investigator and/or those that 
require intervention. All AEs are to be followed until the event resolves or the clinical course is 
stabilized.  
Serious Adverse Events 
For SAEs, a SAE form must be completed with as much information as possible and submitted 
in the time frame described below. 
All SAEs that occur during the course of the study (from the signing of the ICF and throughout 
patient participation in the study procedures) must be reported by the Investigator to PPD and 
Sponsor by faxing the SAE form within 24 hours from the point in time when the Investigator 
becomes aware of the SAE.  All SAEs and deaths must be reported regardless of relationship to 
investigational drug.   
   
SAE Reporting: 
PPD Medical Monitor 
PPD Inc. 
 
 
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If there are serious, unexpected AEs that are also associated with the use of the investigational 
drug, the Sponsor will notify the appropriate regulatory agency(ies) and all appropriate parties on 
an expedited basis.  It is the responsibility of the Investigator to promptly notify the Institutional 
Review Board (IRB) of all unexpected SAEs involving risk to human patients. 
 
14.4. 
Emergency Sponsor Contact 
In the event of a medical emergency (i.e., an event that requires immediate attention regarding 
the treatment of a patient, operation of the clinical study, and/or the use of investigational drug), 
investigational site personnel must immediately contact the Medical Monitor. 
 
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15. 
STATISTICS 
Statistics Analysis Overview 
The study will be considered complete with regard to the primary endpoint once all eligible 
subjects have completed up to 2 months after the last dose of ACE-011. Patients will be 
randomized to one of three ACE-011 treatment groups (0.1, 0.3 and 0.5 mg/kg) or placebo with a 
ratio of 2:2:2:1.  Patients will be stratified according to administration of either single agent 
weekly chemotherapy or less frequent chemotherapy regimens.  
15.1. 
Determination of Sample Size 
With an anticipated dropout rate of 20%, a sample size of 30 patients per dose level is estimated 
to achieve at least 80% power with 2 sided significance level of 0.05 to differentiate targeted 
response rate of p1=0.45 from null hypothesis p0=0.20. An additional 15 patients will be 
enrolled to the placebo group for safety comparison. A total of 105 patients will be randomized 
to three ACE-011 dose groups (0.1, 0.3, and 0.5 mg/kg) and placebo with a ratio of 2:2:2:1.  
15.2. 
Analysis Populations 
For this study, the following populations will be defined and used in the analysis and 
presentation of the data. 
Modified Intent-to-Treat (MITT) population: The MITT population is defined as all patients 
randomized who received at least one dose of ACE-011/placebo. 
Per-Protocol (PP) population: The PP population is defined as all patients randomized who have 
confirmed chemotherapy induced anemia, received at least one dose of ACE-011 and on study 
(treatment) for at least 2 months (57 days). 
Safety population: The safety population is defined as all patients who received at least one dose 
of ACE-011 or placebo. 
15.3. 
Background and Demographic Characteristics 
Summary statistics (mean, standard deviation, median, minimum and maximum) will be 
provided for those variables measured on a continuous scale.  The frequency distribution 
(number and percentage) will be provided for those variables measured on a nominal scale. 
15.3.1. 
Patient Disposition 
Patient disposition (analysis population allocation, entered, discontinued, along with primary 
reason for discontinuation) will be summarized using frequency and percent for each dose group.  
A summary of patients enrolled by site will be provided.  
 
 
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15.3.2. 
ACE-011 
ACE-011 treatment exposure (total dosage received) will be summarized for each dose group as 
well as for each cycle for each dose level.  Listings for dose adjustment will be provided. 
15.3.3. 
Concomitant Therapy 
By-patient listings will be provided for all concomitant medications and therapies taken during 
the study.  All concomitant medications will be coded and categorized by the WHO drug coding 
system.  Usage frequency of each coded concomitant medications will be summarized by each 
dose group. 
15.4. 
Efficacy Evaluation 
15.4.1. 
Primary Efficacy Analysis 
The primary efficacy endpoint is the hematopoietic response rate at each dose level.  It is defined 
as the proportion of patients who have a hematopoietic response of an increase in hemoglobin of 
≥ 1.0 g/dL for 28 consecutive days during the treatment period including up to 2 months after the 
last dose of ACE-011, in the absence of any RBC transfusions and/or ESAs. The ACE-011 
treatment period is defined as from the time of first ACE-011 dose to up to 2 months after the 
last dose of ACE-011 treatment.  To be considered as a responder, all hemoglobin measurements 
during a 28 consecutive day period or longer must have an increase of ≥ 1.0 g/dL from baseline. 
If RBC transfusions and/or ESAs are required, no hemoglobin measurements within 28 days will 
be used to determine the hemoglobin response. Primary efficacy analysis will be based on PP 
population.  Primary efficacy analysis will also be conducted on MITT population as supportive 
to the PP based analysis.  Patients who do not receive ACE-011 will be excluded from primary 
efficacy analysis.  Patients who discontinue the ACE-011 treatment prematurely, with no 
sufficient hemoglobin measurement, will be counted as non-responder in the calculation of 
response rate.     
A 95% confidence interval (CI) for the response rate for each dose level will be provided to 
assess whether 95% CI of response rate contains null hypothesis response rate, p0=0.20.  The 
response rate and 95% CI will also be provided for patients with chemotherapy on weekly basis 
versus those with chemotherapy on a less frequent basis for each dose level as well as overall (all 
three doses levels analyzed together).  
An exploratory analysis with the Kaplan Meier approach will be considered to account for those 
patients who discontinue the ACE-011 treatment prematurely if the drop out rate is greater than 
20%.  Exploratory analysis of comparing hematopoietic response rates between active and 
placebo will be performed using Fisher’s exact test.  Due to the nature of the study (phase 2 dose 
determination study), no multiplicity adjustment will made for the multiple comparisons.  
 
 
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15.4.2. 
Secondary Efficacy Analyses 
The secondary efficacy endpoints include: 
• Proportion of patients achieving an increase in hemoglobin of  ≥ 2 g/dL and/or 
hemoglobin concentration ≥ 11 g/dL for 28 consecutive days during the treatment period 
and up to 2 months after the last dose of ACE-011 in the absence of any RBC 
transfusions and/or ESAs.   
• Duration of hematopoietic response (days) defined as the first time hemoglobin increases 
at least  ≥ 1 g/dL, ≥ 2 g/dL and/or hemoglobin concentration ≥ 11 g/dL from baseline to 
the last time there is hemoglobin ≥ 1 g/dL, ≥ 2 g/dL and/or hemoglobin concentration ≥ 
11 g/dL increase from baseline.  Duration of response is only calculated for a responder 
and will be at least 28 days.  The duration of response will be at least 28 days is only 
calculated for a patient who meets the primary efficacy endpoint.  
• Time to achieve hematopoietic response (days) defined as time from first dose of ACE-
011 to the first time a hemoglobin result at least  ≥ 1 g/dL, ≥ 2 g/dL and/or hemoglobin 
concentration ≥ 11 g/dL increase from baseline and maintained for a period of at least 28 
consecutive days. 
• Proportion of patients receiving red blood cell (RBC) transfusions and/or ESAs in each 
dose group as well as within each cycle of each ACE-011 dose level. 
• Objective tumor response rate for each dose level using RECIST criteria. 
• Progression-Free Survival is defined as the time from the start date of current 
chemotherapy regimen to the first observation of documented disease progression or 
death due to any cause.  If the subject has not progressed or died at the time of final 
analysis, PFS will be censored at the time of last tumor assessment.   
The statistical analysis for binary endpoints will be similar to the primary efficacy analysis.  For 
time to event endpoints, the Kaplan-Meier method will be used to estimate the survival curve and 
median time to event.  These analyses will be performed for each dose group and all ACE-011 
groups combined.   
15.5. 
Safety Evaluation 
Safety variables will be tabulated and presented for all patients who receive ACE-011.  Adverse 
events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA).  
Incidence of treatment-emergent adverse events will be presented by system organ class (SOC) 
and preferred term.  Adverse events will also be presented by severity, and relationship to 
investigational drug.  Change from baseline in clinical laboratory parameters and vital signs will 
be summarized across time.  Shift tables will be presented for selected laboratory parameters.  
Physical examination results will be presented in listings.  
 
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Data from all patients who receive one or more doses of ACE-011/placebo will be included in 
the safety analyses. To assess clinical safety, adverse events, vital sign measurements and 
clinical laboratory information will be summarized by visit. Adverse events and laboratory 
results will also be summarized by severity grade (NCI CTCAE v3.0). Descriptive statistics will 
be generated and shift tables provided as appropriate.  
15.6. 
Pharmacokinetic Evaluation 
Listing of individual patient serum ACE-011 concentrations, actual blood sampling times and 
graphs of concentration vs. time will be prepared for each dose group.  Summaries of PK 
parameters will be summarized by dose group. The trough concentrations will be summarized for 
all patients who provide pharmacokinetic samples by dose group. Exploratory analyses will be 
performed to correlate trough concentrations with efficacy, bone biomarker data, and safety data, 
however these analyses will be data-driven and only conducted if warranted by the data.  
15.6.1. 
Anti-drug Antibody Data 
The results of anti-drug and neutralizing antibodies will be presented over time.  Exploratory 
analysis will be performed on the potential effect of anti-drug antibody on ACE-011 PK and 
drug exposure if anti-drug antibody tests are deemed positive. 
15.7. 
Interim Analysis  
There is no planned interim analysis for this study.   
15.8. 
Deviation from Original Analysis Plan 
Deviations from the statistical analyses outlined in this protocol will be indicated in the statistical 
analysis plan; any further modifications will be noted in the final clinical study report. 
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16. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
16.1. 
Study Monitoring 
The Clinical Monitor will arrange to visit the Investigator sites at regular intervals during the 
study.  The monitoring visits must be conducted according to the applicable ICH and GCP 
guidelines to ensure protocol adherence, quality of data, drug accountability, compliance with 
regulatory requirements, and continued adequacy of the investigational site and its facilities.  
During these visits, CRFs and other data related to the study will be reviewed and any 
discrepancies or omissions will be resolved.  The Clinical Monitor will be given access to study 
relevant source documents (including medical records) for purposes of source data verification. 
During and/or after completion of the study, quality assurance officers named by the Sponsor or 
the regulatory authorities may wish to perform on-site audits.  The Investigator is expected to 
cooperate with any audit and provide assistance and documentation (including source data) as 
requested. 
16.2. 
Audits and Inspections 
The Investigators and clinical sites will permit trial related monitoring, audits, IRB review, and 
regulatory inspections as requested by FDA, the Sponsor or designee, including direct access to 
source data/documents (i.e., original medical records, laboratory reports, hospital documents, 
progress reports, signed ICFs, etc.) in addition to CRFs. 
 
 
 
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17. 
QUALITY CONTROL AND QUALITY ASSURANCE 
17.1. 
Data Quality Control and Quality Assurance 
17.1.1. 
Investigator responsibility 
The investigator is responsible for ensuring the study is conducted according to the protocol, 
Code of Federal Regulations (CFR), GCP, and any other applicable regulatory requirements. The 
investigator responsibilities are outlined in these documents along with ensuring that 
documentation of a signed informed consent, is obtained prior to patient participation in the 
study.  
17.1.2. 
Protocol modifications 
The investigator may not modify the protocol without agreement from the Sponsor and prior 
review or approval by the IRB. Any deviations from the protocol should be documented by the 
investigator or designee.  
17.2. 
Financing and Insurance 
Financing and insurance are addressed in a separate document. 
17.3. 
Confidentiality 
To maintain patient privacy, all CRFs, drug accountability records, study reports and 
communications will identify the patient by the assigned patient identification number.  The 
Investigator will grant monitor(s) and auditor(s) from the Sponsor or designee and regulatory 
authority(ies) access to the patient’s original medical records for verification of data gathered on 
the CRFs and to audit the data collection process.  The patient’s confidentiality will be 
maintained and will not be made publicly available to the extent permitted by the applicable laws 
and regulations. 
All information regarding the investigational product supplied by the Sponsor to the Investigator 
is privileged and confidential information.  The Investigator agrees to use this information to 
accomplish the study and will not use it for other purposes without consent from the Sponsor.  It 
is understood that there is an obligation to provide the Sponsor with complete data obtained 
during the study.  The information obtained from the clinical study will be used towards the 
development of the investigational product and may be disclosed to regulatory authority(ies), 
other Investigators, corporate partners, or consultants as required. 
17.4. 
Publication Policy 
All information concerning ACE-011 is considered confidential and shall remain the sole 
property of the Sponsor.  The Investigator agrees to use this information only in conducting the 
study and shall not use it for any other purposes without the Sponsor’s written approval.  The 
Investigator agrees not to disclose the Sponsor’s confidential information to anyone except to  
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people involved in the study that need such information to assist in conducting the study, and 
then only on like terms of confidentiality and nonuse. 
It is understood by the Investigator that the information developed from this clinical study will 
be used by the Sponsor in connection with the development of ACE-011, and therefore may be 
disclosed as required to regulatory agencies.  To allow for the use of the information derived 
from clinical studies, it is understood that there is an obligation to provide the Sponsor with 
complete test results and all data developed in the study. 
No publication or disclosure of study results will be permitted except as specified in a separate, 
written, agreement between the Sponsor and the Investigator. 
17.5. 
Protocol Amendments 
Protocol amendments that impact patient safety change the scope of the investigation, or affect 
the scientific quality of the study must be approved by the IRB and submitted to the appropriate 
regulatory authorities before implementation of such modifications to the study. 
In the event that the protocol needs to be modified immediately to eliminate an apparent hazard 
to a patient, the Sponsor will amend and implement the protocol change and subsequently notify 
the regulatory authorities and/or the IRB, as appropriate. 
 
 
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18. 
ETHICS 
18.1. 
Institutional Review Board or Independent Ethics Committee 
The Investigator must obtain written IRB approval of the protocol, approval for relevant 
supporting information and all types of patient recruitment and advertisement and ICF prior to 
starting the study.  The IRB will meet all Food and Drug Administration (FDA) requirements 
governing IRBs (Code of Federal Regulations, Title 21, Part 56). 
The Sponsor or designee must approve the ICF submitted to the investigational site’s IRB. All 
patient recruitment and advertisements must be submitted to the Sponsor or designee prior to 
submission to the IRB, for review. 
18.2. 
Ethical Conduct of the Study 
The Sponsor and the Investigator must comply with all instructions, regulations, and agreements 
in this protocol and in the applicable International Conference on Harmonisation (ICH) and GCP 
guidelines, and must also conduct the study in accordance with local regulations.   
18.3. 
Written Informed Consent 
18.3.1. 
Informed Consent 
Informed written consent is required from each patient prior to any testing under this protocol, 
including screening tests and evaluations.  The consent form, as specified by the clinical site’s 
IRB, must follow the Protection of Human Patients regulations listed in the Code of Federal 
Regulations, Title 21, Part 50.   
The background of the proposed study and the benefits and risks of the procedures and study 
must be explained to the patients.  It is the responsibility of the Investigator to obtain consent and 
to provide the patient with a copy of the signed and dated ICF.  Confirmation of a patient’s 
informed consent must also be documented in the patient’s medical record prior to any testing 
under this protocol, including screening tests and evaluations. 
All ICFs used in this study must be approved by the appropriate IRB and by the Sponsor or 
designee.  The ICF must not be altered without the prior agreement of the relevant IRB and the 
Sponsor.   
18.3.2. 
Patient Data Protection 
Prior to any testing under this protocol, including screening tests and evaluations, patients must 
authorize the release and use of protected health information (PHI), as required by local law. 
The patient will not be identified by name in the CRF or in any study reports.  These reports will 
be used for research purposes only.  The Sponsor, its designee, and various government health 
agencies may inspect the records of this study.  Every effort will be made to keep the patient’s 
personal medical data confidential. 
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19. 
DATA HANDLING AND RECORDKEEPING 
19.1. 
Case Report Form Completion 
CRFs will be completed for each randomized patient.  It is the Investigator’s responsibility to 
ensure the accuracy, completeness, and timeliness of the data reported in the patient’s CRF.  
Source documentation supporting the CRF data should indicate the patient’s participation in the 
study and should document the dates and details of study procedures, AEs, and patient status. 
Investigators will maintain copies of the CRFs at the clinical site.  For patients who discontinue 
or terminate from the study, the CRFs will be completed as much as possible, and the reason for 
the discontinuation or termination clearly and concisely specified on the appropriate CRF. 
19.2. 
Retention of Records 
The Investigator will maintain all study records according to ICH-GCP and applicable regulatory 
requirements.  Records will be retained for at least 2 years after the last marketing application 
approval or 2 years after formal discontinuation of the clinical development of the investigational 
product or according to applicable regulatory requirements.  If the Investigator withdraws from 
the responsibility of keeping the study records, custody must be transferred to a person willing to 
accept the responsibility.  The Sponsor must be notified in writing if a custodial change occurs. 
 
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20. 
REFERENCES 
 
      1.   Groopman JE, Itri LM. (1999). Chemotherapy-Induced Anemia in Adults: Incidence and  
 
   Treatment. Journal of the National Cancer Institute 91, 1616-1634.  
2. NCCN Clinical Practice Guidelines in Oncology: Cancer and Chemotherapy Induced 
Anemia, V.3. 2009 http://www.nccn.org/professionals/physician_gls/PDF/anemia.pdf; 
2008. 
3. Ying S-Y. (1988). Inhibins, activins, and follistatins: gonadal proteins modulating the 
secretion of follicle-stimulating hormone. Endocrine Rev 9, 267-93. 
4. Woodruff TK. (1998). Regulation of cellular and system function by activin. Biochem 
Pharmacol 55, 953-63. 
5. Perrien DS, Akel NS, Edwards PK, Carver AA, Bendre MS, Swain FL, Skinner RA, 
Hoque WR, Nicks KM, Pierson TM, Suva LJ, and Gaddy D. (2007). Inhibin A is an 
endocrine stimulator of bone mass and strength. Endocrinology 148, 1654-65. 
6. Rivier J, Spiess J, McClintock R, Vaughan J and Vale W. (1985). Purification and partial 
characterization of inhibin from porcine follicular fluid. Biochem Biophys Res Commun 
133, 120-7. 
7. Murata M, Onomichi K, Eto Y, Shibai H, and Muramatsu M. (1988). Expression of 
erythroid differentiation factor (EDF) in Chinese hamster ovary cells.  Biochem Biophys 
Res Commun 151, 230-5. 
8. Shiozaki M, Sakai R, Tabuchi M, Nakamura T, Sugino K, Sugino H, and Eto Y. (1992). 
Evidence for the participation of endogenous activin A/erythroid differentiation factor in 
the regulation of erythropoiesis.  Proc Natl Acad Sci USA 89, 1553-6. 
9. Shiozaki M, Sakai R, Tabuchi M, Eto Y, Kosaka M, and Shibai H. (1989). In vivo 
treatment with erythroid differentiation factor (EDF/activin A) increases erythroid 
precursors (CFU-E and BFU-E) in mice. Biochem Biophys Res Commun 165, 1155-61. 
10. Nakao K, Kosaka M and Saito S. (1991). Effects of erythroid differentiation factor (EDF) 
on proliferation and differentiation of human hematopoietic progenitors. Exp Hematol 19, 
1090-5 
11. Chen Y-G, Lui HM, Lin S-L, Lee JM, and Ying S-Y. (2002). Regulation of cell 
proliferation, apoptosis, and carcinogenesis by activin. Exp Biol Med 227, 75-87. 
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12. Mathews LS. (1994). Activin receptors and cellular signaling by the receptor serine 
kinase family. Endocr Rev 15, 310-25. 
13. Chantry A, Heath D, Mulivor A, Coulton L, Evans H, Abdul N, Werner ED, Bouxsein 
ML, Pearsall RS, Seehra J, Vanderkerken K, and Croucher PI. (2008). Inhibiting activin-
A signalling stimulates bone formation, prevents tumor-induced osteolytic bone 
destruction and blocks bone metastasis. Submitted 2008. 
14. Pearsall RS, Canalis E, Cornwall-Brady M, Underwood KW, Haigis B, Ucran J, Kumar 
R, Pobre E, Grinberg A, Werner ED, Glatt V, Stadmeyer L, Smith D, Seehra J, and 
Bouxsein ML. (2008). A soluble activin type IIA receptor induces bone formation and 
improves skeletal integrity. Proc Natl Acad Sci USA 105, 7082-7 
15. Lotinun S, Fajardo RJ, Pearsall RS, Bouxsein ML, and Baron R. (2008). A soluble 
activin receptor type IIA fusion protein, ACE-011, increases bone mass by stimulating 
bone formation and inhibiting bone resorption in cynomolgus monkeys. ASBMR 30th 
annual meeting, 2008. 
16. Ruckle J, Jacobs M, Kramer W, Pearsall AE, Kumar R, Underwood KW, Seehra J, Yang 
Y, Condon CH, Sherman ML. (2008).  A single-dose, randomized, double-blind, 
placebo-controlled study of ACE-011 (ActRIIA-IgG1) in postmenopausal women.  J 
Bone Miner Res: 1-42.  Posted online on 2 Dec 2008. 
17. Functional Assessment of Chronic Illness, FACT-Fatigue Version 4. 
http://www.facit.org/qview/qlist.aspx. 2003. 
 
 
 
 
 
 
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21. 
APPENDICES 
Appendix 1: Response Evaluation Criteria in Solid Tumors 
 
 
Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 
  
Terms 
Definition 
Measurable disease  
 The presence of at least one measurable lesion by CT or MRI. If the 
measurable disease is restricted to a solitary lesion, its neoplastic nature 
should be confirmed by cytology/histology. 
All measurements should be taken and recorded in metric notation, using a 
ruler or calipers. All baseline evaluations should be performed as closely as 
possible to the beginning of treatment and never more than 4 weeks before 
the beginning of the treatment.  
Measurable lesions 
Lesions that can be accurately measured in least one dimension by CT scan 
with longest diameter > 10 mm (CT scan thickness no greater than 5 mm). 
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during 
follow-up.  
Non-measurable lesion 
All other lesions, including small lesions (longest diameter <10mm or 
pathological lymph nodes with P10 to <15mm short axis) as well as truly 
non-measurable lesions. Lesions considered truly non-measurable include: 
leptomeningeal disease, ascites, pleural or pericardial effusion, 
inflammatory breast disease, lymphangitic involvement of skin or lung, 
abdominal masses/abdominal organomegaly identified by physical exam 
that is not measurable by reproducible imaging techniques. 
 
 
 
 
 
 
 
 
 
 
 
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RECIST Criteria-Response Evaluation 
Evaluation of target lesions 
  
  
Complete Response (CR) 
 Disappearance of all target lesions. 
Any pathological lymph nodes (whether target or non-target) 
must have reduction in short axis to <10 mm. 
Partial Response (PR): 
At least a 30% decrease in the sum of diameters of target lesions, 
taking as reference the baseline sum diameters. 
Stable Disease (SD):   
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum 
diameters while on study. 
Progressive Disease (PD):  
At least a 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest sum on study (this includes the 
baseline sum if that is the smallest on study). In addition to 
the relative increase of 20%, the sum must also demonstrate 
an absolute increase of at least 5 mm.  
(Note: the appearance of one or more new lesions is also 
considered progression). 
 
 
 
 
Evaluation of non-target 
lesions 
  
  
Complete Response (CR):  
Disappearance of all non-target lesions and normalisation of 
tumour marker level. All lymph nodes must be non-pathological 
in size (<10mm short axis). 
 
Non-CR/Non-PD 
 
Persistence of one or more non-target lesion(s) and/or 
maintenance of tumour marker level above the normal limits. 
Progressive Disease (PD):  
Unequivocal progression (see comments below) of existing non-
target lesions.  
(Note: the appearance of one or more new lesions is also 
considered progression). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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                                              Acceleron Pharma  
 
 
 
RECIST Criteria-Response 
Evaluation cont- 
 
 
 
 
 
 
Evaluation of best overall 
response 
The best overall response is the best response recorded 
from the start of the treatment until disease 
progression/recurrence (taking as reference for PD the 
smallest measurements recorded since the treatment 
started). In general, the patient's best response assignment 
will depend on the achievement of both measurement and 
confirmation criteria. 
 
Patients with a global deterioration of health status 
requiring discontinuation of treatment without objective 
evidence of disease progression at that time should be 
classified as having “symptomatic deterioration”. Every 
effort should be made to document the objective 
progression even after discontinuation of treatment.  
 
In some circumstances it may be difficult to distinguish 
residual disease from normal tissue. When the evaluation of 
complete response depends on this determination, it is 
recommended that the residual lesion be investigated (fine 
needle aspirate/biopsy) to confirm the complete response 
status.  
 
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R,  Dancey J, Arbuck S, Gwyther S, Mooney M, 
Rubinstein L, Shankar L, Dodd L, Kaplan R,  Lacombe D, Verweij J.New response evaluation criteria in solid tumours: Revised 
RECIST guideline (version 1.1)  (2009). European Journal of Cancer 45, 228-247. 
 
 
 
 
 
 
 
 
 
 
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Appendix 2: ECOG Performance Status 
The ECOG scale is used to assess a patient’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 
patient.  
 
Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., Carbone, P.P. (1982) Toxicity And Response 
Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Onco 5:649-655. 
 
 
 
 
 
 
 
 
 
 
 
 
 
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, e.g., 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 
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                                              Acceleron Pharma  
 
 
 
 
Appendix 3:  National Cancer Institute (NCI) Common Terminology Criteria 
for Adverse Events (CTCAE) Version 3.0 
 
See http://ctep.cancer.gov/reporting/ctc.html  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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                                              Acceleron Pharma  
 
 
 
 
Appendix 4: New York Heart Association- Classification of heart failure 
Class 1 - Class 1 heart failure - no limitation of activities. No symptoms from ordinary activities. 
Class 2 - Class 2 heart failure- mild limitation of activity. Comfortable with rest or mild exertion. 
Class 3 - Class 3 heart failure- marked limitation of activity and be comfortable only at rest. 
Class 4 –Class 4 heart failure- complete rest, confined to bed or chair; any physical activity brings on  
discomfort and symptoms occur at rest. 
 National Heart, Lung, and Blood Institute, National Institutes of Health. New York Heart Association Classification. 2008. 
 
 
 
 
 
 
 
 
 
 
 
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Protocol Amendment – Summary of Changes 
CLINICAL STUDY PROTOCOL 
A Phase 2, Double-Blind, Randomized, Placebo-Controlled 
Study of ACE-011 for the Treatment of Chemotherapy 
Induced Anemia in Patients with Metastatic Breast Cancer 
 
 
STUDY DRUG: 
 
 
ACE-011 
 
PROTOCOL NUMBER: 
 
 
A011-08 
 
SPONSOR:  
             
 
Celgene Corporation 
 
 
 
 
 
 
86 Morris Avenue 
 
 
 
 
 
 
Summit, NJ  07901 
 
MEDICAL MONITOR: 
                 PPD Inc. 
 
                
 
                                                          
 
 
 
 
 
          
 
 
 
 
 
          
 
      
 
 
PROTOCOL DATE: 
                 13 March 2009 
AMENDMENT #1: 
                 22 April 2009 
AMENDMENT #2:  
 
           21 May 2009 
AMENDMENT #3: 
 
           07 October 2009 
AMENDMENT #4: 
                 04 February 2010 
 
 
04Feb10 
                                                     
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Protocol A011-08                                                                                                                           Confidential                                      
Revision 4.0 
Section 2. Protocol Synopsis 
 
Name of Sponsor 
o Deletion of Acceleron Pharma 
o Addition of Celgene Corporation 
Study center 
o Amend the number of sites to 35-45 centers 
Duration of study 
o Language was amended to state that patients may be asked to return to the 
clinic every 3 months if a positive anti-drug antibody is noted, until a 
negative result is noted.  
Safety 
o Deletion of “assessment of quality of life”.  
o Amended the frequency of the ECG collection timepoints. 
Section 2. Protocol Synopsis 
and Section 6.3 Exploratory 
objectives 
Objectives  
o Deletion of urine NTX 
 
Section 2. Protocol Synopsis- 
Inclusion/Exclusion criteria 
and Section 8-Selection 
 
Inclusion criteria (Section 8.2.1 Patient inclusion criteria) 
o Amend inclusion criteria #4 to include capecitabine 
o Amend inclusion criteria #10 to add AST/ALT ≤ 5x ULN when there is 
evidence of liver metastases. 
Exclusion criteria (Section 8.2.2 Patient exclusion criteria) 
o Addition of language to exclusion #3 “not including the current 
chemotherapy regimen” 
o Amend language of exclusion #6 to “Recent history of thrombosis, deep 
vein thrombosis (DVT), pulmonary emboli, or embolic stroke, occurring 
within the last 6 months; if on anticoagulation therapy must be clinically 
stable as determined by the Investigator.” 
o Amend language of exclusion #10 to be “Administration of IV antibiotics 
or febrile (temperature elevation > 38 ° C) within 14 days of Day 1.”  
o Addition of language to exclusion #12 “or active hepatitis C.” 
o Amend language of exclusion criteria #13 “Clinically significant iron 
(transferrin saturation < 20%), vitamin B12, or folate deficiency.” 
o Amend timeframe for exclusion criteria #15 from 12 months to 6 months 
for active gastrointestinal bleeding.  
 
 
 
 
 
 
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Schedule of Events ( Table 7) 
o Formatting 
o Deletion of the following visits days from the schedule of events: Day 22, 
36, 64, 99, 197, and 253.  
o Decrease in frequency of the collection of ECGs, coagulation, chemistry 
and anti-drug antibody blood samples.  
o Deletion of urine NTX biomarker, serum ferritin and transferrin blood 
sample collection. 
o Addition of blood pressure measurements during the follow up period of 
the study. 
o Deletion of assessment of collection of menstrual cycle information  
o Addition of the following language to footnote 1: For patients with 
previous history of CNS metastases, if BP value increases by one or more 
NCI CTCAE v3.0 grades, the patient must return within 7 days to have BP 
assessed again. Patients with a recent change in anti-hypertensive 
medication or a change in the past month should be seen weekly for BP 
measurements.   
o Clarification provided regarding ECG collection 
o Deleted language regarding withdraw criteria in footnote 19 and 20 
Section 5.4.3 A011-04: A 
Phase 2a Study in Patients 
with Osteolytic Lesions of 
Multiple Myeloma  
o Replaced language regarding data review with “Please refer to the 
Investigator Brochure for further information.” 
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Section 7. Investigational 
Plan 
o Administrative changes 
o Language was amended to state that patients may be asked to return to the 
clinic every 3 months if a positive anti-drug antibody is noted, until a 
negative result is noted.  
 Section 8. Selection 
Section 8.3 Patient Withdrawal Criteria 
o Clarification of reason for withdrawal and the visit(s) to be complete upon 
patient withdrawal.  
Section 9. Treatment of 
Patients 
Updated language through to reflect the changes in protocol visits 
Section 9.1.1 General Concomitant Medication Usage 
o Addition of language- “Patients with a recent change in anti-hypertensive 
medication or a change in the past month should be seen weekly for BP 
measurements.” 
Section 9.1.2.1 Iron supplementation 
o Replace serum ferritin level with transferrin saturation < 20 % 
Section 9.6 Treatments Administered 
o Amended language regarding withdrawal criteria to reference section 8.3 
only 
o Deletion of language regarding chemotherapy treatment 
Section 10. Study Procedures 
and Schedule 
Administrative changes 
Section 10.1.2 Screening ( within 14 days of Day 1) 
• 
Amended language regarding the ECGs: At two different time 
intervals (approximately 1 hour apart) triplicate (12 lead) ECGs to be 
performed at 3 minute intervals (± 1min) with the use of a digital ECG 
machine 
o If a local ECG machine is used, a single (12 lead) ECG is to 
be performed. 
• 
Replace transferrin and serum ferritin with transferrin saturation % 
• 
Deletion of: Females of childbearing potential- collection of menstrual 
cycle information of the start and end date of the last menstruation. 
• 
Screening bone scan collection timeframe amended from 4 weeks 
prior to start of chemotherapy regimen to 6 weeks prior.  
Section 10.1.3 Initial Dosing: Day 1 
o Deletion of the following language: A patient will be considered 
randomized once a multi-digit patient identification number has been 
assigned to the patient through the IVRS/IWRS.  
o Added the following language : “and the patient has been randomized 
(through IVRS/IWRS)” 
o Amended language regarding the ECGs: Triplicate (12 lead) ECGs to be 
performed at 3 minute intervals (± 1min) with the use of a digital ECG 
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machine 
o If a local ECG machine is used, a single (12 lead) ECG is to be 
performed. 
o Replace transferrin and serum ferritin with transferrin saturation % 
o Deletion of urine NTX 
o Deletion of: Females of childbearing potential- collection of menstrual 
cycle information of the start and end date of the last menstruation. 
Section 10.1.4 ACE-011/placebo administration: Days 29, 57, and 85 (± 3 days) 
o Replace transferrin and serum ferritin with transferrin saturation % on Day 
57 only 
o Collection of coagulation and anti-drug antibody blood samples on Day 57 
only 
o Amended language regarding ECGs: Triplicate (12 lead) ECGs to be 
performed at 3 minute intervals (± 1min) with the use of a digital ECG 
machine (Day 57 only) 
o If a local ECG machine is used, a single (12 lead) ECG is to be 
performed. 
o Deletion of urine NTX 
o Deletion of: Females of childbearing potential- collection of menstrual 
cycle information of the start and end date of the last menstruation. 
Section 10.1.5 Additional visits during the Treatment Period: Days 8, 15, (± 1 
day), 43 and 71 (± 2 days) 
o Patients with previous history of CNS metastases, if blood pressure (BP) 
value increases by one or more grade(s) per the NCI CTCAE v3.0, the 
patient must return within 7 days to have BP assessed again 
o Amended language regarding ECGs : Triplicate (12 lead) ECGs to be 
performed at 3 minute intervals (± 1min) with the use of a digital ECG 
machine (Day 8 only) 
o If a local ECG machine is used, a single (12 lead) ECG is to be 
performed. 
o Deletion of collection of serum chemistry, folate and coagulation 
o Section 10.1.6 Treatment Period Follow-up visits : Days 113 and 141(± 
7 days) Amended language regarding ECGs : Triplicate (12 lead) ECGs to 
be performed at 3 minute intervals (± 1min) with the use of a digital ECG 
machine (Day 113 only) 
o If a local ECG machine is used, a single (12 lead) ECG is to be 
performed. 
o Deletion of urine NTX 
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o Extended window for CT/MRI scan from +/- 5 days to +/- 7 days 
Section 10.1.7 Post treatment follow up period visits: Day 169 and 225 (± 7 days) 
o Addition of blood pressure value collection 
Section 10.1.8 Termination Visit: Day 281 (± 7 days) 
o Replace transferrin and serum ferritin with transferrin saturation % 
o Amended language regarding ECGs: Triplicate (12 lead) ECGs to be 
performed at 3 minute intervals (± 1min) with the use of a digital ECG 
machine 
o If a local ECG machine is used, a single (12 lead) ECG is to be 
performed. 
o Deletion of urine NTX and serum folate 
o Extended window for bone scan from +/- 5 days to +/- 7 days 
o Additional language regarding positive anti-drug antibody test follow up 
 Section 13 Assessment of 
Safety 
Section 13.1.2 Clinical laboratory tests 
o Deletion of serum ferritin, transferrin, and uNTX 
Section 14. Adverse Event 
o Formatting. 
o Additional text added regarding AEs, SAEs, and Pregnancy  
Section 16. Direct Access to 
Source Data/Documents 
Section 19. Data Handling 
and Record Keeping 
o Additional language added for clarification purposes.  
 
 
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                                 CLINICAL STUDY PROTOCOL 
A Phase 2, Double-Blind, Randomized, Placebo-Controlled 
Study of ACE-011 for the Treatment of Chemotherapy Induced 
Anemia in Patients with Metastatic Breast Cancer 
 
 
STUDY DRUG: 
 
 
ACE-011 
 
PROTOCOL NUMBER: 
 
 
A011-08 
 
IND NUMBER:  
 
 
 
 
103,362 
 
SPONSOR:  
     
 
 
 
Celgene Corporation 
 
 
 
 
 
 
 
 
 
 
86 Morris Avenue 
 
 
 
 
 
 
 
 
 
 
Summit, NJ  07901 
 
MEDICAL MONITOR: 
      PPD Inc. 
 
     
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
     
 
 
 
 
 
 
 
 
 
 
 
 
      
PROTOCOL DATE: 
     13 March 2009 
AMENDMENT #1: 
     22 April 2009 
AMENDMENT #2: 
     21 May 2009 
AMENDMENT #3: 
     07 October 2009 
AMENDMENT #4: 
     04 February 2010 
 
 
 
 
Confidentiality Statement 
This confidential information in this document is provided to you as an investigator or consultant for review by you, your staff, 
and the applicable institutional Review Board/Independent Ethics Committee.  Your acceptance of this document constitutes 
agreement that you will not disclose the information contained herein to others without written authorization from the Sponsor. 
 
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PROCEDURES IN CASE OF EMERGENCY 
 
Table 1: 
Emergency Contact Information 
Role in Study 
Name 
Address and Telephone number 
PPD Medical Monitor 
PPD Inc. 
1800 Perimeter Park Drive,  Suite 275 
Morrisville, NC 27560-7200 USA 
 
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2. 
PROTOCOL SYNOPSIS 
Name of Sponsor/Company:           Celgene Corporation 
 
 
 
 
 
 
 
 
 
 
86 Morris Avenue 
 
 
 
 
 
 
 
 
 
 
Summit, NJ  07901 
Name of Investigational Product: ACE-011 
Name of Active Ingredient:   
ACE-011 is a fully human fusion protein consisting of the extracellular domain (ECD) of the 
activin receptor IIA (ActRIIA) linked to the human IgG1 Fc domain.  
Mechanism of Action: ACE-011 is a disulfide-linked, glycosylated, dimeric protein. ACE-011 
competes with the activin receptor IIA that binds a number of TGF-β superfamily ligands 
including activin, myostatin (growth differentiation factor [GDF]-8), and GDF-11. 
Title of Study:  A Phase 2, Double-Blind, Randomized, Placebo-Controlled Study of ACE-011 
for the Treatment of Chemotherapy Induced Anemia in Patients with Metastatic Breast 
Cancer. 
Study center(s): approximately 35-45 centers  
Phase of development: 2 
Objectives 
Primary:  
1. To evaluate the proportion of patients in each ACE-011 dose regimen who achieve a 
hematopoietic response during the treatment period including up to 2 months after the 
last dose of ACE-011 treatment of chemotherapy induced anemia in patients with 
metastatic breast cancer. Hematopoietic response is defined as an increase in 
hemoglobin of ≥ 1.0 g/dL above the study baseline value for 28 consecutive days 
during the treatment period including up to 2 months after the last dose of ACE-011, in 
the absence of any RBC transfusions and/or ESAs. 
Secondary: 
1. To evaluate the safety and tolerability of ACE-011 for the treatment of chemotherapy 
induced anemia in patients with metastatic breast cancer.  
2. To evaluate the percentage of patients who achieve an increase in hemoglobin of  ≥ 2 
g/dL and/or hemoglobin concentration ≥ 11 g/dL for 28 consecutive days during the 
treatment period including up to 2 months after the last dose of ACE-011 in the 
absence of any RBC transfusions and/or ESAs.   
3. To estimate the duration of the hematopoietic response associated with each ACE-011 
dose regimen. 
4. To estimate the time to the hematopoietic response associated with each ACE-011 dose 
regimen. 
5. To estimate the proportion of patients receiving red blood cell (RBC) transfusions 
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04Feb10                                                                           5                                                                                                                            
                                                                                                                             
 
 
 
and/or ESAs within each cycle of ACE-011 with each dose regimen. 
6. To estimate the effect of each ACE-011 dose regimen on progression free survival 
(PFS) and objective response rate (ORR). 
Exploratory objectives: 
1. To estimate the effect of each ACE-011 dose regimen on serum bone biomarkers (OC, 
BSAP, P1NP, CTX, and TRACP-5b), bone mineral density (dual-energy X-ray 
absorptiometry [DXA] scans of lumbar spine and hip) and incidence of skeletal related 
events (SREs). 
2. To evaluate the quality of life in relation to the treatment of chemotherapy induced 
anemia in patients with metastatic breast cancer during the study. 
Methodology: This is a Phase 2, double-blind, randomized, placebo-controlled study to 
evaluate the efficacy, safety, and tolerability of ACE-011 for the treatment of chemotherapy 
induced anemia in patients with metastatic breast cancer. Patients will be randomized to one of 
three treatment arms or placebo: 
 
1. ACE-011 0.1 mg/kg subcutaneously (SC) every 28 days for up to 4 doses. 
2. ACE-011 0.3 mg/kg SC every 28 days for up to 4 doses.  
3. ACE-011 0.5 mg/kg SC every 28 days for up to 4 doses. 
4. Placebo SC every 28 days for up to 4 doses. 
 
  
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Number of patients (planned): 105 patients 
Diagnosis and main criteria for inclusion 
 
Inclusion Criteria: 
1. Women > 18 years of age. 
2. Histologically or cytologically confirmed diagnosis of breast cancer. 
3. Evidence of metastatic breast cancer with a minimum of one measurable lesion or non 
measurable lesion per RECIST v1.1 criteria (Appendix 1). 
4. Receiving a multicycle myelosuppressive chemotherapy regimen including one of the 
following: anthracycline, taxane, gemcitabine, vinorelbine or capecitabine. 
5. Anticipated treatment with the same myelosuppressive chemotherapy regimen for a 
minimum of 9 weeks after Day 1 of ACE-011/placebo administration.  
6. Hemoglobin value between ≥ 6.5 to < 11.0 g/dL (≥ 65 to < 110 g/L).  
7. ≥ 30 days must have elapsed (from Day 1) since previous treatment with erythropoiesis-
stimulating agent (including concurrent treatment with IV iron) for chemotherapy induced 
anemia.  
8. ≥ 7 days have elapsed (from Day 1) since the last RBC blood transfusion and receipt of ≤ 2 
units of blood in the past 30 days.  
9. ECOG Performance status of 0 – 2 (Appendix 2). 
10. Adequate renal (creatinine ≤ 1.5 x ULN or creatinine clearance ≥ 40 mL/min) and hepatic 
function [bilirubin < 1.5 x ULN; AST/ALT < 2.5 x ULN (AST/ALT ≤ 5 x ULN when 
there is evidence of liver metastases)]. 
11. Females of childbearing potential  participating in the study are to use adequate birth 
control measures (i.e. oral contraceptives or two forms of barrier method birth control) 
during study participation. Females of childbearing potential must have a negative serum 
pregnancy test within 7 days to ACE-011/placebo administration (Day 1). A female of 
childbearing potential is a sexually mature woman who has not undergone a hysterectomy 
or who has not been postmenopausal for at least 24 consecutive months (i.e. who has had 
menses at some time in the preceding 24 months). 
12. Life expectancy of ≥ 6 months. 
13. Is willing to adhere to the study visit schedule, understand and comply with all protocol 
requirements. 
14. Understand and sign a written informed consent. 
 
 
 
 
 
 
 
 
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Exclusion Criteria: 
1. At the time of screening patients who have any grade > 3 toxicity (as per NCI CTCAE 
v3.0 (Appendix 3)) (except for the following disease related toxicities:  hematological 
events- anemia, thrombocytopenia or neutropenia or non hematological events- nausea, 
vomiting, fatigue, or muscle or bone/joint pain).  
2. Prior radiation therapy to > 20% of the whole skeleton.  
3. Have received more than 5 prior chemotherapy treatment regimens for metastatic breast 
cancer (not including the current chemotherapy regimen).  
4. Clinically significant pulmonary, endocrine, neurologic, gastrointestinal, hepatic or 
genitourinary disease unrelated to underlying hematologic disorder.  
5. Patients with heart failure as classified by the New York Heart Association (NYHA) 
classification of 3 or higher (Appendix 4). 
6. Recent history of thrombosis, deep vein thrombosis (DVT), pulmonary emboli, or embolic 
stroke, occurring within the last 6 months; if on anticoagulation therapy must be clinically 
stable as determined by the Investigator.  
7. Untreated CNS metastases or CNS metastases treated with whole brain radiotherapy < 6 
months prior to Day 1. 
8. Diagnosis of a myeloid malignancy or known history of myelodysplasia.  
9. History of second malignancy within 5 years (except excised and cured basal cell 
carcinoma, squamous cell carcinoma of the skin or cervical carcinoma in situ).  
10. Administration of IV antibiotics or febrile (temperature elevation > 38 ° C) within 14 days 
of Day 1.  
11. Uncontrolled hypertension. If hypertension is considered clinically stable, systolic blood 
pressure (BP) must be < 150 mmHg and diastolic BP must be < 100 mmHg.  
12. Known history of hepatitis B surface antigen (HBsAg and HB core Ab), human 
immunodeficiency virus (HIV) antibody or active hepatitis C.   
13. Clinically significant iron (transferrin saturation < 20%), vitamin B12, or folate deficiency.  
14. History of anemia as a result of inherited hemoglobinopathy such as sickle cell anemia or 
thalassemia.  
15. History of autoimmune or hereditary hemolysis; active gastrointestinal bleeding (within 
the last 6 months as compared to Day 1). 
16. Patient received treatment with another investigational drug or device within 1 month prior 
to Day 1, or if the half life of the previous product is known, within 5 times the half life 
prior to dosing, whichever may be longer.  
17. Pregnant or lactating females. 
18. History of severe allergic or anaphylactic reactions or hypersensitivity to recombinant 
proteins or excipients in the investigational product.    
19. Major surgery within 30 days prior to Day 1 (patients must have completely recovered 
from any previous surgery prior to Day 1). 
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Investigational product, dosage and mode of administration:  
ACE-011/placebo will be administered as a SC injection, approximately every 28 days, on 
days 1, 29, 57, and 85 of the treatment period.  Each patient will be randomized to one of three 
treatment arms or placebo: 
 
 
 
 
 
 
 
 
Patients with grade ≥ 3 toxicity related to ACE-011 will be discontinued from ACE-011/ 
placebo treatment except for the following: Patients with grade 3 hypertension that decreases 
to grade ≤ 1 within 7 days after treatment with anti-hypertensive therapy may continue on 
ACE-011/placebo treatment.  Dose reduction rules will apply at the subsequent scheduled 
dosing day(s).  Patients with a hemoglobin level above the upper limit of normal at any time 
during the study after Day 1 will be discontinued.   
ACE-011/placebo dose modification rules are based on hemoglobin values and blood pressure 
measurements during each treatment cycle. ACE-011/placebo dose interruption and dose 
reduction rules will be implemented for those patients with hemoglobin of ≥ 11 g/dL, an 
increase of ≥ 2 g/dL/ 28 days, or hypertension ≥ Grade 2 within each cycle (see Figure 1). 
Dose  
Number of  Patients 
0.1 mg/kg 
30 
0.3 mg/kg 
30 
0.5 mg/kg 
30 
Placebo 
15 
Total patients enrolled (planned): 105 
Duration of study: Patients will be followed for a minimum of 7 months following their last 
dose of ACE-011/placebo. Study participation for each patient is approximately 10.5 months 
(14 day screening period, 3 month treatment period with a 2 month treatment follow up period, 
and a 5 month post treatment follow-up period). The start date of the chemotherapy regimen 
used in this protocol to treat metastatic breast cancer will be recorded. If a patient begins a new 
chemotherapy regimen during the study, the patient will discontinue further ACE-011/placebo 
treatment, complete the Day 281/Termination visit procedures and be followed for survival 
only. If a patient has a positive anti-drug antibody result at the Day 281/Termination visit, they 
may be asked to return to the clinical site every 3 months until a negative result is obtained.  
The study is complete when the last patient enrolled has completed the last protocol required 
follow up visit. 
Criteria for evaluation 
Efficacy: The primary endpoint is to establish the proportion of patients who have a 
hematopoietic response of an increase in hemoglobin of ≥ 1.0 g/dL above the study baseline 
value for 28 consecutive days during the treatment period including up to 2 months after the 
last dose of ACE-011, in the absence of any RBC transfusions and/or ESAs.   
The proportion of patients with an increase in hemoglobin of ≥ 2 g/dL and/or hemoglobin 
concentration ≥ 11 g/dL for 28 consecutive days during the treatment period up to 2 months 
after the last dose of ACE-011 in the absence of any RBC transfusions and/or ESAs will be 
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evaluated as a secondary efficacy endpoint. 
The hematopoietic endpoints will be determined by the monitoring of hematologic laboratory 
values, RBC transfusion and/or ESAs administration. The evaluation of response will be from 
the first dose of ACE-011 through 2 months after the last dose (for each patient).  Additional 
endpoints will be evaluated with the assessment of disease progression by CT/MRI and bone 
scan and bone mineral density by DXA scans.  Bone biomarkers will be evaluated in all 
patients and incidence of SREs will be recorded, as applicable. SREs are defined as pathologic 
fracture, radiation therapy to bone, surgery to bone, or spinal cord compression. 
Safety: Throughout the study, safety will be evaluated by the sponsor, medical monitor and 
principal investigator.  Additionally, the DMC will review safety parameters for patients 
enrolled in the study. All patients will be assessed for safety by monitoring adverse events, 
clinical laboratory tests, vital signs and physical examinations on an ongoing basis.  ECGs will 
also be performed during screening, prior to dosing on the first cycle, during the first and third 
cycle, Day 113 (28 days after the last dose of ACE-011) and at Day 281/Termination visit to 
monitor safety.  Blood pressure and lab values will be assessed at each study visit during the 
treatment and treatment follow up period.  
Pharmacokinetics: The blood samples will be collected at selected study sites from 
approximately one-third of patients for the evaluation of serum concentrations of ACE-011.  
Pre-dose PK samples will be collected on Day 1.  See Appendix 5 for PK sampling schedule. 
Statistical methods  
Sample size determination: With an anticipated dropout rate of 20%, a sample size of 30 
patients per dose level is planned to achieve at least 80% power with 2 sided significance level 
of 0.05 to differentiate targeted response rate of p1=0.45 from null hypothesis p0=0.20. An 
additional 15 patients will be enrolled into the placebo group for safety comparison. A total of 
105 patients will be randomized to three ACE-011 dose groups or placebo with a ratio of 
2:2:2:1. 
Efficacy analysis: The primary endpoint is the proportion of patients who have a 
hematopoietic response of an increase in hemoglobin of ≥ 1.0 g/dL above the study baseline 
value for 28 consecutive days during the treatment period including up to 2 months after the 
last dose of ACE-011, in the absence of any RBC transfusions and/or ESAs. The proportion of 
responders will be determined together with 95% confidence interval.  
For binary endpoints, the proportion of responders and 95% confidence interval will be 
calculated. For time to event endpoints, the Kaplan-Meier method will be used to estimate the 
survival curve and median time to event.  Due to the nature of the study, no multiplicity 
adjustment will be made for efficacy analysis. 
Safety analysis: Data from all patients who receive at least one dose of ACE-011/placebo will 
be included in the safety analyses. To assess clinical safety, adverse events, vital sign 
measurements and clinical laboratory information will be summarized. Adverse events and 
laboratory results will also be summarized by severity grade (NCI CTCAE v3.0). Changes 
from baseline clinical laboratory values and vital signs will be summarized over time. 
Descriptive statistics and shift tables will be generated as appropriate.  
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  1    Vital signs include weight, heart rate, seated systolic and diastolic blood pressure (BP), and temperature will be assessed at each visit  Height will be collected at screening only   For patients with previous history of CNS metastases, if BP value increases by one or    
       more NCI CTCAE v3 0 grades, the patient must return within 7 days to have BP assessed again  Patients with a recent change in anti-hypertensive medication or a change in the past month should be seen weekly for BP measurements   
  2   On dosing days (1, 29, 57 and 85), study procedure to be done prior to dosing of ACE-011/placebo    
  3     Use of  Digital ECG machine-Screening- At two different time intervals (approximately 1 hour apart) triplicate (12 lead) ECGs to be performed at 3 minute intervals (± 1min),  On all other specified days, one time interval of triplicate (12 lead) ECGs is to be   
       performed at 3 minute intervals (± 1min), prior to dosing as applicable  If a local ECG machine is used, a single (12 lead) ECG is to be performed   
 4       Coagulation (central lab only) prothrombin time (PT), partial thromboplastin time (PTT), fibrinogen    
 5     Chemistry (central lab only): AST, ALT, lactate dehydrogenase (LDH), total bilirubin, indirect bilirubin, alkaline phosphatase, total protein, albumin, sodium, potassium, chloride, carbon dioxide, calcium, phosphorus, blood urea nitrogen (BUN), creatinine, uric  
      acid, glucose, amylase, and lipase   
 6  Hematology (local lab) hemoglobin and hematocrit  On dosing days (1, 29, 57 and 85), local hemoglobin and hematocrit values are to be drawn and resulted (up to 1 day) prior to dosing to apply dose modification rules for ACE-011/placebo   Hematology (central   
       lab only) complete blood count (CBC) with differential and platelet, CBC includes red blood cells (RBC), white blood cells (WBC),  hemoglobin, hematocrit, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin       
      concentration (MCHC), Peripheral blood smear will also be done on Days 1, 57 and at the termination visit   Reticulocyte should be done on days 1, 8, 15, 29, 57, 85, and at the termination visit.  
  7      If a patient has a positive anti-drug antibody result at the Termination visit, they may be asked to return to the clinical site every 3 months until a negative result is obtained  
  8    Serum samples will be collected at each visit  
 9      Labs may be drawn within 1 day prior to Day 1  Confirmatory labs for eligibility criteria must be drawn and resulted within 7 days of Day 1   
10   For females of child bearing potential only urine (dipstick) pregnancy test to be collected and resulted prior to dosing of ACE-011/placebo on dosing days  
11    Urinalysis to be performed at screening, prior to administration ACE-011/placebo (Days 1 and 85) and termination visit  Assessments (central lab only): pH, specific gravity, protein, glucose, ketones, blood, leukocyte esterase, and nitrite  Microscopy required only 
to follow-up abnormal findings  
12   Screening- any concomitant treatments taken 28 days prior to day 1 including up to 90 days after the last dose of ACE-011/placebo   
13  AEs will be reported from day 1 post dose including up to 90 days after the last dose of ACE-011/placebo  Additional AEs noted after 90 days from the last dose of ACE-011/placebo will be reported at the discretion of the investigator   SREs and SAEs will be 
followed through out the study   If a patient is followed for survival only, SREs and SAEs will be captured up to 90 days from the last dose of ACE-011/placebo  
14   A CT/MRI scan acquired within 6 weeks of initiating the current chemotherapy regimen may be used for the screening assessment   Head, neck, thoracic, abdominal, and pelvic scans are to be acquired   One measurable or non measurable lesion per RECIST v1 1 is 
to be identified by the scan  Brain (head) CT only to be done to rule out CNS metastases in patients with suspicious clinical symptoms or prior history of CNS metastases   
15  Follow-up CT/MRI scans may be acquired +/- 7 day window for Day 113  Additional CT/MRI scans acquired during the post treatment follow up period will be performed at the discretion of the investigator   
16  Hip and lumbar spine BMD assessment  Refer to Imaging Acquisition Guidelines for guidelines regarding washout period for contrast (if used) for radiological images, prior to collection of DXA  
17  Bone scans will be acquired within 6 weeks of initiating the current chemotherapy regimen for those patients who have bone metastases identified  Follow up bone scan, when the baseline bone scan was abnormal, may be acquired +/- 7 day window for Day 281  
18    All study visit day dates (inclusive of windows) are calculated from Day 1(day of initial ACE-011/placebo administration)   
19   Chemotherapy  regimens will be administered to the patient as per standard of care  Continuation of the same chemotherapy regimen may be done through the follow up period of the study at the discretion of the investigator   
20   If a patient withdraws from the study (section 8 3), the Day 281/Termination visit procedures are to be completed and the patient will be followed for survival  If withdrawal reason is due to ESA administration or ACE-011 related toxicity, the patient should enter the   
      treatment follow up period  
Schedule of Events cont. 
 
  Screen 
Treatment Period 
 
ACE-011/Placebo 
Dose period 
 
#1 
#2 
#3 
#4 
Follow-up  
 
Post Treatment Follow up Period 
 
Term 
Visit20 
Day 
     -14-0 
1 
8 
(± 1d) 
15 
 (± 1d) 
 
29 
(± 3d) 
 
43 
(± 2d) 
57 
(± 3d) 
 
71 
 (± 2d) 
85 
 (± 3d) 
113 
(± 7d) 
    141 
 (± 7d) 
 
169 
(± 7d) 
225 
(± 7d) 
281 
(± 7d) 
Evaluation of  AEs 
and SAEs13 
X-SAE 
only 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X-SRE and SAE only 
 
X 
CT/MRI scan 
   X14 
 
 
 
 
 
 
 
 
  X15 
  
 
 
 
Dual-energy X-ray 
absorptiometry 
(DXA16) 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
Bone scans17 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
ACE-011/placebo 
administration18 
 
X 
 
 
X 
 
X 
 
X 
 
 
 
 
 
Chemo regimen19 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
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                                             Acceleron Pharma   
 
3. 
TABLE OF CONTENTS, LIST OF TABLES AND LIST OF 
FIGURES  
TABLE OF CONTENTS 
1. 
TITLE PAGE..............................................................................................................1 
2. 
PROTOCOL SYNOPSIS .............................................................................................4 
3. 
TABLE OF CONTENTS, LIST OF TABLES AND LIST OF FIGURES................12 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................18 
5. 
INTRODUCTION......................................................................................................21 
5.1. 
Indication and Rationale.............................................................................................21 
5.2. 
Description of ACE-011.............................................................................................21 
5.3. 
Activin Biology ..........................................................................................................22 
5.3.1. 
Pharmacology Studies ................................................................................................22 
5.3.2. 
Toxicology..................................................................................................................24 
5.4. 
Summary of Clinical Experience................................................................................25 
5.4.1. 
A011-01: A Phase 1a Study in Healthy Postmenopausal Women .............................25 
5.4.2. 
A011-02: A Phase 1b Study in Healthy Postmenopausal Women.............................26 
5.4.3. 
A011-04: A Phase 2a Study in Patients with Osteolytic Lesions of Multiple 
Myeloma.....................................................................................................................29 
5.5. 
Potential Risks for Human Use...................................................................................31 
6. 
TRIAL OBJECTIVES AND PURPOSE....................................................................33 
6.1. 
Primary objective........................................................................................................33 
6.2. 
Secondary objectives ..................................................................................................33 
6.3. 
Exploratory objectives................................................................................................33 
7. 
INVESTIGATIONAL PLAN.....................................................................................34 
7.1. 
Overall Study Design and Plan...................................................................................34 
8. 
SELECTION AND WITHDRAWL OF PATIENTS.................................................38 
8.1. 
Number of Patients .....................................................................................................38 
8.2. 
Entry Criteria ..............................................................................................................38 
8.2.1. 
Patient Inclusion Criteria............................................................................................38 
8.2.2. 
Patient Exclusion Criteria...........................................................................................39 
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8.3. 
Patient Withdrawal Criteria........................................................................................40 
9. 
TREATMENT OF PATIENTS..................................................................................41 
9.1. 
Concomitant Medications...........................................................................................41 
9.1.1. 
General Concomitant Medication Usage....................................................................41 
9.1.2. 
Concomitant treatment for anemia .............................................................................41 
9.1.2.1. 
Iron supplementation ..................................................................................................41 
9.1.2.2. 
Erythropoiesis-stimulating agents (ESAs)..................................................................41 
9.1.2.3. 
RBC Transfusions.......................................................................................................41 
9.2. 
Chemotherapy.............................................................................................................42 
9.3. 
Treatment Compliance................................................................................................42 
9.4. 
Rescreening.................................................................................................................42 
9.5. 
Randomization............................................................................................................42 
9.5.1. 
Blinding ......................................................................................................................42 
9.5.2. 
Unblinding..................................................................................................................43 
9.6. 
Treatments Administered............................................................................................43 
9.6.1. 
Selection of Doses in the Study..................................................................................43 
9.6.2. 
Selection and Timing of Dosing for Each Patient ......................................................43 
9.6.2.1. 
ACE-011 Treatment Related Toxicity........................................................................43 
9.6.2.2. 
ACE-011 Dose Modification Rules............................................................................44 
10. 
STUDY PROCEDURES AND SCHEDULE ............................................................47 
10.1.1. 
Written Informed consent...........................................................................................47 
10.1.2. 
Screening (Within 14 days of dosing) ........................................................................47 
10.1.3. 
Initial Dosing: Day 1 ..................................................................................................48 
10.1.4. 
ACE-011/placebo administration: Days 29, 57, and 85 (± 3 days)............................49 
10.1.5. 
Additional visits during Treatment Period: Days 8, 15  (± 1 day), 43, and 71 
(± 2 days)....................................................................................................................50 
10.1.6. 
Treatment Period Follow-up visits : Days 113 and 141 (± 7 days)............................51 
10.1.7. 
Post Treatment Period Follow-up visits : Days 169 and 225 (± 7 days)....................52 
10.1.8. 
Termination Visit:  Day 281 (± 7 days)......................................................................52 
10.2. 
Discontinuation of Study............................................................................................53 
11. 
INVESTIGATIONAL PRODUCT MATERIALS AND MANAGEMENT.............54 
11.1. 
Reference Product.......................................................................................................54 
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11.2. 
Investigational Product Packaging and Labeling .......................................................54 
11.3. 
Investigational Product Storage..................................................................................54 
11.4. 
Investigational Product Preparation............................................................................54 
11.5. 
Administration............................................................................................................54 
11.6. 
Drug Accountability ...................................................................................................54 
11.7. 
Investigational Product Handling and Disposal .........................................................55 
12. 
ASSESSMENT OF EFFICACY ................................................................................56 
13. 
ASSESSMENT OF SAFETY.....................................................................................57 
13.1. 
Safety Parameters .......................................................................................................57 
13.1.1. 
Adverse Events...........................................................................................................57 
13.1.2. 
Clinical Laboratory Tests ...........................................................................................57 
13.1.3. 
Other Safety Assessments...........................................................................................58 
13.2. 
Pharmacokinetics........................................................................................................58 
14. 
ADVERSE EVENT....................................................................................................59 
14.1. 
Adverse Event Classification......................................................................................60 
14.2. 
Recording Adverse Events .........................................................................................60 
14.3. 
Reporting Adverse Events..........................................................................................61 
14.4. 
Emergency Sponsor Contact.......................................................................................63 
14.5. 
Pregnancy ...................................................................................................................63 
15. 
STATISTICS..............................................................................................................64 
15.1. 
Determination of Sample Size....................................................................................64 
15.2. 
Analysis Populations ..................................................................................................64 
15.3. 
Background and Demographic Characteristics ..........................................................64 
15.3.1. 
Patient Disposition......................................................................................................64 
15.3.2. 
ACE-011.....................................................................................................................65 
15.3.3. 
Concomitant Therapy .................................................................................................65 
15.4. 
Efficacy Evaluation ....................................................................................................65 
15.4.1. 
Primary Efficacy Analysis..........................................................................................65 
15.4.2. 
Secondary Efficacy Analyses .....................................................................................66 
15.5. 
Safety Evaluation........................................................................................................66 
15.6. 
Pharmacokinetic Evaluation.......................................................................................67 
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15.6.1. 
Anti-drug Antibody Data............................................................................................67 
15.7. 
Interim analysis...........................................................................................................67 
15.8. 
Deviation from Original Analysis Plan ......................................................................67 
16. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................68 
16.1. 
Study Monitoring........................................................................................................68 
16.2. 
Audits and Inspections................................................................................................68 
17. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................69 
17.1. 
Data Quality Control and Quality Assurance.............................................................69 
17.1.1. 
Investigator responsibility ..........................................................................................69 
17.1.2. 
Protocol modifications................................................................................................69 
17.2. 
Financing and Insurance.............................................................................................69 
17.3. 
Confidentiality............................................................................................................69 
17.4. 
Publication Policy.......................................................................................................69 
17.5. 
Protocol Amendments ................................................................................................70 
18. 
ETHICS ......................................................................................................................71 
18.1. 
Institutional Review Board or Independent Ethics Committee ..................................71 
18.2. 
Ethical Conduct of the Study......................................................................................71 
18.3. 
Written Informed Consent..........................................................................................71 
18.3.1. 
Informed Consent .......................................................................................................71 
18.3.2. 
Patient Data Protection ...............................................................................................71 
19. 
DATA HANDLING AND RECORDKEEPING.......................................................72 
19.1. 
Case Report Form Completion...................................................................................72 
19.2. 
Retention of Records ..................................................................................................72 
20. 
REFERENCES ...........................................................................................................73 
21. 
APPENDICES............................................................................................................75 
Appendix 1: Response Evaluation Criteria in Solid Tumors.........................................................75 
Appendix 2: ECOG Performance Status........................................................................................78 
Appendix 3:  National Cancer Institute (NCI) Common Terminology Criteria for 
Adverse Events (CTCAE) Version 3.0.......................................................................79 
Appendix 4: New York Heart Association- Classification of heart failure...................................80 
Appendix 5- Pharmacokinetic Sampling .......................................................................................81 
 
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LIST OF TABLES 
 
Table 1: 
Emergency Contact Information...................................................................................3 
Table 2: 
Abbreviations and Specialist Terms ...........................................................................18 
Table 3: 
A011-02: A Phase 1b Study in Healthy Postmenopausal Women: 
Hemoglobin Evaluation..............................................................................................27 
Table 4: 
A011-02: Incidence of Most Common Adverse Events.............................................28 
Table 5: 
A011-02: A Phase 1b Study in Healthy Postmenopausal Women: BMD..................29 
Table 6: 
Study Design...............................................................................................................34 
Table 7: 
Schedule of Events .....................................................................................................36 
Table 8: 
ACE-011/Placebo Dose Reduction Levels.................................................................46 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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LIST OF FIGURES 
Figure 1: 
ACE-011/Placebo Dose Modification Rules (after initial dose of ACE-
011/placebo) ...............................................................................................................45 
 
 
 
 
 
 
 
 
 
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4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
The following abbreviations and specialist terms are used in this study protocol. 
Table 2: 
Abbreviations and Specialist Terms   
Term 
Definition 
ACTH 
Adrenocorticotropic hormone 
ActRIIA 
Activin receptor IIA  
AE 
Adverse event 
ALT 
Alanine aminotransferase  
AST 
Aspartate aminotransferase  
AUC 
Area under the plasma concentration - time curve 
AUC(0-last) 
AUC from time 0 to time of last quantifiable sample  
AUC(0-∞) 
AUC extrapolated to infinity  
BMD 
Bone mineral density 
BP 
Blood pressure 
BSAP 
Bone specific alkaline phosphatase 
BUN 
Blood urea nitrogen 
CBC 
Complete Blood Count 
CFR 
Code of Federal Regulations (US) 
CH 
Constant domain 
CI 
Confidence interval 
CIA 
Chemotherapy induced anemia 
CL 
Clearance 
CL/F 
Total clearance 
Cmax 
Maximum observed concentration  
CNS 
Central nervous system 
CO2 
Carbon dioxide 
CRF 
Case report form 
CRO 
Clinical research organization 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTX 
Serum C-terminal type I collagen telopeptide 
DLT 
Dose-limiting toxicity 
DXA 
Dual-energy x-ray absorptiometry 
DMC 
Data Monitoring Committee 
DVT 
Deep vein thrombosis 
ECD 
Extracellular domain 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EDF 
Erythroid differentiation factor  
ESA 
Erythropoiesis-stimulating agents 
F 
Bioavailability (absolute) 
FACT 
Functional Assessment of Chronic Illness 
FDA 
Food and Drug Administration  
FSH 
Follicle-stimulating hormone 
GCP 
Good Clinical Practices 
GH 
Growth hormone 
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Term 
Definition 
HBV 
Hepatitis B virus 
Hct 
Hematocrit 
HCV 
Hepatitis C virus 
Hgb 
Hemoglobin 
HIV 
Human immunodeficiency virus 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug 
IP 
Intraperitoneal 
IRB 
Institutional Review Board 
IV 
Intravenous 
IVRS 
Interactive Voice Response System 
Kd 
Binding coefficient 
λz 
Elimination rate constant 
LDH 
Lactate dehydrogenase 
LH 
Luteinizing hormone 
MCH 
Mean corpuscular hemoglobin 
MCHC 
Mean corpuscular hemoglobin concentration 
MCV 
Mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MITT 
Modified Intent to Treat (population) 
MPT 
Melphalan, Prednisolone,Thalidomide  
MRI 
Magnetic resonance imaging 
NOAEL 
No adverse events level  
NYHA 
New York Heart Association 
OC 
Osteocalcin 
ORR 
Objective response rate 
OVX 
Ovariectomized 
PD 
Progressive disease 
PFS 
Progression free survival 
PHI 
Protected health information 
P1NP 
Serum intact procollagen type I N terminal propeptide 
PK 
Pharmacokinetic 
PP 
Per-protocol (population) 
PT 
Prothrombin time 
PTH 
Parathyroid hormone 
PTT 
Partial thromboplastin time 
RAP-011 
Murine version of ACE-011, ActRIIA mFc 
RBC 
Red blood cell (count) 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SC 
Subcutaneous 
SERM 
Selective estrogen receptor modulator 
SHAM 
Sham-operated 
SPEP 
Serum protein electrophoresis 
SRE 
Skeletal-related event 
T1/2 
Elimination half-life  
TIBC 
Total iron binding capacity 
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Term 
Definition 
Tmax 
Time to Cmax 
TRACP-5b 
Serum tartrate-resistant acid phosphatase isoform-5b 
ULN 
Upper limit of normal 
Vz/F 
Volume of distribution 
WBC 
White blood cell (count) 
 
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5. 
INTRODUCTION 
5.1. 
Indication and Rationale 
This study is designed to evaluate the efficacy, safety, and tolerability of ACE-011 for the 
treatment of chemotherapy induced anemia in patients with metastatic breast cancer. 
Treatment of patients with metastatic breast cancer with myelosuppressive chemotherapy is 
frequently associated with anemia. Chemotherapy induced anemia (CIA) is a significant problem 
for patients with cancer, causing fatigue and reduced quality of life (1).  Patients with CIA are 
currently treated with blood transfusion and/or erythropoiesis-stimulating agents (2). However, 
with these treatment options CIA is still an area of unmet medical need. Erythropoiesis-
stimulating agents (ESAs) can successfully mitigate transfusion need in a proportion of these 
patients, but concerns have emerged regarding apparent negative effects on survival and/or tumor 
progression in certain patient populations. The murine surrogate to ACE-011, RAP-011, has been 
tested as a single agent in breast cancer cell lines MDA-MB-231 and MCF-7 and no effect on 
enhanced proliferation of these cell lines has been observed in vitro. Therefore, treatment with 
ACE-011 may provide a distinct benefit/risk profile to patients with chemotherapy induced 
anemia.  
In both a Phase 1 single dose and multiple dose study of ACE-011 in postmenopausal women, 
increases in hemoglobin and hematocrit were observed following ACE-011 treatment and 
remained elevated over the course of study.  The observed hemoglobin and hematocrit effects of 
ACE-011 were dose and time dependent.  Please refer to the Investigator Brochure for further 
information.  
Based on the effect of ACE-011 on hematopoiesis and consistent biological phenomena observed 
in both non clinical and clinical studies, it is hypothesized that the blockade of ActRIIA receptor 
signaling impedes the terminal differentiation step in erythropoiesis to allow additional rounds of 
cell replication before cells enter the final differentiation phase. The result is a substantial 
increase in mature erythrocytes released into the circulation.  Since this proposed mechanism is 
different to that of known ESAs, ACE-011 may provide a different clinical profile in the 
treatment of CIA.  
This study will provide information on the pharmacodynamics (PD) properties regarding the 
ability of ACE-011 to increase hemoglobin in patients with CIA. 
5.2. 
Description of ACE-011 
ACE-011 (ActRIIA-IgG1) is a fully human fusion protein consisting of the extracellular domain 
(ECD) of activin receptor IIA (ActRIIA) linked to the human IgG1 Fc domain, which includes 
the heavy chain hinge and constant domains, CH2 and CH3.  ACE-011 avidly binds to activin A 
with a binding coefficient (Kd) approximately 8.9 pM and prevents its binding to endogenous 
receptors, thereby inhibiting biological effects of activin.   
 
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5.3. 
Activin Biology 
Activin A was initially identified as a gonadal differentiation factor involved in modulating 
follicle stimulating hormone (FSH) secretion from the pituitary (3). Subsequently, the pleiotropic 
nature of activin A has become more apparent (4).   There is a growing body of data suggesting a 
role for activin A in bone remodeling, specifically as a negative regulator of bone growth (5).  
Before the two molecules were shown to be identical (6), activin A was also described as 
erythroid differentiation factor (EDF), affecting red blood cells in the later stages of maturation 
(7).  The mechanism(s) by which activin A influences erythropoiesis remain under investigation 
and, in fact, there are data from studies in vitro and in animals that support erythropoiesis-
stimulatory (8,9) and -inhibitory effects (10).   
At the cellular level, activin A binds initially to the high-affinity Type II receptor (ActRIIA).  The 
ligand-bound ActRIIA then recruits the low-affinity Type I receptor (ActRIA or ALK-4).  The 
receptor heterocomplex, through its cytoplasmic protein kinase activity, then activates the Smad 
signal cascade to eventually influence nuclear transcriptional factors (11, 12).  The competitive 
binding of activin A in the blood by the ACE-011 soluble fusion protein can result in inhibition 
of ActRIIA receptor signaling pathway by impeding biological processes attributed to activin A.  
Activin has also been attributed to erythroid differentiation and has been reported to have 
proerythrocytic effects and to induce terminal differentiation of RBCs.  Inhibition of activin may 
lead to increases in proliferation of the erythroid lineage.  Based on its pharmacologic effects, 
ACE-011 (ActRIIA-IgG1) is being developed for the treatment of bone loss associated with 
various disease states (e.g., osteoporosis and treatment of osteolytic lesions in patients with 
multiple myeloma), and treatment of anemia associated with a variety of disorders, such as 
chemotherapy induced anemia. 
The extracellular domain sequence of ActRIIA is completely conserved among numerous species 
including mouse, rat, cynomolgus monkey and humans, thus ACE-011 is active in these animals.  
However, in order to reduce the potential immunogenicity of the fully human molecule, ACE-
011, in mice and to maximize the opportunity to maintain exposures in chronic models, a murine 
surrogate molecule was constructed by exchanging the human immunoglobulin Fc sequence 
portion of ACE-011 with its murine IgG2a homolog.  The resultant construct is referred to as 
RAP-011 (ActRIIA-mIgG2aFc).   
5.3.1. 
Pharmacology Studies 
RAP-011 was evaluated in a broad range of animal pharmacology studies to assess the effects of 
inhibition of activin A on the biological processes attributed to that regulatory protein.  RAP-011 
has been shown to have significant effects on the red cell compartment.  RAP-011 treatment of 
mice at 10, 30 and 50 mg/kg by intraperitoneal injection (IP) twice per week for 3 months 
resulted in a 16-26% increase in red blood cell (RBC) counts compared to control animals.  Rats 
treated with RAP-011 at 0.3, 3 and 30 mg/kg once per week for 3 months showed RBC count 
increases of 6-15% over control animals.  Finally, in cynomolgus monkeys treated with 10, 30 or  
 
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50 mg/kg of ACE-011 twice per month for 3 months there was a 21- 24% increase in RBC counts 
compared to control animals.  In this study, the RBC count increase was apparent as early as 2 
weeks following the initial dose of ACE-011.   
While the mechanism(s) underlying the stimulation effect of ACE-011 on erythropoiesis are not 
yet fully understood, it is hypothesized that a blockade of ActRIIA receptor signaling impedes the 
terminal differentiation step in erythropoiesis to allow additional rounds of erythroid cell 
replication before cells enter the terminal differentiation phase.  The result is a substantial 
increase in mature erythrocytes released into circulation.   
RAP-011 administered at 10 mg/kg to mice three days prior to administration of paclitaxel at 30 
mg/kg was sufficient to prevent decreases in red blood cell parameters seen three days later.  
Mice receiving paclitaxel alone had decreased hematocrit from 43% to 38% three days later.  
RAP-011 administered 3 days prior to paclitaxel injection was sufficient to keep the hematocrit 
above 42% at three days and up to two weeks after paclitaxel administration.  Therefore 
prophylactic treatment with RAP-011 was able to prevent paclitaxel induced anemia in mice. 
RAP-011 has also been shown to significantly increase bone mineral density and strength in 
normal animals and in a variety of animal models of bone loss (13, 14, 15).  In a murine 
ovariectomy (OVX)-induced model of osteopenia, RAP-011 (10 mg/kg IV, twice per week x 12 
weeks) increased trabecular BMD > 25% in 6-12 weeks compared to the phosphate buffered 
saline (PBS)-treated controls (p<0.002).  RAP-011 treatment was able to reverse the accelerated 
bone loss associated with ovariectomy.  As expected sham-operated (SHAM) mice (i.e., intact 
ovaries) started the study with a greater trabecular BMD than OVX mice.  PBS-treated SHAM 
mice showed a 10% decrease in trabecular BMD after 12 weeks of treatment compared to 
baseline, while SHAM-RAP-011 mice had a 32% increase in trabecular BMD over the same 
period.  These data demonstrate that RAP-011 is able to increase trabecular BMD in both the 
normal state and in a model of established bone loss.  The femurs of both the RAP-011 treated 
OVX and SHAM mice showed statistically significant increases in all measured parameters of 
bone strength (i.e., maximum load, stiffness, energy, ultimate strength, and elastic modulus).  In 
summary, treatment with RAP-011 produced bone of superior quality consistent with an anabolic 
agent. 
RAP-011 was evaluated in a mouse model of skeletal metastasis using luciferase-tagged, human 
MDA-MB-231 breast cancer cells (estrogen receptor negative).  Mice were pretreated for 2 
weeks with RAP-011 (10 mg/kg, biweekly, SC) prior to intracardiac injection of tumor cells.  
Treatment with RAP-011 was continued for an additional 5 weeks following tumor implantation. 
A parallel study was conducted to examine the effect of RAP-011 treatment, as described above, 
on survival of MDA-MB-231 bearing mice. 
The data demonstrate that RAP-011 treatment acts to inhibit MDA-MB-231 metastasis to bone 
and may also play a role in inhibiting tumor growth in soft tissue.  Furthermore, in the presence 
of tumor cells, RAP-011 is able to prevent lytic disease through an anabolic mechanism of bone 
formation.  Lastly, inhibition of tumor growth and metastasis with RAP-011 leads to a greater 
than 25% survival benefit in this model.  
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The efficacy of RAP-011 was examined in an orthotopic model of breast cancer using luciferase-
tagged human MCF-7 breast cancer cells (estrogen receptor positive). Mice were pretreated for 2 
weeks with RAP-011 (10 mg/kg, biweekly, SC) prior to the implantation of tumor cells into the 
mammary fat pad of female nude mice. Treatment with RAP-011 was continued for an additional 
7 weeks following tumor implantation at which time mice were sacrificed and assessed for tumor 
burden. RAP-011 effectively lowered the tumor burden in mice as detected by bio-luminescence. 
In addition, a 60% reduction in tumor weight was observed in the RAP-011 treated mice.  
The ability of RAP-011 to repair osteolytic lesions caused by metastatic disease was investigated 
in mice.  In this model athymic nude mice received an intratibial injection of MDA-MB-231-Luc 
cells to mimic bone metastasis.  Mice were treated with a chemotherapy regimen of paclitaxel (20 
mg/kg, IP, every three days) starting seven days after tumor injection and continuing for the 
duration of the study.  On study day 42 mice with a detectable tumor burden by bioluminescent 
imaging were divided into two groups and began treatment with RAP-011 (10 mg/kg, SC, 
biweekly) or vehicle.  Prior to dosing, μCT scans of the tumor bearing tibia were conducted to 
identify osteolytic lesions.  RAP-011 treatment continued for four weeks (to study day 70) and a 
final μCT scan of the tibia was performed.  On study day 70 osteolytic lesions remained the same 
or had progressed further when compared to study day 42 in the vehicle treated mice.  While 
some mice showed progression of osteolytic lesions (most likely related to tumor burden) on 
study day 70, a majority of mice treated with RAP-011 demonstrated repair of the osteolytic 
lesions seen on study day 42.  Therefore treatment with RAP-011 has the ability to repair 
osteolytic lesions caused by tumors and after cytoxic chemotherapy with paclitaxel. 
5.3.2. 
Toxicology 
ACE-011 has been evaluated for toxicological effects in two species, Sprague-Dawley rats and 
cynomolgus monkeys.  The dose levels ranged from 0.3 to 30 mg/kg in rats and from 1 to 50 
mg/kg in monkeys.  These dose ranges were designed to support Phase 1a single-dose levels of 
0.01 to 3.0 mg/kg IV and Phase 1b multiple doses of 0.1 to 2 mg/kg (monthly, SC).  Weekly 
dosing in animals was designed to provide continuous, but fluctuating serum concentrations of 
ACE-011, which would be mimicked by a one-month dosing interval in humans. 
Initial studies utilized IV dosing to identify target organs while longer-term studies (3 months in 
rats; 3 and 6 months in monkeys) utilized SC dosing to mimic the intended dosing regimen for 
patients.  The expected pharmacologic effect, increased red blood cells (RBCs), hemoglobin 
(Hgb), hematocrit (HCT) and reticulocytes, was observed in all studies, presumably based on the 
ability of ACE-011 to inhibit activin.  A second expected pharmacologic effect of ACE-011, 
based on inhibition of activin, was the reversible reduction in sperm production and testicular 
tubular damage in rats.  Since male cynomolgus monkeys were sexually immature in these 
studies, it was not possible to monitor this effect in this species. 
Effects on the adrenal gland were only seen in rats and were more pronounced in female rats. 
This toxicological observation may not be relevant for predicting effects in humans since adrenal 
toxicity was not seen in cynomolgus monkeys.  Dose-limiting toxicity and no observable adverse 
effect levels (NOAELs) were primarily based on renal toxicity in both rats and monkeys.  There  
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was some indication that kidney toxicity was an indirect effect, based on the formation of 
antibody/antigen complexes, but since these studies were not designed to investigate 
toxicological mechanisms, a definitive cause of renal impairment and renal damage was not 
determined.  Development of antibodies to ACE-011 was noted in all of these studies, which is 
an expected immune reaction in rats and monkeys dosed with a human protein.  
The no observable adverse effect level (NOAELs) from the 3 month SC studies was 3 and 30 
mg/kg in rats and monkeys, respectively. Because the kidney findings were observed at all dose 
levels, the NOAEL from the 6 month monkey study is < 10 mg/kg.  
5.4. 
Summary of Clinical Experience 
5.4.1. 
A011-01: A Phase 1a Study in Healthy Postmenopausal Women  
ACE-011 was first studied in a randomized, Phase 1a, single dose, dose escalation study in 
healthy, post-menopausal females (16).  ACE-011 was diluted in normal saline administered as 
an IV infusion (over approximately 1 hour) or as a SC injection on Day 1.  Dose levels were 0.01, 
0.03, 0.1, 0.3, 1.0, and 3.0 mg/kg IV and 0.03 and 0.1 mg/kg SC.  A total of 48 subjects were 
enrolled; 5 active and 1 placebo at each of the IV and SC dose levels.  All subjects were followed 
for 4 months following a single dose administration. 
The pharmacokinetics of ACE-011 was linear for all IV and SC doses.  Across IV doses ranging 
from 0.1 through 3.0 mg/kg, the mean clearance (CL) ranged from 0.092 to 0.128 mL/h/kg, the 
volume of distribution ranged from 73.7 to 110 mL/kg, and the mean T1/2 ranged from 23.7 to 
31.8 days, with no apparent dependence on dose.  After SC administration of 0.03 and 0.1 mg/kg, 
ACE-011 was completely absorbed, and the mean T1/2 was approximately 30 days, with no 
apparent dependence on dose.   
The most commonly occurring treatment-emergent adverse events (AEs; i.e., those occurring in 
more than 1 subject in any treatment group) were headache, infusion site reaction, injection site 
hemorrhage, and toothache.  The majority of the injection site reactions and injection site 
hemorrhages were in the first IV cohort and were related to infiltration of the IV site.  The 
majority of treatment-emergent AEs were mild in severity and were judged to be unrelated to 
ACE-011.  No deaths, serious AEs (SAEs), or AEs leading to discontinuation were reported.  
Changes in red blood cells (RBCs), hemoglobin, reticulocytes, liver function tests, glucose, uric 
acid, amylase and lipase occurred in some subjects; however, none of these laboratory results 
were reported as adverse events.  Mild, transient elevations in pancreas enzymes, liver enzymes, 
or glucose were reported as AEs in five patients.  There were no clinically significant changes 
from baseline in vital signs, physical examination, endocrine function, or electrocardiogram 
(ECG) data.  Preservation of adrenal cortical function was monitored through evaluation of serum 
electrolytes (sodium and potassium levels) and through cortisol response to adrenocorticotropic 
hormone (ACTH) stimulation.  No clinically significant findings were observed at doses up to 3.0 
mg/kg IV, and ACE-011 was well tolerated in healthy, post-menopausal female volunteers in 
single dose levels up to 0.1 mg/kg SC and 3.0 mg/kg IV, the highest dose levels tested in this 
study. 
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5.4.2. 
A011-02: A Phase 1b Study in Healthy Postmenopausal Women  
ACE-011 was studied in a Phase 1b, single-center, randomized, double-blind, placebo-controlled, 
multi-dose, dose-escalating study to evaluate the safety, tolerability and pharmacodynamics of 
ACE-011 in healthy postmenopausal women.  Four cohorts of 10 subjects each were planned at 
the following dose levels: 0.1, 0.3, 1.0, and 2.0 mg/kg administered subcutaneously.  Within each 
cohort, subjects were to be randomized to either active or placebo treatment in an 8:2 ratio. 
Subjects were to receive one SC injection of ACE-011 or placebo every 28 days for a total of 4 
doses. All subjects were to be followed for 12 weeks after the last dose. 
The treatment phase of the study was terminated early after a dose-limiting pharmacodynamic 
effect was observed.  While on study, one subject in the 1.0 mg/kg cohort experienced a Serious 
Adverse Event (SAE) of progressive and persistent hypertension that was attributed to a rapid 
and significant rise in hemoglobin and hematocrit levels.  Due to symptoms of headaches, nausea, 
eye pain, dizziness and vomiting approximately 1 week following the second dose, the subject 
was hospitalized for monitoring and evaluation of her hypertension.  The head MRI, fundoscopy, 
and ECG performed were reported as normal and headache symptoms resolved following 
therapeutic phlebotomy. The SAE resolved and the subject was discharged from the hospital the 
following day.  The hypertension was monitored closely and managed initially with 
antihypertensive medication.  The hypertension resolved by the end of the study without need of 
any antihypertensive medication. The subject received aspirin prophylactically until the end of 
the study and continued taking ibuprofen as needed for headaches.  Further details can be found 
in the Investigator Brochure.  
Based on the magnitude of the hematopoietic response, the Sponsor suspended dose escalation to 
the 2.0 mg/kg dose level and further dosing in all cohorts as a result of this dose-limiting 
pharmacodynamic effect at the 1.0 mg/kg dose level.  In total, 31 subjects were enrolled and 
treated.  Dose levels of ACE-011 administered included 0.1, 0.3, and 1.0 mg/kg (Cohorts 1, 2, 
and 3 respectively).  All subjects randomized to active treatment in Cohort 1 received all 4 
planned doses of ACE-011.  Due to early discontinuation of study drug, subjects randomized to 
active treatment in Cohort 2 received 3 doses of ACE-011, and subjects randomized to active 
treatment in Cohort 3 received 2 doses of ACE-011.  Subjects randomized to placebo treatment 
received between 1 and 4 doses of study treatment.   
In the analysis of the unblinded data, after the administration of the first dose, a dose and time 
dependent increase in hemoglobin values was observed (see Table 3 below): 
 
 
 
 
 
 
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Table 3: 
A011-02: A Phase 1b Study in Healthy Postmenopausal Women: Hemoglobin 
Evaluation 
       
*The number of placebo subjects with data decreases over time as a result of the early discontinuation of the study (i.e., there were placebo 
subjects in each dosing cohort).  There were seven placebo subjects with data at baseline, Days 8, 15, and 36; six subjects with data at Days 29, 
43, 57, and 85; five subjects with data on Days 71 and 113; four subjects with data on Day 64; three subjects with data on Day 141; two subjects 
with data on Day 99; and one subject with data on Days 92 and 169. 
** Number of doses administered per treatment group: 0.1 mg/kg 4 doses; 0.3 mg/kg 3 doses; 1.0 mg/kg 2 doses.  Data beyond this study day are 
considered follow-up results. 
***n=1 
No severe or life-threatening events were reported. The incidence of the most common treatment-
emergent AEs (i.e., occurring in more than one subject in any treatment group) is presented 
below (see Table 4). The most notable AEs were those related to increases in hematologic 
laboratory measures in the 1.0 mg/kg dose group: hematocrit, hemoglobin, and RBC count.  AEs 
of increased hemoglobin and/or hematocrit were reported for seven of the eight subjects in this 
dose group.  These events were reported as mild or moderate elevations; all were considered 
probably related to study drug treatment. Three of the subjects in the 1.0 mg/kg group with 
elevated hemoglobin levels underwent phlebotomies and all hemoglobin elevations were resolved 
by the end of the follow-up period. No erythroid lineage AEs were reported in the 0.1 or 0.3 
mg/kg treatment groups.   
 
Mean Change from Baseline (g/dL) 
Evaluation Time Point 
Placebo 
 
N=7* 
ACE-011 
0.1 mg/kg 
N=8 
ACE-011 
0.3 mg/kg 
N=8 
ACE-011 
1.0 mg/kg 
N=8 
Baseline Mean, pre-Dose 1 
13.20 
13.11 
13.30 
12.71 
Day 8 
0.17 
0.68 
0.85 
1.21 
Day 15 
-0.27 
0.43 
0.44 
1.75 
Day 29 
0.27 
0.61 
1.21 
    2.68** 
Day 36 
0.56 
0.64 
1.89 
2.96 
Day 43 
-0.02 
0.89 
1.21 
2.85 
Day 57 
0.27 
1.28 
    1.64** 
2.09 
Day 64 
0.53 
1.11 
2.49 
2.21 
Day 71 
-0.10 
1.34 
2.09 
1.66 
Day 85 
0.38 
    1.18** 
2.55 
1.86 
Day 92 
      0.00*** 
1.04 
      1.60*** 
      3.80*** 
Day 99 
-0.20 
1.21 
      3.20*** 
      1.28*** 
Day 113 
-0.02 
1.30 
1.29 
1.04 
Day 141 
 0.30 
0.95 
0.34 
2.30 
Day 169 
       0.20*** 
0.06 
 
      2.00*** 
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Headache was reported frequently in all treatment groups with no apparent dose response trend, 
though the reports in the higher dose groups were more often considered possibly related to 
treatment.  Most headaches were reported as mild (one headache was reported as moderate).  
Paresthesia and dizziness were reported more frequently in the ACE-011 groups, though the 
events were generally not considered drug related.  Other frequently reported events (e.g. fatigue, 
upper respiratory infection) did not appear to increase with dose and were generally mild.  
 
Table 4: 
A011-02: Incidence of Most Common Adverse Events    
Dose Group 
System Organ Class and Preferred Term 
Placebo 
N=7 
n (%) 
0.1 mg/kg 
N=8 
n (%) 
0.3 mg/kg 
N=8 
n (%) 
1.0 mg/kg 
N=8 
n (%) 
GASTROINTESTINAL DISORDERS 
     Diarrhea 
0 (0.0%) 
2 (25.0%) 
0 (0.0%) 
0 (0.0%) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
     Asthenia 
0 (0.0%) 
1 (12.5%) 
2 (25.0%) 
0 (0.0%) 
     Fatigue 
2 (28.6%) 
0 (0.0%) 
1 (12.5%) 
2 (25.0%) 
INFECTIONS AND INFESTATIONS 
     Viral upper respiratory tract infection 
0 (0.0%) 
4 (50.0%) 
0 (0.0%) 
0 (0.0%) 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
     Limb injury 
0 (0.0%) 
1 (12.5%) 
0 (0.0%) 
2 (25.0%) 
INVESTIGATIONS 
     Hematocrit increased 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
6 (75.0%) 
     Hemoglobin increased 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
7 (87.5%) 
     Red blood cell count increased 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
3 (37.5%) 
METABOLISM AND NUTRITION DISORDERS 
     Decreased Appetite 
1 (14.3%) 
0 (0.0%) 
2 (25.0%) 
0 (0.0%) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
     Arthralgia 
2 (28.6%) 
0 (0.0%) 
2 (25.0%) 
0 (0.0%) 
     Muscle spasms 
0 (0.0%) 
1 (12.5%) 
0 (0.0%) 
2 (25.0%) 
NERVOUS SYSTEM DISORDERS 
     Dizziness 
0 (0.0%) 
0 (0.0%) 
2 (25.0%) 
2 (25.0%) 
     Headache 
2 (28.6%) 
4 (50.0%) 
3 (37.5%) 
2 (25.0%) 
     Paresthesia 
1 (14.3%) 
0 (0.0%) 
0 (0.0%) 
3 (37.5%) 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
     Oropharyngeal pain 
2 (28.6%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
VASCULAR DISORDERS 
     Hot flush 
0 (0.0%) 
2 (25.0%) 
0 (0.0%) 
1 (12.5%) 
Note: Table presents AEs reported in more than one subject in any treatment group. 
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Hemoglobin levels for all subjects with elevations had returned to within normal limits by the end 
of the study.   
Adrenal cortical function was monitored through evaluation of serum electrolytes (sodium and 
potassium levels) and through cortisol response to adrenocorticotropic hormone (ACTH) 
stimulation. All ACTH simulation test results were normal. 
PK results confirmed that the PK of ACE-011 is linear following the first SC doses of all three 
dose levels tested, 0.1, 0.3, and 1.0 mg/kg. The terminal half life (T1/2) of ACE-011 following the 
last dose in all three dose groups was identical, with mean T1/2 being approximately 23 days. The 
mean CL/F ranged from 3.05 to 3.90 mL/d/kg, the mean Vz/F ranged from 97.47 to 103.03 
mL/kg, and the mean T1/2 ranged from 20.92 to 23.34 days in all 3 dose levels, with no apparent 
dependence on dose.  
Bone mineral density was assessed by dual-energy X-ray absorptiometry (DXA).  Mean change 
and mean percent change in BMD results from baseline to study end are summarized in the table 
below.  A dose-dependent increase in the BMD of the total hip from baseline to end of study was 
observed, with a significant and rapid increase of 2.4% in the 1.0 mg/kg dose group, compared to 
a 0.7% decrease in the placebo group.  BMD results for lumbar spine showed slight increases of 
0.4% to 1.0% from baseline to study end in all active treatment groups, compared with a 0.5% 
decrease in the placebo group (see Table 5 below): 
Table 5: 
A011-02: A Phase 1b Study in Healthy Postmenopausal Women: BMD 
 
5.4.3. 
A011-04: A Phase 2a Study in Patients with Osteolytic Lesions of Multiple 
Myeloma  
Study A011-04 is an ongoing, non-IND, Phase 2a, multi-center, randomized, multiple-dose study 
to evaluate the safety, tolerability and efficacy of ACE-011 in patients with osteolytic lesions of 
multiple myeloma.  Safety evaluations include adverse events (AEs), clinical laboratory tests, 
standard 12-lead electrocardiogram (ECG), vital signs, Eastern Cooperative Oncology Group  
Treatment Group 
Placebo 
 
N=7 
ACE-011 
0.1 mg/kg 
N=8 
ACE-011 
0.3 mg/kg 
N=8 
ACE-011 
1.0 mg/kg 
N=8 
 
Mean 
Change 
Mean Percent 
Change 
Mean 
Change 
Mean Percent 
Change 
Mean 
Change 
Mean Percent 
Change 
Mean 
Change 
Mean Percent 
Change 
Lumbar Spine 
(g/cm2) 
-0.0020 
-0.5% 
0.0099 
0.7% 
0.0082 
1.0% 
0.0051 
0.4% 
Total Hip 
(g/cm2) 
-0.0062 
-0.7% 
0.0050 
0.6% 
0.0075 
0.9% 
0.0220 
2.4% 
Number of doses administered and day of last dose per treatment group: 0.1 mg/kg 4 doses (Day 85); 0.3 mg/kg 3 doses (Day 57); 1.0 mg/kg 2 
doses (Day 29).  Data beyond this study day are considered follow-up results. 
 
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Phase 1a single dose and Phase 1b multiple dose healthy volunteer clinical studies.  These 
parameters were evaluated up to doses of 3.0 mg/kg IV and 1.0 mg/kg SC, and no clinically 
significant perturbations in adrenal function were observed.     
Laboratory findings from the Phase 1a single dose study showed elevations in hematology 
results, pancreas and liver enzymes, and uric acid.  The most commonly seen treatment-emergent 
adverse events in this study were headache, infusion site reaction, injection site hemorrhage, and 
toothache.  
Based on data from the Phase 1b study, the most notable AEs were increases in hematologic 
laboratory measures in the 1.0 mg/kg dose group: hematocrit, hemoglobin, and RBC count.  AEs 
of increased hemoglobin and/or hematocrit were reported for seven of the eight subjects in this 
dose group.  These events were reported as mild or moderate elevations; all were considered 
probably related to study drug treatment.  No erythroid lineage AEs were reported in the 0.1 or 
0.3 mg/kg treatment groups.  Hematologic parameters will be monitored carefully in this study.   
Headache was reported frequently in all treatment groups with no apparent dose response trend, 
though the reports in the higher dose groups were more often considered possibly related to 
treatment.  Most headaches were reported as mild (one headache was reported as moderate).  
Paresthesia and dizziness were reported more frequently in the ACE-011 groups, though the 
events were generally not considered drug related.  Other frequently reported events (e.g. fatigue, 
upper respiratory infection) did not appear to increase with dose and were generally mild. 
In the Phase 1b multiple-dose healthy volunteer study, some subjects treated with ACE-011 
showed elevations in blood pressure.  One subject who had received two doses of ACE-011 at the 
1.0 mg/kg dose level had a serious adverse event.  The patient was hospitalized for further 
evaluation of increases in blood pressure and symptoms that may have been caused by the 
increase in blood pressure.  The symptoms that the subject experienced included headache, 
dizziness, nausea, vomiting, and elevated hematology values (increases in the number of red 
blood cells).  This serious adverse event was judged to be probably related to the study drug and 
resolved following discharge from hospital the following day. Throughout the course of the 
follow up period hematologic parameters were monitored frequently until the hemoglobin and 
hematocrit levels returned to within normal limits. Further details are outlined in the Investigator 
Brochure.  
As with all biologics there is the potential for anti-drug antibodies that can be associated with 
increased drug clearance and hypersensitivity reactions.  An immune response to ACE-011 has 
been seen in monkeys that received the drug for 1 month and longer.  Some of those animals 
developed kidney inflammation possibly related to that immune response.  Anti-drug antibody 
formation will be assessed in this study to examine the immunogenicity of ACE-011, and to 
monitor reversibility of any AEs over time.   
Please refer to the Investigator Brochure for more information. 
 
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6. 
TRIAL OBJECTIVES AND PURPOSE 
6.1. 
Primary objective  
1. To evaluate the proportion of patients in each ACE-011 dose regimen who achieve a 
hematopoietic response during the treatment period including up to 2 months after the last 
dose of ACE-011 treatment of chemotherapy induced anemia in patients with metastatic 
breast cancer. Hematopoietic response is defined as an increase in hemoglobin of ≥ 1.0 
g/dL above the study baseline value for 28 consecutive days during the treatment period 
including up to 2 months after the last dose of ACE-011, in the absence of any RBC 
transfusions and/or ESAs. 
6.2. 
Secondary objectives 
1. To evaluate the safety and tolerability of ACE-011 for the treatment of chemotherapy 
induced anemia in patients with metastatic breast cancer.  
2. To evaluate the percentage of patients who achieve an increase in hemoglobin of  ≥ 2 
g/dL and/or hemoglobin concentration ≥ 11 g/dL for a consecutive 28 day period during 
the treatment period including up to 2 months after the last dose of ACE-011 in the 
absence of any RBC transfusions and/or ESAs.  
3. To estimate the duration of the hematopoietic response associated with each ACE-011 
dose regimen. 
4. To estimate the time to the hematopoietic response associated with each ACE-011 dose 
regimen. 
5. To estimate the proportion of patients receiving red blood cell (RBC) transfusions and/or 
ESAs within each cycle of ACE-011 with each dose regimen. 
6. To estimate the effect of each ACE-011 dose regimen on progression free survival (PFS) 
and objective response rate (ORR). 
6.3. 
Exploratory objectives  
1. To estimate the effect of each ACE-011 dose regimen on serum bone biomarkers (OC, 
BSAP, P1NP, CTX, and TRACP-5b), bone mineral density (DXA scans of lumbar spine 
and hip) and incidence of skeletal related events (SREs). 
2. To evaluate the quality of life in relation to the treatment of chemotherapy induced 
anemia in patients with metastatic breast cancer during the study. 
.  
 
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7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design and Plan 
This is a Phase 2, double-blind, randomized, placebo-controlled study to evaluate the efficacy, 
safety, and tolerability of ACE-011 for the treatment of chemotherapy induced anemia in patients 
with metastatic breast cancer. A total of approximately 105 patients will be enrolled. 
The Data Monitoring Committee (DMC) is responsible for reviewing safety. The DMC will be 
comprised of a minimum of 3 members.  The DMC will meet regularly during the study to 
review serious adverse events (SAEs), adverse events (AEs), laboratory results, and vital signs. 
Safety data will be reviewed throughout the study by the DMC, Medical Monitor and the 
Investigator. DMC responsibilities, membership, meeting frequencies and procedures will be 
outlined in the DMC charter.  
Patients will be evaluated for study inclusion/exclusion criteria by the Investigator. Patients who 
meet the study entry criteria will be enrolled within 14 days of the screening visit. Local lab 
values for hemoglobin and central lab values will be utilized for the evaluation of patient 
eligibility. Central labs will also be used in the evaluation of patient safety throughout the study. 
Local lab values for hemoglobin and hematocrit will be collected and reported from screening 
(for eligibility) through the Day 281/Termination visit.  Three cohorts of 30 patients each are 
planned at the following doses of ACE-011: 0.1 mg/kg, 0.3 mg/kg and 0.5 mg/kg. Fifteen 
patients will be enrolled into the placebo cohort (as shown in Table 6). 
Table 6: 
Study Design    
 
 
 
  
 
 
 
 
Each eligible patient will be randomized to one of the four cohorts to receive a dose administered 
as a subcutaneous injection every 28 days for up to 4 doses. Dosing will be administered on days 
1, 29, 57, and 85. Concurrent treatment with a myelosuppressive chemotherapy regimen for 
metastatic breast cancer will also be administered per standard of care at the site. Patients will be 
stratified according to administration of either single agent weekly chemotherapy or less frequent 
chemotherapy regimens.  
Blood samples will be collected from approximately one-third of patients participating in the 
study at selected study sites for the evaluation of serum concentrations of ACE-011.  Pre-dose PK 
samples will be collected as specified in Appendix 5 (PK sampling schedule.) 
Dose  
Number of  Patients 
0.1 mg/kg 
30 
0.3 mg/kg 
30 
0.5 mg/kg 
30 
Placebo 
15 
Total patients enrolled (planned): 105 
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Patients will be assessed for safety by monitoring adverse events, clinical laboratory tests, vital 
signs and physical examinations on an ongoing basis.  ECGs will be performed during screening, 
prior to dosing on the first cycle, during the first and third cycle, Day 113 (28 days after the last 
dose of ACE-011) and at Day 281/ Termination visit to monitor safety.  Blood pressure and lab 
values will be assessed at each study visit during the treatment and treatment follow up period. 
Local laboratory hemoglobin values and blood pressure values will be evaluated prior to dosing 
per the dose modification criteria, as applicable.  
Patients will be followed for a minimum of 7 months following their last dose of ACE-
011/placebo. Study participation for each patient is approximately 10.5 months (14 day screening 
period, 3 month treatment period with a 2 month treatment follow up period, and a 5 month post 
treatment follow-up period). If a patient discontinues the study due to progression of disease 
(metastatic breast cancer) and/or begins another chemotherapy regimen, the patient will 
discontinue ACE-011/placebo treatment, complete the Day 281/Termination visit procedures, and 
be followed for survival only (a minimum 7 months from the last dose of ACE-011/placebo).   
Anti-drug antibody testing will be performed at Day 281/Termination visit and if positive, the 
patient may be asked to return every 3 months until a negative result is obtained  
Back up (serum) blood samples will be collected for future testing for the evaluation of novel 
tumor markers, such as endoglin and ALK-1 (activin receptor-like kinase-1). The samples will 
the stored at the central lab until this evaluation is performed. 
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  1    Vital signs include weight, heart rate, seated systolic and diastolic blood pressure (BP), and temperature will be assessed at each visit  Height will be collected at screening only   For patients with previous history of CNS metastases, if BP value increases by one or    
       more NCI CTCAE v3 0 grades, the patient must return within 7 days to have BP assessed again  Patients with a recent change in anti-hypertensive medication or a change in the past month should be seen weekly for BP measurements   
  2   On dosing days (1, 29, 57 and 85), study procedure to be done prior to dosing of ACE-011/placebo    
  3     Use of  Digital ECG machine-Screening- At two different time intervals (approximately 1 hour apart) triplicate (12 lead) ECGs to be performed at 3 minute intervals (± 1min),  On all other specified days, one time interval of triplicate (12 lead) ECGs is to be   
       performed at 3 minute intervals (± 1min), prior to dosing as applicable  If a local ECG machine is used, a single (12 lead) ECG is to be performed   
 4       Coagulation (central lab only) prothrombin time (PT), partial thromboplastin time (PTT), fibrinogen    
 5     Chemistry (central lab only): AST, ALT, lactate dehydrogenase (LDH), total bilirubin, indirect bilirubin, alkaline phosphatase, total protein, albumin, sodium, potassium, chloride, carbon dioxide, calcium, phosphorus, blood urea nitrogen (BUN), creatinine, uric  
      acid, glucose, amylase, and lipase   
 6  Hematology (local lab) hemoglobin and hematocrit  On dosing days (1, 29, 57 and 85), local hemoglobin and hematocrit values are to be drawn and resulted (up to 1 day) prior to dosing to apply dose modification rules for ACE-011/placebo   Hematology (central   
       lab only) complete blood count (CBC) with differential and platelet, CBC includes red blood cells (RBC), white blood cells (WBC),  hemoglobin, hematocrit, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin       
      concentration (MCHC), Peripheral blood smear will also be done on Days 1, 57 and at the termination visit   Reticulocyte should be done on days 1, 8, 15, 29, 57, 85, and at the termination visit.  
  7      If a patient has a positive anti-drug antibody result at the Termination visit, they may be asked to return to the clinical site every 3 months until a negative result is obtained  
  8    Serum samples will be collected at each visit  
 9      Labs may be drawn within 1 day prior to Day 1  Confirmatory labs for eligibility criteria must be drawn and resulted within 7 days of Day 1   
10   For females of child bearing potential only urine (dipstick) pregnancy test to be collected and resulted prior to dosing of ACE-011/placebo on dosing days  
11    Urinalysis to be performed at screening, prior to administration ACE-011/placebo (Days 1 and 85) and termination visit  Assessments (central lab only): pH, specific gravity, protein, glucose, ketones, blood, leukocyte esterase, and nitrite  Microscopy required only 
to follow-up abnormal findings  
12   Screening- any concomitant treatments taken 28 days prior to day 1 including up to 90 days after the last dose of ACE-011/placebo   
13  AEs will be reported from day 1 post dose including up to 90 days after the last dose of ACE-011/placebo  Additional AEs noted after 90 days from the last dose of ACE-011/placebo will be reported at the discretion of the investigator   SREs and SAEs will be 
followed through out the study   If a patient is followed for survival only, SREs and SAEs will be captured up to 90 days from the last dose of ACE-011/placebo  
14   A CT/MRI scan acquired within 6 weeks of initiating the current chemotherapy regimen may be used for the screening assessment   Head, neck, thoracic, abdominal, and pelvic scans are to be acquired   One measurable or non measurable lesion per RECIST v1 1 is 
to be identified by the scan  Brain (head) CT only to be done to rule out CNS metastases in patients with suspicious clinical symptoms or prior history of CNS metastases   
15  Follow-up CT/MRI scans may be acquired +/- 7 day window for Day 113  Additional CT/MRI scans acquired during the post treatment follow up period will be performed at the discretion of the investigator   
16  Hip and lumbar spine BMD assessment  Refer to Imaging Acquisition Guidelines for guidelines regarding washout period for contrast (if used) for radiological images, prior to collection of DXA  
17  Bone scans will be acquired within 6 weeks of initiating the current chemotherapy regimen for those patients who have bone metastases identified  Follow up bone scan, when the baseline bone scan was abnormal, may be acquired +/- 7 day window for Day 281  
18    All study visit day dates (inclusive of windows) are calculated from Day 1(day of initial ACE-011/placebo administration)   
19   Chemotherapy  regimens will be administered to the patient as per standard of care  Continuation of the same chemotherapy regimen may be done through the follow up period of the study at the discretion of the investigator   
20   If a patient withdraws from the study (section 8 3), the Day 281/Termination visit procedures are to be completed and the patient will be followed for survival  If withdrawal reason is due to ESA administration or ACE-011 related toxicity, the patient should enter the   
      treatment follow up period  
Schedule of Events cont. 
 
  Screen 
Treatment Period 
 
ACE-011/Placebo 
Dose period 
 
#1 
#2 
#3 
#4 
Follow-up   
 
Post Treatment Follow up Period 
 
Term 
Visit20 
Day 
     -14-0 
1 
8 
(± 1d) 
15 
 (± 1d) 
 
29 
(± 3d) 
 
43 
(± 2d) 
57 
(± 3d) 
 
71 
 (± 2d) 
85 
 (± 3d) 
113 
(± 7d) 
    141 
 (± 7d) 
 
169 
(± 7d) 
225 
 (± 7d) 
281 
(± 7d) 
Evaluation of  AEs 
and SAEs13 
X-SAE 
only 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X-SRE and SAE only 
 
X 
CT/MRI scan 
   X14 
 
 
 
 
 
 
 
 
  X15 
  
 
 
 
Dual-energy X-ray 
absorptiometry 
(DXA16) 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
Bone scans17 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
ACE-011/placebo 
administration18 
 
X 
 
 
X 
 
X 
 
X 
 
 
 
 
 
Chemo regimen19 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
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8. 
SELECTION AND WITHDRAWL OF PATIENTS 
8.1. 
Number of Patients 
The study will include three dose levels of ACE-011 at 0.1 mg/kg, 0.3 mg/kg and 0.5 mg/kg and 
a placebo group. A total of approximately 105 patients will be treated with ACE-011 or placebo. 
8.2. 
Entry Criteria 
8.2.1. 
Patient Inclusion Criteria 
1. Women > 18 years of age. 
2. Histologically or cytologically confirmed diagnosis of breast cancer. 
3. Evidence of metastatic breast cancer with a minimum of one measurable lesion or non 
measurable lesion per RECIST v1.1 criteria (Appendix 1). 
4. Receiving a multicycle myelosuppressive chemotherapy regimen including one of the 
following: anthracycline, taxane, gemcitabine, vinorelbine or capecitabine. 
5. Anticipated treatment with the same myelosuppressive chemotherapy regimen for a 
minimum of 9 weeks after Day 1 of ACE-011/placebo administration.  
6. Hemoglobin value between ≥ 6.5 to < 11.0 g/dL (≥ 65 to < 110 g/L).  
7. ≥ 30 days must have elapsed (from Day 1) since previous treatment with erythropoiesis-
stimulating agent (including concurrent treatment with IV iron) for chemotherapy 
induced anemia.  
8. ≥ 7 days have elapsed (from Day 1) since the last RBC blood transfusion and receipt of ≤ 
2 units of blood in the past 30 days.  
9. ECOG Performance status of 0 – 2 (Appendix 2). 
10. Adequate renal (creatinine ≤ 1.5 x ULN or creatinine clearance ≥ 40 mL/min) and hepatic 
function [bilirubin < 1.5 x ULN; AST/ALT < 2.5 x ULN (AST/ALT ≤ 5 x ULN when 
there is evidence of liver metastases)]. 
11. Females of childbearing potential  participating in the study are to use adequate birth 
control measures (i.e. oral contraceptives or two forms of barrier method birth control) 
during study participation. Females of childbearing potential must have a negative serum 
pregnancy test within 7 days to ACE-011/placebo administration (Day 1). A female of 
childbearing potential is a sexually mature woman who has not undergone a 
hysterectomy or who has not been postmenopausal for at least 24 consecutive months 
(i.e. who has had menses at some time in the preceding 24 months). 
12. Life expectancy of ≥ 6 months. 
13. Is willing to adhere to the study visit schedule, understand and comply with all protocol 
requirements. 
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14. Understand and sign a written informed consent. 
8.2.2. 
Patient Exclusion Criteria 
1. At the time of screening patients who have any grade > 3 toxicity (as per NCI CTCAE 
v3.0 (Appendix 3)) (except for the following disease related toxicities:  hematological 
events- anemia, thrombocytopenia or neutropenia or non hematological events- nausea, 
vomiting, fatigue, or muscle or bone/joint pain).  
2. Prior radiation therapy to > 20% of the whole skeleton. 
3. Have received more than 5 prior chemotherapy treatment regimens for metastatic breast 
cancer (not including the current chemotherapy regimen). 
4. Clinically significant pulmonary, endocrine, neurologic, gastrointestinal, hepatic or 
genitourinary disease unrelated to underlying hematologic disorder.  
5. Patients with heart failure as classified by the New York Heart Association (NYHA) 
classification of 3 or higher (Appendix 4). 
6. Recent history of thrombosis, deep vein thrombosis (DVT), pulmonary emboli, or 
embolic stroke occurring within the last 6 months; if on anticoagulation therapy must be 
clinically stable as determined by the Investigator.  
7. Untreated CNS metastases or CNS metastases treated with whole brain radiotherapy < 6 
months prior to Day 1. 
8. Diagnosis of a myeloid malignancy or known history of myelodysplasia.  
9. History of second malignancy within 5 years (except excised and cured basal cell 
carcinoma, squamous cell carcinoma of the skin or cervical carcinoma in situ).  
10. Administration of IV antibiotics or febrile (temperature elevation > 38 ° C) within 14 
days of Day 1. 
11. Uncontrolled hypertension. If hypertension is considered clinically stable, systolic blood 
pressure (BP) must be < 150 mmHg and diastolic BP must be < 100 mmHg.  
12. Known history hepatitis B surface antigen (HBsAg and HB core Ab), human 
immunodeficiency virus (HIV) antibody or active hepatitis C.   
13. Clinically significant iron (transferrin saturation < 20%), vitamin B12, or folate 
deficiency. 
14. History of anemia as a result of inherited hemoglobinopathy such as sickle cell anemia or 
thalassemia.  
15. History of autoimmune or hereditary hemolysis; active gastrointestinal bleeding (within 
the last 6 months as compared to Day 1). 
16. Patient received treatment with another investigational drug or device within 1 month 
prior to Day 1, or if the half life of the previous product is known, within 5 times the half 
life prior to dosing, whichever may be longer.  
17. Pregnant or lactating females. 
18. History of severe allergic or anaphylactic reactions or hypersensitivity to recombinant 
proteins or excipients in the investigational product. 
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19. Major surgery within 30 days prior to Day 1 (patients must have completely recovered 
from any previous surgery prior to Day 1).   
8.3. 
Patient Withdrawal Criteria 
Patients will be informed that they have the right to withdraw from the study at any time for any 
reason without prejudice to their medical care.   
Patients must be withdrawn from the study for any of the following reasons:  
• Patient request 
• Patient is unwilling or unable to comply with the protocol 
• ESA administration during the treatment period 
• Medical reason, such as beginning a new chemotherapy regimen, cancer or treatment 
related toxicity, or at the discretion of the Investigator and/or the Medical Monitor(s) 
• Patients with a hemoglobin level above the upper limit of normal at any time during the 
study after Day 1  
• Grade ≥ 3 toxicity related to ACE-011 [except grade 3 hypertension that decreases to 
grade ≤ 1 within 7 days after treatment with anti-hypertensive therapy (section 9.6.2.1)] 
• Pregnancy 
The reasons for withdrawal must be recorded in the patient’s case report form (CRF).  The 
Investigator must notify the Medical Monitor and the contract research organization (CRO) 
immediately when a patient has been discontinued/withdrawn due to an AE.  All patients who 
are withdrawn from the study should complete the tests and evaluations scheduled for Day 
281/Termination at the time of withdrawal. Discontinued/withdrawn patients should be followed 
for survival only for 7 months after the last dose of ACE-011/placebo. If a patient begins a new 
chemotherapy regimen during the study, the patient will discontinue further ACE-011/placebo 
treatment, complete the Day 281/Termination visit procedures and be followed for survival only. 
Patients who withdraw due to ESA administration during the treatment period or due to ACE-
011 related toxicity should enter the treatment follow-up period.  
 
 
 
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9. 
TREATMENT OF PATIENTS 
9.1. 
Concomitant Medications 
9.1.1. 
General Concomitant Medication Usage 
During screening, and during the study, patients may take only stable doses of medications for 
chronic conditions that are not specifically excluded by the protocol (see Sections 8.2.1 Patient 
Inclusion Criteria and 8.2.2 Patient Exclusion Criteria).  The Medical Monitor should be 
consulted by the Investigator if there are any concerns about what constitutes a stable dose or 
what is a chronic condition.  Patients with a recent change in anti-hypertensive medication or a 
change in the past month should be seen weekly for BP measurements. Concomitant medications 
will be recorded in the CRF through 90 days from the last dose of ACE-011/placebo.   
9.1.2. 
Concomitant treatment for anemia 
Concurrent therapy with a new prescription medication related to treatment of anemia during the 
course of the study must first be discussed with the Investigator and Medical Monitor prior to 
administration, unless appropriate medical care necessitates that medication should begin before 
the Medical Monitor can be consulted.  
9.1.2.1. 
Iron supplementation 
Iron supplementation within 7 days of Day 1 (besides an oral general multivitamin with iron) 
will not be allowed. If a patient becomes iron replete during study treatment (transferrin 
saturation < 20%), treatment with iron supplementation is at the discretion of the investigator.  
9.1.2.2. 
Erythropoiesis-stimulating agents (ESAs) 
If concurrent treatment with erythropoiesis-stimulating agent is required in the opinion of the 
investigator, the erythropoiesis-stimulating agent label instructions are to be followed. The 
patient is to discontinue further treatment with ACE-011/placebo and enter the treatment follow- 
up period of the study. See Table 7 for Schedule of Events.  
9.1.2.3. 
RBC Transfusions 
Concurrent treatment for chemotherapy induced anemia with blood transfusions is recommended 
when hemoglobin value is < 8 g/dL or at investigator discretion if the hemoglobin value is above 
8 g/dL and associated with anemia symptoms such as hemodynamic or pulmonary compromise 
that require treatment. If a transfusion is given to a patient during the treatment period, ACE-
011/placebo should be administered no sooner than 7 days from the date of the transfusion.  
After the transfusion, the hemoglobin value should be assessed no later than 7 days from the date 
of the transfusion.  On the day of ACE-011/placebo administration, the hemoglobin value and 
blood pressure will be assessed. See Figure 1 for ACE-011/placebo dose modification rules.  
 
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9.2. 
Chemotherapy 
Chemotherapy treatment for metastatic breast cancer is to be given as per standard of care at the 
site.  ACE-011/placebo administration should be given prior to chemotherapy administration on 
ACE-011/placebo administration days.  Continuation of treatment with the same chemotherapy 
regimen through the follow-up period of the study is at the discretion of the investigator. 
9.3. 
Treatment Compliance 
Each dose of ACE-011/placebo will be administered as a SC injection at the clinical site by the 
study staff and will be documented in the study record.  Monitoring for patient compliance with 
the treatment regimen is therefore unnecessary.  
9.4. 
Rescreening 
If a patient receives a screening number through Interactive Voice/Web Response System 
(IVRS/IWRS) and does not continue to meet eligibility criteria (prior to randomization), the 
patient may be re-screened once during the enrollment period of the study. Evaluation and 
decision to re-screen a patient will be done by the site, Medical Monitor, and Acceleron (as 
needed). All screening procedures are to be re-performed to verify patient eligibility. The 
screening DXA scan is to be re-done if more than 45 days has elapsed since the initial screening 
DXA scan. Informed consent must be signed by the patient if more than 14 days has elapsed 
since initially signing consent.  
Patients who have been randomized but have not received the first dose of ACE-011/placebo and 
no longer meet eligibility criteria will require further evaluation by the site, Medical Monitor, 
and Acceleron (as needed) for continued participation in the study. 
9.5. 
Randomization  
Patients will be randomized to limit scientific bias within the study. Randomization assignments 
will be generated through a computerized system, provided by an Interactive Voice/Web 
Response System (IVRS/IWRS). Patients will be stratified according to frequency of the planned 
chemotherapy regimen (weekly chemotherapy vs. less frequent chemotherapy administration). 
9.5.1. 
Blinding 
The Investigators, patients, and sponsor or representative will remain blinded to the treatment 
arm assignment of each patient. The unblinded statistician will remain uninvolved in the study 
conduct until database lock and unblinding of the data has occurred.  
Safety parameters will be reviewed on an ongoing basis throughout the study including adverse 
events, serious adverse events, laboratory listings, and vital signs. If substantial toxicity trends 
are observed in one treatment group versus another, the DMC will have access to the unblinded 
treatment code assignment schema.  
 
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9.5.2. 
Unblinding 
In the event of a medical emergency for an individual patient in which knowledge of the study 
medication is critical to the patient’s medical management, the investigator may request to break 
the blind for that patient. However, prior to breaking the blind, every effort must be made by the 
investigator to first discuss the need to break the blind with the sponsor or sponsor 
representative. Further, it must be determined by the investigator that breaking the treatment 
blind is necessary information for the medical management of that patient. If the blind is broken, 
the patient must withdraw from the study by completing the Day 281/Termination visit 
procedures and be followed for survival only 
9.6. 
Treatments Administered 
9.6.1. 
Selection of Doses in the Study 
Single dose administration of ACE-011 up to 3.0 mg/kg was previously demonstrated to be safe 
and to have durable effects on markers of bone formation and resorption as well as red blood 
cells following a single IV administration.  A dose-limiting pharmacodynamic effect of ACE-
011 with increases in hemoglobin, hematocrit and RBCs was established in healthy post-
menopausal women at the 1.0 mg/kg dose level following multiple SC administration.  This 
study will confirm the safety in following repeated SC administration of ACE-011 and further 
evaluate the potential efficacy in patients with chemotherapy induced anemia.  The safety and 
preliminary efficacy of ACE-011 following multiple doses up to 0.5 mg/kg will be assessed 
using a parallel randomization design. 
9.6.2. 
Selection and Timing of Dosing for Each Patient 
Patients will be enrolled and receive their assigned dose of ACE-011/placebo every 28 days (i.e. 
on Days 1, 29, 57, and 85). After completion of ACE-011/placebo treatment, patients will return 
to the site monthly for 2 follow-up assessment (Days 113 and 141).  Subsequently, the patient 
will return to the site for 2 post treatment follow-up assessments (i.e. Days 169 and 225). The 
patient will return to the site for a termination visit approximately 2 months after the post 
treatment follow-up period (Day 281).  Patients will be discontinued from the ACE-011/placebo 
treatment for reasons listed in section 8.3 of the protocol.  
9.6.2.1. 
ACE-011 Treatment Related Toxicity  
Patients with grade ≥3 toxicity related to ACE-011 will be discontinued from ACE-011/placebo 
treatment except for the following.  Patients with grade 3 hypertension that decreases to grade 
≤ 1 within 7 days after treatment with anti-hypertensive therapy may continue on ACE-
011/placebo treatment.  Dose reduction rules will apply at the subsequent scheduled dosing 
day(s). 
 
 
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9.6.2.2. 
ACE-011 Dose Modification Rules 
Throughout the study blood pressure and hemoglobin values will be evaluated for patient safety. 
The local hemoglobin values and blood pressure values will be evaluated at each study visit and 
on each ACE-011/placebo dosing day.  The hemoglobin values from the previous 28 days 
between each ACE-011/placebo dosing day and blood pressure will be reviewed and evaluated 
for dose modifications.  The parameters below outline rules for dosing modifications (Figure 1).  
Table 8 outlines the dose reduction levels of ACE-011.  
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10. 
STUDY PROCEDURES AND SCHEDULE 
10.1.1. 
Written Informed consent 
Patients will be required to sign an Institutional Review Board/Institutional Ethics Committee 
(IRB/IEC) approved informed consent form (ICF) prior to any study related procedures, 
including screening evaluations. 
Screen failure information will be maintained, including but not limited to, reason for failure.   
10.1.2. 
Screening (Within 14 days of dosing) 
The following will be collected within 14 days prior to the initial dosing Day 1.  Labs to confirm 
eligibility criteria must be drawn and resulted within 7 days of Day 1: 
• Informed consent 
• Assessment of inclusion/exclusion criteria 
• Complete Medical History and Physical Examination 
• Vital signs including weight (kg), heart rate (beats/min), seated systolic and diastolic 
blood pressure (mmHg), temperature (°C) and height. 
• FACT-Fatigue survey 
• At two different time intervals (approximately 1 hour apart) triplicate (12 lead) ECGs 
to be performed at 3 minute intervals (± 1min) with the use of a digital ECG machine 
o If a local ECG machine is used, a single (12 lead) ECG is to be performed. 
• Serum iron, transferrin saturation %, and total iron binding capacity (TIBC) 
• Vitamin B12 and serum folate levels 
• Coagulation 
• Serum chemistry  
• Hematology 
• LH, FSH, testosterone, progesterone, and estradiol  
• Serum Pregnancy Test for females of childbearing potential- to be assessed within 7 
days of Day 1. 
• Urinalysis 
• Evaluation of transfusion frequency (including history of transfusion up to 8 weeks 
prior to Day 1) 
• Documentation of concomitant medications (any treatments taken 28 days prior to 
Day 1) 
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• CT/MRI scan:  A CT/MRI scan acquired within 6 weeks of initiating the current 
chemotherapy regimen may be used for the screening assessment. One measurable or 
non-measurable lesion per RECIST v1.1 is to be identified by the scan.  
o Scans of the anatomical areas of head (if applicable), neck, thoracic, 
abdominal, and pelvic are to be available for evaluation. If one of the 
anatomical areas listed has not be acquired, prior to screening, then a CT/MRI 
must be done, during screening for this study,  to ensure a scan of the  head (if 
applicable), neck, thoracic, abdominal, and pelvic is available.  
 Brain (head) CT only to be done to rule out CNS metastases in patients 
with suspicious clinical symptoms or prior history of CNS metastases.  
• Dual-energy X-ray absorptiometry (DXA) of  lumbar spine and hip 
o Refer to Imaging Acquisition Guidelines for guidelines regarding washout 
period for contrast (if used) for radiological images, prior to acquiring DXA 
scan. 
• Bone scans (only for patients with bone metastases) acquired within 6 weeks of 
initiating the current chemotherapy regimen may be used for the screening 
assessment. 
10.1.3. 
Initial Dosing: Day 1  
Patients will be dosed on Day 1.  Results from screening evaluations must be reviewed prior to 
randomization to confirm patient eligibility.  After the inclusion/exclusion criteria have been met 
and the patient has been randomized (through IVRS/IWRS), ACE-011/placebo administration 
may begin. 
Chemotherapy regimen will be administered per standard of care at the site. The following tests 
must be performed prior to ACE-011/placebo administration: 
• Confirm eligibility of patient by inclusion/exclusion criteria (local lab hemoglobin 
value and central lab values). The local hemoglobin value should be drawn prior to 
ACE-011/placebo administration (up to 1 day prior to Day 1).  
• Physical Examination 
• Vital signs including weight (kg), heart rate (beats/min), seated systolic and diastolic 
blood pressure (mmHg), and temperature (°C)  
• FACT-Fatigue survey 
• Triplicate (12 lead) ECGs to be performed at 3 minute intervals (± 1min) with the use 
of a digital ECG machine 
o If a local ECG machine is used, a single (12 lead) ECG is to be performed. 
• Serum iron, transferrin saturation %, and total iron binding capacity 
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• Coagulation 
• Serum Chemistry   
• Hematology 
• Serum erythropoietin marker  
• LH, FSH, testosterone, progesterone, and estradiol  
• Anti-drug antibody test 
• Bone biomarkers- osteocalcin (OC), procollagen type 1 N-terminal propeptide 
(P1NP), serum bone specific alkaline phosphatase (BSAP), C-terminal type 1 
collagen telopeptide (CTX), and tartrate-resistant acid phosphatase isoform-5b 
(TRACP-5b). 
o Please refer to the Study Reference Guide, provided under separate cover, for 
the Bone Biomarker Collection and Handling Guidelines for instructions the 
on collection of serum for the biomarkers.  
• Back-up blood sample to be drawn for future testing 
• Females of childbearing potential- Urine (dipstick) pregnancy test to be collected and 
resulted prior to ACE-011/placebo dosing 
• Urinalysis 
• Evaluation of transfusion frequency  
• Documentation of concomitant medications  
• Evaluation of adverse events (after ACE-011/placebo administration)  
• Patients will be administered ACE-011/placebo before the chemotherapy regimen 
begins during the study visits.  
After ACE-011/placebo and chemotherapy are administered, the patient may leave the clinic, 
based on the clinical judgment of the staff.   
All study visit day dates (inclusive of windows) are calculated from Day 1(day of initial ACE-
011/placebo administration). 
10.1.4. 
ACE-011/placebo administration: Days 29, 57, and 85 (± 3 days)  
Chemotherapy regimen will be administered per standard of care at the site. ACE-011/placebo 
will be administered approximately every 28 days. The following procedures must be performed 
prior to ACE-011/placebo administration: 
• Physical Examination 
• Vital signs including weight (kg), heart rate (beats/min), seated systolic and diastolic 
blood pressure (mmHg), and temperature (°C)  
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• FACT-Fatigue survey 
• Serum iron, transferrin saturation %, and total iron binding capacity (Day 57 only) 
• Coagulation (Day 57 only) 
• Serum chemistry  
• Hematology 
• Serum erythropoietin marker  
• Triplicate (12 lead) ECGs to be performed at 3 minute intervals (± 1min) with the use 
of a digital ECG machine (Day 57 only) 
o If a local ECG machine is used, a single (12 lead) ECG is to be performed. 
• LH, FSH, testosterone, progesterone, and estradiol 
• Anti-drug antibody test (Day 57 only) 
• Bone biomarkers- OC, BSAP, P1NP, CTX, and TRACP-5b 
o Please refer to the Study Reference Guide, provided under separate cover, for 
the Bone Biomarker Collection and Handling Guidelines for instructions the 
collection of serum for the biomarkers.  
• Back-up blood sample to be drawn for future testing 
• Females of childbearing potential -urine (dipstick) pregnancy test to be collected and 
resulted prior to ACE-011/placebo dosing 
• Urinalysis (Day 85 only) 
• Evaluation of transfusion frequency  
• Documentation of concomitant medications  
• Evaluation of adverse events  
Hemoglobin (HgB) (by review of local lab values) and blood pressure (BP) measurement must 
be assessed prior to ACE-011/placebo dose administration. Local Hgb must be done within 1 day 
prior to the ACE-011/placebo dosing day. 
10.1.5. 
Additional visits during Treatment Period: Days 8, 15  (± 1 day), 43, and 71 (± 2 
days) 
 
Chemotherapy regimen will be administered per standard of care at the site.  The following 
procedures are to be performed during the study visit.  Patients with previous history of CNS 
metastases, if blood pressure (BP) value increases by one or more grade(s) per the NCI 
CTCAE v3.0, the patient must return within 7 days to have BP assessed again.  
 
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• Vital signs including weight (kg), heart rate (beats/min), seated systolic and diastolic 
blood pressure (mmHg), and temperature (°C)  
• Triplicate (12 lead) ECGs to be performed at 3 minute intervals (± 1min) with the use 
of a digital ECG machine (Day 8 only) 
o If a local ECG machine is used, a single (12 lead) ECG is to be performed. 
• Hematology 
• Back-up blood sample to be drawn for future testing 
• Evaluation of transfusion frequency  
• Documentation of concomitant medications 
• Evaluation of adverse events  
If patient terminates ACE-011/placebo early and/or begins a new chemotherapy regimen, the 
patient should complete the Day 281/Termination visit procedures and be followed for survival 
only. 
10.1.6. 
Treatment Period Follow-up visits : Days 113 and 141 (± 7 days) 
Chemotherapy regimen will be administered per standard of care at the site.  The following 
procedures are to be performed during the study visit: 
• Physical Examination 
• Vital signs including weight (kg), heart rate (beats/min), seated systolic and diastolic 
blood pressure (mmHg), and temperature (°C)  
• Triplicate (12 lead) ECGs to be performed at 3 minute intervals (± 1min) with the use 
of a digital ECG machine (Day 113 only) 
o If a local ECG machine is used, a single (12 lead) ECG is to be performed. 
• Serum Chemistry 
• Hematology   
• Serum erythropoietin marker  (Day 141 only) 
• LH, FSH, testosterone, progesterone, and estradiol  
• Anti-drug antibody test  
• Bone biomarkers- OC, BSAP, P1NP, CTX, and TRACP-5b  
o Please refer to the Study Reference Guide, provided under separate cover, for 
the Bone Biomarker Collection and Handling Guidelines for instructions on  
the collection of serum for the biomarkers. 
• Back-up blood sample to be drawn for future testing 
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• Evaluation of transfusion frequency  
• Documentation of concomitant medications 
• Evaluation of adverse events  
• CT/MRI scan (Day 113 only, +/-7 day window). Same modality and anatomical areas 
as acquired prior to enrollment should be used for follow up scans. Tumor response 
assessments to be evaluated by the investigator. 
• DXA of  lumbar spine and hip (Day 113 only) 
o Refer to Imaging Acquisition Guidelines for guidelines regarding washout 
period for contrast (if used) for radiological images, prior to acquiring DXA 
scan. 
10.1.7. 
Post Treatment Period Follow-up visits : Days 169 and 225 (± 7 days) 
If a CT/MRI and bone scan (if applicable) is performed as per standard of care during the post 
treatment period follow up, results may be collected within the CRF to capture the status of the 
disease. Chemotherapy regimen will be administered per standard of care at the site, if 
applicable. The following procedures are to be performed during the study visit: 
• Vital signs including weight (kg), heart rate (beats/min), seated systolic and diastolic 
blood pressure (mmHg), and temperature (°C)  
• Hematology 
• Evaluation of transfusion frequency  
• Documentation of concomitant medications (up to 90 days from the last dose of 
ACE-011/placebo) 
• Evaluation of adverse events  (up to 90 days from the last dose of ACE-011/placebo) 
10.1.8. 
Termination Visit:  Day 281 (± 7 days) 
Day 281 is the final visit.  If a patient terminates the study early, the Day 281 procedures should 
be followed. The following procedures are to be performed during the study visit: 
• Physical Examination 
• Vital signs including weight (kg), heart rate (beats/min), seated systolic and diastolic 
blood pressure (mmHg), and temperature (°C)  
• FACT-Fatigue survey 
• Triplicate (12 lead) ECGs to be performed at 3 minute intervals (± 1min) with the use 
of a digital ECG machine 
o If a local ECG machine is used, a single (12 lead) ECG is to be performed. 
• Serum iron, transferrin saturation %, and total iron binding capacity  
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• Coagulation 
• Serum chemistry  
• Hematology  
• Serum erythropoietin marker 
• Anti-drug antibody test 
• Bone biomarkers- OC, BSAP, P1NP, CTX, and TRACP-5b  
o Please refer to the Study Reference Guide, provided under separate cover, for 
the Bone Biomarker Collection and Handling Guidelines for instructions on 
the collection of serum for the biomarkers. 
• Back-up blood sample to be drawn for future testing 
• Females of childbearing potential -urine (dipstick) pregnancy test  
• Urinalysis 
• Evaluation of transfusion frequency  
• Documentation of concomitant medications (up to 90 days from the last dose of 
ACE-011/placebo) 
• Evaluation of adverse events (up to 90 days from the last dose of ACE-011/placebo) 
• DXA of  lumbar spine and hip 
o Refer to Imaging Acquisition Guidelines for guidelines regarding washout 
period for contrast (if used) for radiological images, prior to acquiring DXA 
scan. 
• Bone scan (+/- 7 day window). Follow-up scan to be acquired if performed at 
baseline and the scan was abnormal. 
If a patient has a positive anti-drug antibody result at the Day 281/Termination visit, they may be 
asked to return to the clinical site every 3 months until a negative result is obtained,   
10.2. 
Discontinuation of Study 
The Sponsor may terminate this study, after consultation with the Investigator, at any time for 
safety or administrative reasons.  The Sponsor may terminate the study if the occurrence of 
serious adverse events (SAEs) or other findings suggest unacceptable risk to the health of the 
patients.   
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11. 
INVESTIGATIONAL PRODUCT MATERIALS AND 
MANAGEMENT 
11.1. 
Reference Product 
The placebo (control agent) to be used in this study will be sterile normal saline (0.9% Sodium 
Chloride for Injection) administered as a SC injection.  Sterile, normal saline will be supplied by  
the investigational site’s pharmacy, as applicable.  The manufacturer’s directions for placebo 
storage and handling are to be followed, as are standard clinical practices for ensuring sterility of 
the placebo. 
11.2. 
Investigational Product Packaging and Labeling 
ACE-011 will be supplied in 2 mL clear glass vials with gray stoppers and red flip-top seals that 
contain 1 mL of ACE-011.  The investigational drug product consists of ACE-011 in PBS at a 
nominal concentration of approximately 50 mg/mL. 
11.3. 
Investigational Product Storage 
ACE-011 is recommended to be stored at ≤ -65°C. 
11.4. 
Investigational Product Preparation 
See ACE-011 Handling and Administration Guidelines. 
11.5. 
Administration 
ACE-011/placebo will be administered by subcutaneous injection (SC). Subcutaneous injections 
will be given in the upper arm and/or thigh. Please refer to ACE-011 Handling and 
Administration Guidelines document for further information. 
Dose modifications will be determined by the investigator after reference to the dose 
modification rules listed in Figure 1. In the case of a dose interruption or dose reduction of ACE-
011/placebo, the investigator or designee will notify the pharmacy staff, who is unblinded, of the 
treatment decision for appropriate preparation of the investigational drug to maintain the blind of 
the study.  
11.6. 
Drug Accountability 
Accountability for ACE-011/placebo is the responsibility of the Investigator.  Investigational 
clinical supplies must be received by a designated person at the clinical site and kept in a secured 
location.  The investigational site must maintain accurate records demonstrating dates and 
amounts of ACE-011/placebo received, to whom it was dispensed (patient-by-patient 
accounting), and accounts of any ACE-011/placebo accidentally or deliberately destroyed or 
returned.  Unless otherwise notified, all vials of ACE-011/placebo, both used and unused, must 
be saved for drug accountability.  The used vials may be discarded, per the institution’s standard  
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practice, after drug accountability has been completed by the monitor. The Investigator must 
return all unused vials of ACE-011 to the Sponsor at the end of the study, or the ACE-011 vials 
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. 
11.7. 
Investigational Product Handling and Disposal 
Please refer to the ACE-011 Handling and Administration Guidelines, provided under separate 
cover, for detailed drug handling, administration, and storage instructions.   
 
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12. 
ASSESSMENT OF EFFICACY 
Efficacy measurements will include assessments for hematopoietic response which is defined as 
an increase in hemoglobin of ≥ 1 g/dL, ≥ 2 g/dL and/or hemoglobin concentration ≥ 11 g/dL 
above the study baseline value for 28 consecutive days during the treatment period including up 
to 2 months after the last dose of ACE-011, in the absence of any RBC transfusions and/or 
ESAs, at each dose level. The hematopoietic endpoints will be determined by the monitoring of 
hematologic laboratory values and RBC transfusion and/or ESA administration. Secondary 
endpoints associated with assessment of disease progression will be evaluated by CT/MRI scan 
and bone mineral density by DXA scans, respectively. Bone biomarkers and incidence of 
skeletal related events (SREs) will also be evaluated for all patients. SREs are defined as 
pathologic fracture, radiation therapy to bone, surgery to bone, or spinal cord compression. 
Quality of life assessment (FACT-Fatigue) will be evaluated for each patient.  
 
 
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13. 
ASSESSMENT OF SAFETY 
13.1. 
Safety Parameters 
13.1.1. 
Adverse Events 
All patients will be assessed for safety by monitoring adverse events, clinical laboratory tests, 
vital signs and physical examinations. AE information will be collected throughout the study. 
See Section 14 Adverse Events for a full description of AE definitions, AE and SAE reporting 
procedures, and emergency procedures. 
13.1.2. 
Clinical Laboratory Tests 
The following laboratory safety assessments will be drawn at the investigational site’s local 
laboratory according to the laboratory collection recommendations. The samples will then be 
sent to the central lab for value reporting. Please refer to Lab Reference Manual for further 
information. Hemoglobin and hematocrit lab tests will be drawn and evaluated by the local 
laboratory at screening and at each visit day throughout the study. The local hemoglobin 
laboratory value will be used in the evaluation of ACE-011/placebo dose modifications. The 
sponsor may request additional safety tests be performed based on ongoing data review during 
the study.  
• Iron studies: Serum iron, transferrin saturation %, total iron binding capacity (TIBC) on    
 
specified days. 
• 
Nutritional tests: Serum folate and vitamin B12 
• 
Coagulation: prothrombin time (PT), partial thromboplastin time (PTT), and fibrinogen 
• 
Serum chemistry: AST, ALT, lactate dehydrogenase (LDH), total bilirubin, indirect bilirubin, 
alkaline phosphatase, total protein, albumin, sodium, potassium, chloride, carbon dioxide, 
calcium, phosphorus, blood urea nitrogen (BUN), creatinine, uric acid, glucose, amylase, and 
lipase.  
• 
Hematology: complete blood count (CBC) with differential and platelet.  CBC includes red 
blood cells (RBC), white blood cells (WBC), hemoglobin, hematocrit, mean corpuscular 
volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin 
concentration (MCHC).  Reticulocyte percent, erythropoietin levels and peripheral blood 
smear will be collected on specified days.  
• 
Bone biomarkers: (serum) osteocalcin (OC), procollagen type 1 N-terminal propeptide 
(P1NP), serum bone specific alkaline phosphatase (BSAP), C-terminal type 1 collagen 
telopeptide (CTX), and tartrate-resistant acid phosphatase isoform-5b (TRACP-5b). 
• 
Pregnancy test for females of child bearing potential 
• 
Urinalysis: including determination of pH, specific gravity, protein, glucose, ketones, blood, 
leukocyte esterase and nitrite. Microscopy required only to follow-up abnormal findings.  
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13.1.3. 
Other Safety Assessments  
• Physical examinations 
• Vital signs: weight (kg), heart rate (beats/min), seated blood pressure (mmHg) and  
temperature (°C).  Height will be collected at screening only. 
• 12-lead ECG(s) 
• LH, FSH, testosterone, progesterone, and estradiol 
• Anti-drug antibody test 
• CT/MRI scan   
• DXA 
• Bone scans 
13.2. 
Pharmacokinetics 
 See Appendix 5 for further details regarding PK sampling.  
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14. 
ADVERSE EVENT 
Adverse Event 
An adverse event (AE) is any noxious, unintended, untoward medical occurrence that may 
appear or worsen in a patient during the course of a study, which does not necessarily have a 
causal relationship with the administration of study medication.  An AE can be any unfavorable 
and unintended sign (e.g. including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of the investigational drug, whether or not it is considered to 
be investigational drug related.  This includes any newly occurring event or previous condition 
that has increased in severity or frequency since the administration of investigational drug 
(treatment-emergent). 
Patients will be evaluated and questioned generally for AEs during the course of the study, 
starting from baseline (Day 1).  All AEs occurring after ACE-011/placebo administration up to 
90 days from the last dose of ACE-011/placebo are to be documented on the AE CRF. 
 
Serious Adverse Event 
A serious adverse event (SAE) is any AE, occurring at any dose level and regardless of causality 
that: 
• Results in death. 
• Is life-threatening:  Life-threatening means that the patient was at immediate risk of death 
from the reaction as it occurred, (i.e., it does not include a reaction which hypothetically 
might have caused death had it occurred in a more severe form). 
• 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. 
• Is a congenital anomaly/birth defect. 
• Is an important medical event: an important medical event is an event that may not result 
in death, be life-threatening, or require hospitalization but may be considered an SAE 
when, based upon appropriate medical judgment, it may jeopardize the patient and may 
require medical or surgical intervention to prevent one of the outcomes listed in the 
definitions for SAEs.  Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, blood dyscrasias or 
convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse.   
• A hospitalization for an elective procedure will not be considered a SAE.  
 
 
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SAEs will be captured throughout the patient participation in the study through Day 
281/Termination visit (i.e. from the signing of the ICF and throughout patient participation in 
the study procedures). For patients who discontinue from the study early, SAEs will be 
captured up to 90 days from the last dose of ACE-011/placebo for those patients who are 
followed for survival only. 
14.1. 
Adverse Event Classification 
The investigator should use the following classifications should be used when evaluating the 
relationship of AEs and SAEs to the investigational drug (i.e., causality assessment). . 
None: 
No relationship between the experience and the administration of 
investigational drug; related to other etiologies such as concomitant 
medications or patient’s clinical state. 
Unlikely:  
 
 
The current state of knowledge indicates that a relationship is unlikely.   
Possibly: 
A reaction that follows a plausible temporal sequence from administration 
of the investigational drug and follows a known response pattern to the 
suspected investigational drug.  The reaction might have been produced by 
the patient’s clinical state or other modes of therapy administered to the 
patient. 
Probably: 
A reaction that follows a plausible temporal sequence from administration 
of the investigational drug and follows a known response pattern to the 
suspected investigational drug.  The reaction cannot be reasonably 
explained by the known characteristics of the patient’s clinical state or 
other modes of therapy administered to the patient. 
Definitely: 
A reaction that follows a plausible temporal sequence from administration 
of the investigational drug and follows a known response pattern to the 
suspected investigational drug and can be confirmed with a positive re-
challenge test or supporting laboratory data. 
Severity of AEs will be graded by the investigator using the National Cancer Institute (NCI; US) 
Common Terminology Criteria for Adverse Events (CTCAE) v3.0 guidelines (Appendix 3). 
14.2. 
Recording Adverse Events 
The Medical History CRF should be comprehensive of patient’s medical history up to Day 1. All 
AEs occurring after ACE-011/placebo administration up to 90 days from the last dose of ACE-
011/placebo are to be documented on AE CRF. The specific disease or syndrome rather than 
individual associated signs and symptoms should be identified by the investigator and recorded 
on the CRF.  
 
 
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Specifically, skeletal related event information is to be captured and reported for the duration of 
the patient participation in the study through Day 281/Terminiation visit. SREs will be captured 
up to 90 days from the last dose of ACE-011/placebo for those patients who are followed for 
survival only. 
Serious Adverse Events (SAEs) 
For SAEs, a SAE form must be completed with as much information as possible and submitted 
in the time frame described in Section 14.3. The Investigator is required to ensure that the data 
on the SAE form is accurate and consistent.  This requirement applies to all SAEs (regardless of 
relationship to the investigational drug) that occur during the study (from the time the subject 
signs informed consent through Day 281 or 90 days after last dose of study medication for 
subjects who are followed for survival only) .  
The SAE report should provide a detailed description of the SAE and include copies 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 the Sponsor or designee as 
soon as these become available.   
When new significant information is obtained as well as when the outcome of an event is known, 
the investigator should record the information on a new SAE form.  If the patient was 
hospitalized, a copy of the discharge summary must be included as part of the patient medical 
file.  In all instances, the investigator should follow up with patients until the outcome of the 
SAE is known. 
14.3. 
Reporting Adverse Events 
All AEs spontaneously reported by the patient and/or in response to an open question from study 
personnel or revealed by observation, physical examination or other diagnostic procedures will 
be recorded on the AE CRF.  Any clinically relevant change in laboratory assessments or other 
clinical findings is considered an AE and must be recorded on the AE CRF. Clinically significant 
laboratory abnormalities are those that are identified as such by the investigator and/or those that 
require intervention. All AEs are to be followed until the event resolves or the clinical course is 
stabilized.  
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 CRF.  All SAEs must be reported to the Sponsor or designee 
by faxing the completed SAE form within 24 hours from the point in time when the Investigator 
becomes aware of the SAE.  This instruction pertains to initial SAE reports as well as any 
follow-up reports.  All SAEs and deaths must be reported regardless of relationship to 
investigational drug.   
 
 
 
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SAE Reporting: 
PPD Medical Monitor 
PPD Inc. 
Please refer to the SAE Completion Guidelines for appropriate contact information. 
Where required by local legislation, the Investigator is responsible for informing the IRB/EC of 
the SAE and providing them with all relevant initial and follow-up information about the event. 
The Investigator must keep copies of all SAE information on file including correspondence with 
Celgene and the IRB/EC. 
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 the investigational drug  based on the ACE-011 Investigator 
Brochure. 
The Sponsor, or its authorized representative, shall notify the Investigator of the following 
information: 
• Any AE associated with the use of the investigational drug in this study or in other 
studies that is both serious and unexpected (i.e., 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 patients. 
The Investigator must keep copies of all pertinent safety information on file including 
correspondence with the Sponsor, or its designee, and the IRB/EC.   
 
 
 
 
 
 
 
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14.4. 
Emergency Sponsor Contact 
In the event of a medical emergency (i.e., an event that requires immediate attention regarding 
the treatment of a patient, operation of the clinical study, and/or the use of investigational drug), 
investigational site personnel must immediately contact the Medical Monitor. 
14.5. 
Pregnancy 
Any pregnancy that occurs during a clinical study with an investigational drug will be reported 
for tracking purposes only.  All pregnancies that are identified during this study need to be 
followed to conclusion and the outcome reported. Female patients should immediately inform 
the Investigator of any pregnancies and will immediately be discontinued from study treatment.  
The patient will remain in the trial and continue to be followed for survival. The Investigator 
must report all pregnancies to the Sponsor or designee, within 24 hours of awareness, by 
facsimile, using the Initial Pregnancy Report Form.   
The Investigator will follow the female subject until completion of the pregnancy, and must 
notify the Sponsor about the outcome of the pregnancy as a follow-up to the initial SAE report, 
using the Follow-up Pregnancy Report Form.  If the pregnancy ends in abortion (i.e., 
spontaneous, therapeutic, etc) this would be considered an AE/SAE if it meets SAE criteria. 
If the outcome of the pregnancy was abnormal (i.e., spontaneous or therapeutic abortion [any 
congenital anomaly detected in an aborted fetus must be documented], stillbirth, neonatal death, 
or congenital anomaly [including that in an aborted fetus]), the Investigator should follow the 
procedures for reporting SAEs.  All abnormal pregnancy outcomes should be considered 
medically important (i.e., constitutes an important medical event) even if no other seriousness 
criteria apply, and must be reported to the Sponsor, or designee, immediately by facsimile, or 
other appropriate method, within 24 hours of the Investigator’s knowledge of the event) using 
the SAE Report Form, or approved equivalent form.  
All neonatal deaths that occur within 28 days of birth should be reported, without regard to 
causality, as SAEs.  In addition, any infant death after 28 days that the Investigator suspects is 
related to the in utero exposure to the IP should also be reported to the Sponsor, or designee, 
immediately 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. 
 
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15. 
STATISTICS 
Statistics Analysis Overview 
The study will be considered complete with regard to the primary endpoint once all eligible 
subjects have completed up to 2 months after the last dose of ACE-011. Patients will be 
randomized to one of three ACE-011 treatment groups (0.1, 0.3 and 0.5 mg/kg) or placebo with a 
ratio of 2:2:2:1.  Patients will be stratified according to administration of either single agent 
weekly chemotherapy or less frequent chemotherapy regimens.  
15.1. 
Determination of Sample Size 
With an anticipated dropout rate of 20%, a sample size of 30 patients per dose level is estimated 
to achieve at least 80% power with 2 sided significance level of 0.05 to differentiate targeted 
response rate of p1=0.45 from null hypothesis p0=0.20. An additional 15 patients will be 
enrolled to the placebo group for safety comparison. A total of 105 patients are planned to be 
randomized to three ACE-011 dose groups (0.1, 0.3, and 0.5 mg/kg) and placebo with a ratio of 
2:2:2:1.  
15.2. 
Analysis Populations 
For this study, the following populations will be defined and used in the analysis and 
presentation of the data. 
Modified Intent-to-Treat (MITT) population: The MITT population is defined as all patients 
randomized who received at least one dose of ACE-011/placebo. 
Per-Protocol (PP) population: The PP population is defined as all patients randomized who have 
confirmed chemotherapy induced anemia, received at least one dose of ACE-011 and on study 
(treatment) for at least 2 months (57 days). 
Safety population: The safety population is defined as all patients who received at least one dose 
of ACE-011 or placebo. 
15.3. 
Background and Demographic Characteristics 
Summary statistics (mean, standard deviation, median, minimum and maximum) will be 
provided for those variables measured on a continuous scale.  The frequency distribution 
(number and percentage) will be provided for those variables measured on a nominal scale. 
15.3.1. 
Patient Disposition 
Patient disposition (analysis population allocation, entered, discontinued, along with primary 
reason for discontinuation) will be summarized using frequency and percent for each dose group.  
A summary of patients enrolled by site will be provided.  
 
 
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15.3.2. 
ACE-011 
ACE-011 treatment exposure (total dosage received) will be summarized for each dose group as 
well as for each cycle for each dose level.  Listings for dose adjustment will be provided. 
15.3.3. 
Concomitant Therapy 
By-patient listings will be provided for all concomitant medications and therapies taken during 
the study.  All concomitant medications will be coded and categorized by the WHO drug coding 
system.  Usage frequency of each coded concomitant medications will be summarized by each 
dose group. 
15.4. 
Efficacy Evaluation 
15.4.1. 
Primary Efficacy Analysis 
The primary efficacy endpoint is the hematopoietic response rate at each dose level.  It is defined 
as the proportion of patients who have a hematopoietic response of an increase in hemoglobin of 
≥ 1.0 g/dL for 28 consecutive days during the treatment period including up to 2 months after the 
last dose of ACE-011, in the absence of any RBC transfusions and/or ESAs. The ACE-011 
treatment period is defined as from the time of first ACE-011 dose to up to 2 months after the 
last dose of ACE-011 treatment.  To be considered as a responder, all hemoglobin measurements 
during a 28 consecutive day period or longer must have an increase of ≥ 1.0 g/dL from baseline. 
If RBC transfusions and/or ESAs are required, no hemoglobin measurements within 28 days will 
be used to determine the hemoglobin response. Primary efficacy analysis will be based on PP 
population.  Primary efficacy analysis will also be conducted on MITT population as supportive 
to the PP based analysis.  Patients who do not receive ACE-011 will be excluded from primary 
efficacy analysis.  Patients who discontinue the ACE-011 treatment prematurely, with no 
sufficient hemoglobin measurement, will be counted as non-responder in the calculation of 
response rate.     
A 95% confidence interval (CI) for the response rate for each dose level will be provided to 
assess whether 95% CI of response rate contains null hypothesis response rate, p0=0.20.  The 
response rate and 95% CI will also be provided for patients with chemotherapy on weekly basis 
versus those with chemotherapy on a less frequent basis for each dose level as well as overall (all 
three doses levels analyzed together).  
An exploratory analysis with the Kaplan Meier approach will be considered to account for those 
patients who discontinue the ACE-011 treatment prematurely if the drop out rate is greater than 
20%.  Exploratory analysis of comparing hematopoietic response rates between active and 
placebo will be performed using Fisher’s exact test.  Due to the nature of the study (phase 2 dose 
determination study), no multiplicity adjustment will made for the multiple comparisons.  
 
 
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15.4.2. 
Secondary Efficacy Analyses 
The secondary efficacy endpoints include: 
• Proportion of patients achieving an increase in hemoglobin of  ≥ 2 g/dL and/or 
hemoglobin concentration ≥ 11 g/dL for 28 consecutive days during the treatment period 
and up to 2 months after the last dose of ACE-011 in the absence of any RBC 
transfusions and/or ESAs.   
• Duration of hematopoietic response (days) defined as the first time hemoglobin increases 
at least  ≥ 1 g/dL, ≥ 2 g/dL and/or hemoglobin concentration ≥ 11 g/dL from baseline to 
the last time there is hemoglobin ≥ 1 g/dL, ≥ 2 g/dL and/or hemoglobin concentration ≥ 
11 g/dL increase from baseline.  Duration of response is only calculated for a responder 
and will be at least 28 days.  The duration of response will be at least 28 days is only 
calculated for a patient who meets the primary efficacy endpoint.  
• Time to achieve hematopoietic response (days) defined as time from first dose of ACE-
011 to the first time a hemoglobin result at least  ≥ 1 g/dL, ≥ 2 g/dL and/or hemoglobin 
concentration ≥ 11 g/dL increase from baseline and maintained for a period of at least 28 
consecutive days. 
• Proportion of patients receiving red blood cell (RBC) transfusions and/or ESAs in each 
dose group as well as within each cycle of each ACE-011 dose level. 
• Objective tumor response rate for each dose level using RECIST v1.1 criteria. 
• Progression-Free Survival is defined as the time from the start date of current 
chemotherapy regimen to the first observation of documented disease progression or 
death due to any cause.  If the subject has not progressed or died at the time of final 
analysis, PFS will be censored at the time of last tumor assessment.   
The statistical analysis for binary endpoints will be similar to the primary efficacy analysis.  For 
time to event endpoints, the Kaplan-Meier method will be used to estimate the survival curve and 
median time to event.  These analyses will be performed for each dose group and all ACE-011 
groups combined.   
15.5. 
Safety Evaluation 
Safety variables will be tabulated and presented for all patients who receive ACE-011.  Adverse 
events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA).  
Incidence of treatment-emergent adverse events will be presented by system organ class (SOC) 
and preferred term.  Adverse events will also be presented by severity, and relationship to 
investigational drug.  Change from baseline in clinical laboratory parameters and vital signs will 
be summarized across time.  Shift tables will be presented for selected laboratory parameters.  
Physical examination results will be presented in listings.  
 
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Data from all patients who receive one or more doses of ACE-011/placebo will be included in 
the safety analyses. To assess clinical safety, adverse events, vital sign measurements and 
clinical laboratory information will be summarized by visit. Adverse events and laboratory 
results will also be summarized by severity grade (NCI CTCAE v3.0). Descriptive statistics will 
be generated and shift tables provided as appropriate.  
15.6. 
Pharmacokinetic Evaluation 
Listing of individual patient serum ACE-011 concentrations, actual blood sampling times and 
graphs of concentration vs. time will be prepared for each dose group.  Summaries of PK 
parameters will be summarized by dose group. The trough concentrations will be summarized for 
all patients who provide pharmacokinetic samples by dose group. Exploratory analyses will be 
performed to correlate trough concentrations with efficacy, bone biomarker data, and safety data, 
however these analyses will be data-driven and only conducted if warranted by the data.  
15.6.1. 
Anti-drug Antibody Data 
The results of anti-drug and neutralizing antibodies will be presented over time.  Exploratory 
analysis will be performed on the potential effect of anti-drug antibody on ACE-011 PK and 
drug exposure if anti-drug antibody tests are deemed positive. 
15.7. 
Interim analysis 
There is no planned interim analysis for this study.   
15.8. 
Deviation from Original Analysis Plan 
Deviations from the statistical analyses outlined in this protocol will be indicated in the statistical 
analysis plan; any further modifications will be noted in the final clinical study report. 
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16. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
16.1. 
Study Monitoring 
The Clinical Monitor will arrange to visit the investigator sites at regular intervals during the 
study.  The monitoring visits must be conducted according to the applicable ICH and GCP 
guidelines to ensure protocol adherence, quality of data, drug accountability, compliance with 
regulatory requirements, and continued adequacy of the investigational site and its facilities.  
During these visits, CRFs and other data related to the study will be reviewed and any 
discrepancies or omissions will be resolved.  The Clinical Monitor will be given access to study 
relevant source documents (including medical records) for purposes of source data verification. 
During and/or after completion of the study, quality assurance officers named by the Sponsor or 
the regulatory authorities may wish to perform on-site audits.  The Investigator is expected to 
cooperate with any audit and provide assistance and documentation (including source data) as 
requested. 
16.2. 
Audits and Inspections 
The Investigators and clinical sites will permit trial related monitoring, audits, IRB review, and 
regulatory inspections as requested by FDA, EMEA, or Health Canada the Sponsor or designee, 
including direct access to source data/documents (i.e., original medical records, laboratory 
reports, hospital documents, progress reports, signed ICFs, etc.) in addition to CRFs. 
If the investigator is contact by any regulatory authority regarding an inspection, he/she should 
contact Celgene immediately. 
 
 
 
 
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17. 
QUALITY CONTROL AND QUALITY ASSURANCE 
17.1. 
Data Quality Control and Quality Assurance 
17.1.1. 
Investigator responsibility 
The investigator is responsible for ensuring the study is conducted according to the protocol, 
Code of Federal Regulations (CFR), GCP, and any other applicable regulatory requirements. The 
investigator responsibilities are outlined in these documents along with ensuring that 
documentation of a signed informed consent, is obtained prior to patient participation in the 
study.  
17.1.2. 
Protocol modifications 
The investigator may not modify the protocol without agreement from the Sponsor and prior 
review or approval by the IRB. Any deviations from the protocol should be documented by the 
investigator or designee.  
17.2. 
Financing and Insurance 
Financing and insurance are addressed in a separate document. 
17.3. 
Confidentiality 
To maintain patient privacy, all CRFs, drug accountability records, study reports and 
communications will identify the patient by the assigned patient identification number.  The 
Investigator will grant monitor(s) and auditor(s) from the Sponsor or designee and regulatory 
authority(ies) access to the patient’s original medical records for verification of data gathered on 
the CRFs and to audit the data collection process.  The patient’s confidentiality will be 
maintained and will not be made publicly available to the extent permitted by the applicable laws 
and regulations. 
All information regarding the investigational product supplied by the Sponsor to the Investigator 
is privileged and confidential information.  The Investigator agrees to use this information to 
accomplish the study and will not use it for other purposes without consent from the Sponsor.  It 
is understood that there is an obligation to provide the Sponsor with complete data obtained 
during the study.  The information obtained from the clinical study will be used towards the 
development of the investigational product and may be disclosed to regulatory authority(ies), 
other Investigators, corporate partners, or consultants as required. 
17.4. 
Publication Policy 
All information concerning ACE-011 is considered confidential and shall remain the sole 
property of the Sponsor.  The Investigator agrees to use this information only in conducting the 
study and shall not use it for any other purposes without the Sponsor’s written approval.  The 
Investigator agrees not to disclose the Sponsor’s confidential information to anyone except to  
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people involved in the study that needs such information to assist in conducting the study, and 
then only on like terms of confidentiality and nonuse. 
It is understood by the Investigator that the information developed from this clinical study will 
be used by the Sponsor in connection with the development of ACE-011, and therefore may be 
disclosed as required to regulatory agencies.  To allow for the use of the information derived 
from clinical studies, it is understood that there is an obligation to provide the Sponsor with 
complete test results and all data developed in the study. 
No publication or disclosure of study results will be permitted except as specified in a separate, 
written, agreement between the Sponsor and the Investigator. 
17.5. 
Protocol Amendments 
Protocol amendments that impact patient safety change the scope of the investigation, or affect 
the scientific quality of the study must be approved by the IRB and submitted to the appropriate 
regulatory authorities before implementation of such modifications to the study. 
In the event that the protocol needs to be modified immediately to eliminate an apparent hazard 
to a patient, the Sponsor will amend and implement the protocol change and subsequently notify 
the regulatory authorities and/or the IRB, as appropriate. 
 
 
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18. 
ETHICS 
18.1. 
Institutional Review Board or Independent Ethics Committee 
The Investigator must obtain written IRB approval of the protocol, approval for relevant 
supporting information and all types of patient recruitment and advertisement and ICF prior to 
starting the study.  The IRB will meet all Food and Drug Administration (FDA) requirements 
governing IRBs (Code of Federal Regulations, Title 21, Part 56). 
The Sponsor or designee must approve the ICF submitted to the investigational site’s IRB. All 
patient recruitment and advertisements must be submitted to the Sponsor or designee prior to 
submission to the IRB, for review. 
18.2. 
Ethical Conduct of the Study 
The Sponsor and the Investigator must comply with all instructions, regulations, and agreements 
in this protocol and in the applicable International Conference on Harmonisation (ICH) and GCP 
guidelines, and must also conduct the study in accordance with local regulations.   
18.3. 
Written Informed Consent 
18.3.1. 
Informed Consent 
Informed written consent is required from each patient prior to any testing under this protocol, 
including screening tests and evaluations.  The consent form, as specified by the clinical site’s 
IRB, must follow the Protection of Human Patients regulations listed in the Code of Federal 
Regulations, Title 21, Part 50.   
The background of the proposed study and the benefits and risks of the procedures and study 
must be explained to the patients.  It is the responsibility of the Investigator to obtain consent and 
to provide the patient with a copy of the signed and dated ICF.  Confirmation of a patient’s 
informed consent must also be documented in the patient’s medical record prior to any testing 
under this protocol, including screening tests and evaluations. 
All ICFs used in this study must be approved by the appropriate IRB and by the Sponsor or 
designee.  The ICF must not be altered without the prior agreement of the relevant IRB and the 
Sponsor.   
18.3.2. 
Patient Data Protection 
Prior to any testing under this protocol, including screening tests and evaluations, patients must 
authorize the release and use of protected health information (PHI), as required by local law. 
The patient will not be identified by name in the CRF or in any study reports.  These reports will 
be used for research purposes only.  The Sponsor, its designee, and various government health 
agencies may inspect the records of this study.  Every effort will be made to keep the patient’s 
personal medical data confidential. 
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19. 
DATA HANDLING AND RECORDKEEPING 
19.1. 
Case Report Form Completion 
CRFs will be completed for each randomized patient.  It is the Investigator’s responsibility to 
ensure the accuracy, completeness, and timeliness of the data reported in the patient’s CRF.  
Source documentation supporting the CRF data should indicate the patient’s participation in the 
study and should document the dates and details of study procedures, AEs, and patient status. 
Investigators will maintain copies of the CRFs at the clinical site.  For patients who discontinue 
or terminate from the study, the CRFs will be completed as much as possible, and the reason for 
the discontinuation or termination clearly and concisely specified on the appropriate CRF. 
19.2. 
Retention of Records 
The Investigator will maintain all study records according to ICH-GCP and applicable regulatory 
requirements.  Records will be retained for at least 2 years after the last marketing application 
approval in an ICH region and until there are no pending or contemplated marketing applications 
in an ICH region or 2 years after formal discontinuation of the clinical development of the 
investigational product or according to applicable regulatory requirements.  If the Investigator 
withdraws from the responsibility of keeping the study records, custody must be transferred to a 
person willing to accept the responsibility.  The Sponsor must be notified in writing if a custodial 
change occurs. 
 
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20. 
REFERENCES 
 
      1.   Groopman JE, Itri LM. (1999). Chemotherapy-Induced Anemia in Adults: Incidence and  
 
   Treatment. Journal of the National Cancer Institute 91, 1616-1634.  
2. NCCN Clinical Practice Guidelines in Oncology: Cancer and Chemotherapy Induced 
Anemia, V.3. 2009 http://www.nccn.org/professionals/physician_gls/PDF/anemia.pdf; 
2008. 
3. Ying S-Y. (1988). Inhibins, activins, and follistatins: gonadal proteins modulating the 
secretion of follicle-stimulating hormone. Endocrine Rev 9, 267-93. 
4. Woodruff TK. (1998). Regulation of cellular and system function by activin. Biochem 
Pharmacol 55, 953-63. 
5. Perrien DS, Akel NS, Edwards PK, Carver AA, Bendre MS, Swain FL, Skinner RA, 
Hoque WR, Nicks KM, Pierson TM, Suva LJ, and Gaddy D. (2007). Inhibin A is an 
endocrine stimulator of bone mass and strength. Endocrinology 148, 1654-65. 
6. Rivier J, Spiess J, McClintock R, Vaughan J and Vale W. (1985). Purification and partial 
characterization of inhibin from porcine follicular fluid. Biochem Biophys Res Commun 
133, 120-7. 
7. Murata M, Onomichi K, Eto Y, Shibai H, and Muramatsu M. (1988). Expression of 
erythroid differentiation factor (EDF) in Chinese hamster ovary cells.  Biochem Biophys 
Res Commun 151, 230-5. 
8. Shiozaki M, Sakai R, Tabuchi M, Nakamura T, Sugino K, Sugino H, and Eto Y. (1992). 
Evidence for the participation of endogenous activin A/erythroid differentiation factor in 
the regulation of erythropoiesis.  Proc Natl Acad Sci USA 89, 1553-6. 
9. Shiozaki M, Sakai R, Tabuchi M, Eto Y, Kosaka M, and Shibai H. (1989). In vivo 
treatment with erythroid differentiation factor (EDF/activin A) increases erythroid 
precursors (CFU-E and BFU-E) in mice. Biochem Biophys Res Commun 165, 1155-61. 
10. Nakao K, Kosaka M and Saito S. (1991). Effects of erythroid differentiation factor (EDF) 
on proliferation and differentiation of human hematopoietic progenitors. Exp Hematol 19, 
1090-5 
11. Chen Y-G, Lui HM, Lin S-L, Lee JM, and Ying S-Y. (2002). Regulation of cell 
proliferation, apoptosis, and carcinogenesis by activin. Exp Biol Med 227, 75-87. 
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12. Mathews LS. (1994). Activin receptors and cellular signaling by the receptor serine 
kinase family. Endocr Rev 15, 310-25. 
13. Chantry A, Heath D, Mulivor A, Coulton L, Evans H, Abdul N, Werner ED, Bouxsein 
ML, Pearsall RS, Seehra J, Vanderkerken K, and Croucher PI. (2008). Inhibiting activin-
A signalling stimulates bone formation, prevents tumor-induced osteolytic bone 
destruction and blocks bone metastasis. Submitted 2008. 
14. Pearsall RS, Canalis E, Cornwall-Brady M, Underwood KW, Haigis B, Ucran J, Kumar 
R, Pobre E, Grinberg A, Werner ED, Glatt V, Stadmeyer L, Smith D, Seehra J, and 
Bouxsein ML. (2008). A soluble activin type IIA receptor induces bone formation and 
improves skeletal integrity. Proc Natl Acad Sci USA 105, 7082-7 
15. Lotinun S, Fajardo RJ, Pearsall RS, Bouxsein ML, and Baron R. (2008). A soluble 
activin receptor type IIA fusion protein, ACE-011, increases bone mass by stimulating 
bone formation and inhibiting bone resorption in cynomolgus monkeys. ASBMR 30th 
annual meeting, 2008. 
16. Ruckle J, Jacobs M, Kramer W, Pearsall AE, Kumar R, Underwood KW, Seehra J, Yang 
Y, Condon CH, Sherman ML. (2008).  A single-dose, randomized, double-blind, 
placebo-controlled study of ACE-011 (ActRIIA-IgG1) in postmenopausal women.  J 
Bone Miner Res: 1-42.  Posted online on 2 Dec 2008. 
17. Functional Assessment of Chronic Illness, FACT-Fatigue Version 4. 
http://www.facit.org/qview/qlist.aspx. 2003. 
 
 
 
 
 
 
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21. 
APPENDICES 
Appendix 1: Response Evaluation Criteria in Solid Tumors 
 
 
Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 
  
Terms 
Definition 
Measurable disease  
 The presence of at least one measurable lesion by CT or MRI. If the 
measurable disease is restricted to a solitary lesion, its neoplastic nature 
should be confirmed by cytology/histology. 
All measurements should be taken and recorded in metric notation, using a 
ruler or calipers. All baseline evaluations should be performed as closely as 
possible to the beginning of treatment and never more than 4 weeks before 
the beginning of the treatment.  
Measurable lesions 
Lesions that can be accurately measured in least one dimension by CT scan 
with longest diameter > 10 mm (CT scan thickness no greater than 5 mm). 
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during 
follow-up.  
Non-measurable lesion 
All other lesions, including small lesions (longest diameter <10mm or 
pathological lymph nodes with P10 to <15mm short axis) as well as truly 
non-measurable lesions. Lesions considered truly non-measurable include: 
leptomeningeal disease, ascites, pleural or pericardial effusion, 
inflammatory breast disease, lymphangitic involvement of skin or lung, 
abdominal masses/abdominal organomegaly identified by physical exam 
that is not measurable by reproducible imaging techniques. 
 
 
 
 
 
 
 
 
 
 
 
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RECIST Criteria-Response Evaluation 
Evaluation of target lesions 
  
  
Complete Response (CR) 
 Disappearance of all target lesions. 
Any pathological lymph nodes (whether target or non-target) 
must have reduction in short axis to <10 mm. 
Partial Response (PR): 
At least a 30% decrease in the sum of diameters of target lesions, 
taking as reference the baseline sum diameters. 
Stable Disease (SD):   
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum 
diameters while on study. 
Progressive Disease (PD):  
At least a 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest sum on study (this includes the 
baseline sum if that is the smallest on study). In addition to 
the relative increase of 20%, the sum must also demonstrate 
an absolute increase of at least 5 mm.  
(Note: the appearance of one or more new lesions is also 
considered progression). 
 
 
 
 
Evaluation of non-target 
lesions 
  
  
Complete Response (CR):  
Disappearance of all non-target lesions and normalisation of 
tumour marker level. All lymph nodes must be non-pathological 
in size (<10mm short axis). 
 
Non-CR/Non-PD 
 
Persistence of one or more non-target lesion(s) and/or 
maintenance of tumour marker level above the normal limits. 
Progressive Disease (PD):  
Unequivocal progression (see comments below) of existing non-
target lesions.  
(Note: the appearance of one or more new lesions is also 
considered progression). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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RECIST Criteria-Response 
Evaluation cont- 
 
 
 
 
 
 
Evaluation of best overall 
response 
The best overall response is the best response recorded 
from the start of the treatment until disease 
progression/recurrence (taking as reference for PD the 
smallest measurements recorded since the treatment 
started). In general, the patient's best response assignment 
will depend on the achievement of both measurement and 
confirmation criteria. 
 
Patients with a global deterioration of health status 
requiring discontinuation of treatment without objective 
evidence of disease progression at that time should be 
classified as having “symptomatic deterioration”. Every 
effort should be made to document the objective 
progression even after discontinuation of treatment.  
 
In some circumstances it may be difficult to distinguish 
residual disease from normal tissue. When the evaluation of 
complete response depends on this determination, it is 
recommended that the residual lesion be investigated (fine 
needle aspirate/biopsy) to confirm the complete response 
status.  
 
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R,  Dancey J, Arbuck S, Gwyther S, Mooney M, 
Rubinstein L, Shankar L, Dodd L, Kaplan R,  Lacombe D, Verweij J.New response evaluation criteria in solid tumours: Revised 
RECIST guideline (version 1.1)  (2009). European Journal of Cancer 45, 228-247. 
 
 
 
 
 
 
 
 
 
 
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Appendix 2: ECOG Performance Status 
The ECOG scale is used to assess a patient’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 
patient.  
 
Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., Carbone, P.P. (1982) Toxicity And Response 
Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Onco 5:649-655. 
 
 
 
 
 
 
 
 
 
 
 
 
 
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, e.g., 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 
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Appendix 3:  National Cancer Institute (NCI) Common Terminology Criteria 
for Adverse Events (CTCAE) Version 3.0 
 
See http://ctep.cancer.gov/reporting/ctc.html  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Appendix 4: New York Heart Association- Classification of heart failure 
Class 1 - Class 1 heart failure - no limitation of activities. No symptoms from ordinary activities. 
Class 2 - Class 2 heart failure- mild limitation of activity. Comfortable with rest or mild exertion. 
Class 3 - Class 3 heart failure- marked limitation of activity and be comfortable only at rest. 
Class 4 –Class 4 heart failure- complete rest, confined to bed or chair; any physical activity brings on  
discomfort and symptoms occur at rest. 
 National Heart, Lung, and Blood Institute, National Institutes of Health. New York Heart Association Classification. 2008. 
 
 
 
 
 
 
 
 
 
 
 
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Appendix 5- Pharmacokinetic Sampling 
Pharmacokinetics 
Blood samples will be collected from approximately one-third of patients at selected study sites for the evaluation of serum 
concentrations of ACE-011.  
 
Blood samples for PK should be collected in a fasted state (defined by no food or drink except water for at least 4 hours prior to the 
study procedure) with the exception of the Day 1 post 4 hour dose and the Day 85 post 4 hour dose.  Pre-dose samples should be 
collected within 1 hour of ACE-011/placebo dosing (Day 1, 29, 57, and 85).  The post 4 hour collection (± 10 minute window) on Day 
1 and Day 85 is calculated to be 4 hours post the administration of ACE-011/placebo. Chemotherapy regimens scheduled will be 
administered to the patient as per standard of care.  Collection, handling, and shipping procedures for blood samples are provided in 
the Study Reference Guide. 
 
 
Schedule of Events cont. 
 
 Screen 
Treatment Period 
 
ACE-011/Placebo Dose 
period 
 
#1 
#2 
#3 
#4 
Follow-up   
 
Post Treatment Follow up Period 
 
Term 
Visit 
Day 
     -14-0 
1 
8 
(± 1d) 
15 
 (± 1d) 
 
29 
(± 3d) 
 
43 
(± 2d) 
57 
(± 3d) 
 
71 
 (± 2d) 
85 
 (± 3d) 
113 
(± 7d) 
     141 
 (± 7d) 
 
169 
(± 7d) 
225 
 (± 7d) 
281 
(± 7d) 
X 
X 
PK Sampling 
 
X- Post 4 
hours 
X 
X 
X 
 
X 
 
X- Post 4 hours 
X 
 
 
 
 
ACE-011/Placebo 
administration 
 
X 
 
 
X 
 
X 
 
X 
 
 
 
 
 
Chemo regimen 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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SAP_001.pdf: 
Official Protocol Title:
NCT number:
NCT00931606
Document Date:
A Phase 2, Double-Blind, Randomized,
Placebo-Controlled Study of ACE-011 for the
Treatment of Chemotherapy Induced Anemia in
Patients with Metastatic Breast Cancer
27-Oct-2009


CONFIDENTIAL 
STATISTICAL ANALYSIS PLAN 
 
PROTOCOL NUMBER A011-08 
 
A Phase 2, Double-Blind, Randomized, Placebo-Controlled Study of ACE-
011 for the Treatment of Chemotherapy Induced Anemia in Patients with 
Metastatic Breast Cancer 
 
PHASE 2 
 
 
SPONSOR: 
Acceleron Pharma, Inc.  
128 Sidney Street 
Cambridge, Massachusetts 02139-4242 
 
 
Final Version 2.0 
Date: 27 October, 2009 
 
CONFIDENTIAL PROPERTY OF ACCELERON PHARMA, INC. 
This document is a confidential communication of Acceleron Pharma, Inc. Acceptance of 
this document constitutes the agreement by the recipient that no information contained 
herein will be published or disclosed without written authorization from Acceleron 
Pharma, Inc. 
Page 1 of 36
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0883N8


 
 
A011-08 
Statistical Analysis Plan  Final Version 2.0 
27 October, 2009 
 
CONFIDENTIAL 
2.0 
TABLE OF CONTENTS 
1.0 
TITLE PAGE.......................................................................................................................1 
1.1 
APPROVAL SIGNATURES.........................................................................................2 
2.0 
TABLE OF CONTENTS.....................................................................................................3 
3.0 
LIST OF ABBREVIATIONS..............................................................................................5 
4.0 
INTRODUCTION ...............................................................................................................6 
5.0 
DATA QUALITY ASSURANCE.......................................................................................7 
6.0 
OBJECTIVES AND STUDY DESIGN ..............................................................................8 
6.1 
Study Objectives............................................................................................................8 
6.2 
Study Design..................................................................................................................9 
7.0 
ANALYSIS ENDPOINS...................................................................................................11 
7.1 
Primary Efficacy Endpoint ..........................................................................................11 
7.2 
Secondary Efficacy Endpoints.....................................................................................11 
7.3 
Safety Analysis Endpoints...........................................................................................12 
7.4 
Exploratory Analysis Endpoints ..................................................................................12 
8.0 
DETERMINATION OF SAMPLE SIZE..........................................................................14 
9.0 
INTERIM ANALYSIS......................................................................................................15 
10.0 
METHODS OF ANALYSIS AND PRESENTATION.....................................................16 
10.1 
General Principles........................................................................................................16 
10.2 
Analysis Sets................................................................................................................18 
10.3 
Patient Disposition.......................................................................................................18 
10.4 
Demographic and Baseline Characteristics .................................................................18 
10.5 
Medical History ...........................................................................................................19 
10.6 
Concomitant Diagnostic, Surgical, and Therapeutic Procedures.................................19 
10.7 
Prior and Concomitant Medications ............................................................................20 
10.8 
Prior and Current Chemotherapy for Breast Cancer....................................................20 
10.9 
Prior Radiation Therapy...............................................................................................21 
10.10 Investigational Drug Exposure and Dose Modification...............................................21 
10.11 Efficacy Analysis.........................................................................................................21 
10.11.1 
Primary Efficacy Analysis ..............................................................................21 
10.11.2 
Secondary Efficacy Analyses..........................................................................22 
10.12 Safety and Exploratory Analyses.................................................................................25 
10.12.1 
Adverse Events................................................................................................25 
10.12.2 
Clinical Laboratory Evaluations....................................................................27 
10.12.3 
Vital Signs.......................................................................................................31 
10.12.4 
Physical Examinations....................................................................................31 
10.12.5 
12-Lead ECGs ................................................................................................31 
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10.12.6 
Anti-drug Antibody .........................................................................................32 
10.13 Pharmacokinetic Analysis............................................................................................32 
10.14 Pharmacoeconomic Analysis.......................................................................................32 
10.15 Bone Biomarker Analysis............................................................................................32 
10.16 Quality of Life Analysis...............................................................................................33 
10.17 DXA Analysis..............................................................................................................33 
10.18 Changes in the Statistical Analysis Plan from the Protocol Analysis Plan..................34 
11.0 
REFERENCES ..................................................................................................................35 
12.0 
APPENDIX........................................................................................................................36 
 
 
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3.0 
LIST OF ABBREVIATIONS 
Term 
Definition 
AE 
Adverse event 
ATC 
Anatomical therapeutic chemical classification 
BMI 
Body mass index 
BMD 
Body mineral density 
BSAP 
Bone specific alkaline phosphatase 
BUN 
Blood urea nitrogen 
CBC 
Complete blood count 
CI 
Confidence interval 
CIA 
Chemotherapy induced anemia 
CP 
Concomitant procedure 
CRF 
Case Report Form 
CT 
Computer tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTX 
Serum C-terminal type I collagen telopeptide 
DXA 
Dual-energy x-ray absorptiometry 
ECG 
Electrocardiogram 
ESA 
Erythropoiesis-stimulating agents 
FACT 
Functional Assessment of Chronic Illness 
FSH 
Follicle-stimulating hormone 
ICH 
International Conference on Harmonization 
LH 
Luteinizing hormone 
MedDRA 
Medical Dictionary for Regulatory Activities 
MITT 
Modified Intent to Treat (population) 
MRI 
Magnetic resonance imaging 
ORR 
Objective response rate 
PFS 
Progression-free survival 
PINP 
Serum intact procollagen type I N terminal propeptide 
PK 
Pharmacokinetic 
PPD 
Pharmaceutical Product Development 
PP 
Per-protocol (population) 
PT 
Prothrombin time 
PTH 
Parathyroid hormone 
PTT 
Partial thromboplastin time 
RBC 
Red blood cell (count) 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SE 
Standard error 
SRE 
Skeletal-related event 
TIBC 
Total iron binding capacity 
TRACP-5b 
Serum tartrate-resistant acid phosphatase isoform-5b 
WBC 
White blood cell (count) 
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4.0 
INTRODUCTION 
The study is being conducted under the sponsorship of Acceleron Pharma, Inc. The 
clinical monitoring, data management and statistical analysis are being performed under 
contract with PPD, in collaboration with Acceleron Pharma, Inc. 
This document contains detailed information regarding the statistical analysis to be 
performed for study A011-08. The table, appendix, and figure shells planned for this 
study will be maintained in a separate document. This is a Phase 2, double-blind, 
randomized, placebo controlled study to evaluate the efficacy, safety, and tolerability of 
ACE-011 for the treatment of chemotherapy induced anemia in patients with metastatic 
breast cancer. 
The finalization of the SAP is made before the database hard lock. 
This analysis plan was developed based on International Conference on Harmonization 
(ICH) E3 and E9 Guidelines, and with references to the following protocols: 
 Protocol A011-08, dated March 13, 2009 
 Protocol A011-08 Amendment #1, dated April 22, 2009 
 Protocol A011-08 Amendment #2, dated May 21, 2009 
 Protocol A011-08 Amendment #3, dated October 07, 2009 
 
 
 
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5.0 
DATA QUALITY ASSURANCE 
The Clinical, Data Management, and Biostatistics departments at PPD will work 
diligently and collaboratively, internally and with the Sponsor, to ensure that the data 
collected and analyzed for this study are of the highest quality possible.  This will be 
accomplished in part by having thorough edit checks written, programmed, and updated 
as needed to guarantee high quality data. Edit checks will be reviewed by the statistician 
on an ongoing basis to evaluate whether any need to be added. 
 
 
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6.0 
OBJECTIVES AND STUDY DESIGN 
6.1 
Study Objectives 
The primary objective is to evaluate the proportion of patients in each ACE-011 dose 
regimen who achieve a hematopoietic response during the treatment period including up 
to 2 months after the last dose of ACE-011 treatment of chemotherapy induced anemia in 
patients with metastatic breast cancer. Hematopoietic response is defined as an increase 
in hemoglobin of ≥ 1.0 g/dL above the study baseline value for 28 consecutive days 
during the treatment period including up to 2 months after the last dose of ACE-011, in 
the absence of any RBC transfusions and/or ESAs. 
 
The secondary objectives include: 
 
1. To evaluate the safety and tolerability of ACE-011 for the treatment of 
chemotherapy induced anemia in patients with metastatic breast cancer.  
 
2. To evaluate the percentage of patients who achieve an increase in hemoglobin of 
≥ 2 g/dL and/or hemoglobin concentration ≥ 11 g/dL for a consecutive 28 day 
period during the treatment period including up to 2 months after the last dose of 
ACE-011 in the absence of any RBC transfusions and/or ESAs.  
 
3. To estimate the duration of the hematopoietic response associated with each 
ACE-011 dose regimen.  
 
4. To estimate the time to the hematopoietic response associated with each ACE-011 
dose regimen.  
 
5. To estimate the proportion of patients receiving red blood cell (RBC) transfusions 
and/or ESAs within each cycle of ACE-011 with each dose regimen.  
 
6. To estimate the effect of each ACE-011 dose regimen on progression free survival 
(PFS) and objective response rate (ORR).  
 
The exploratory objectives include: 
 
1. To estimate the effect of each ACE-011 dose regimen on serum bone biomarkers 
(OC, BSAP, P1NP, CTX, TRACP-5b), urine bone biomarker (uNTX), bone 
mineral density (DXA scans of lumbar spine and hip) and incidence of skeletal 
related events (SREs).  
 
2. To evaluate the quality of life in relation to the treatment of chemotherapy 
induced anemia in patients with metastatic breast cancer during the study. 
 
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6.2 
Study Design 
This is a Phase 2, double-blind, randomized, placebo-controlled study to evaluate the 
efficacy, safety, and tolerability of ACE-011 for the treatment of chemotherapy induced 
anemia in patients with metastatic breast cancer. A total of 105 patients will be enrolled. 
Patients will be evaluated for study inclusion/exclusion criteria by the Investigator. 
Patients who meet the study entry criteria will be enrolled within 14 days of the screening 
visit. Local lab values for hemoglobin and central lab values will be utilized for the 
evaluation of patient eligibility. Central labs will also be used in the evaluation of patient 
safety throughout the study. Local lab values for hemoglobin and hematocrit will be 
collected and reported from screening (for eligibility) through the Day 281/Termination 
visit. Three cohorts of 30 patients each are planned at the following doses of ACE-011: 
0.1 mg/kg, 0.3 mg/kg and 0.5 mg/kg. Fifteen patients will be enrolled into the placebo 
cohort. 
Each eligible patient will be randomized to one of the four cohorts to receive a dose 
administered as a subcutaneous injection every 28 days for up to 4 doses. Dosing will be 
administered on days 1, 29, 57, and 85. Concurrent treatment with a myelosuppressive 
chemotherapy regimen for metastatic breast cancer will also be administered per standard 
of care at the site. Patients will be stratified according to administration of either single 
agent weekly chemotherapy or less frequent chemotherapy regimens.  
Blood samples will be collected at selected study sites from approximately one-third of 
patients for the evaluation of serum concentrations of ACE-011.   
Patients will be assessed for safety by monitoring adverse events, clinical laboratory tests, 
assessment of quality of life (FACT- Fatigue), vital signs and physical examinations on 
an ongoing basis. ECGs will be performed during screening, prior to dosing on the first 
cycle, during the first, second and third cycle, Day 113 (28 days after the last dose of 
ACE-011) and at Day 281/ Termination visit to monitor safety. Blood pressure and lab 
values will be assessed at each study visit during the treatment and treatment follow up 
period. 
Local laboratory hemoglobin values and blood pressure values will be evaluated prior to 
dosing per the dose modification criteria, as applicable.  
Patients will be followed for a minimum of 7 months following their last dose of ACE-
011/placebo. Study participation for each patient is approximately 10.5 months (14 day 
screening period, 3 month treatment period with a 2 month treatment follow up period, 
and a 5 month post treatment follow-up period). If a patient discontinues the study due to 
progression of disease (metastatic breast cancer) and/or begins another chemotherapy 
regimen, the patient will discontinue ACE-011/placebo treatment, complete the Day 
281/Termination visit procedures, and be followed for survival only (a minimum 7 
months from the last dose of ACE-011/placebo). 
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Anti-drug antibody testing will be performed at Day 281/Termination visit and if 
positive, the patient may be asked to return to the clinical site for additional monthly anti-
drug antibody testing for up to 12 months, after their last dose. 
 
 
 
 
 
 
 
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7.0 
ANALYSIS ENDPOINS 
7.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the hematopoietic response rate at each dose level.  It is 
defined as the proportion of patients who have a hematopoietic response of an increase in 
hemoglobin of ≥ 1 g/dL for 28 consecutive days during the treatment period including up 
to 2 months after the last dose of ACE-011/placebo, in the absence of any RBC 
transfusions and/or ESAs. The ACE-011/placebo treatment period is defined as the time 
period from the first ACE-011/placebo dose to up to 2 months after the last dose of ACE-
011/placebo treatment.  
7.2 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints include: 
 Proportion of patients achieving an increase in hemoglobin of ≥ 2 g/dL for 28 
consecutive days during the treatment period and up to 2 months after the last 
dose of ACE-011/placebo in the absence of any RBC transfusions and/or ESAs. 
 Proportion of patients achieving hemoglobin concentration ≥ 11 g/dL for 28 
consecutive days during the treatment period and up to 2 months after the last 
dose of ACE-011/placebo in the absence of any RBC transfusions and/or ESAs 
 Duration of hematopoietic response (days) defined as the time period from the 
first time hemoglobin increases at least ≥ 1 g/dL from baseline to the last time 
there is hemoglobin  ≥ 1 g/dL increase from baseline.  Duration of response is 
only calculated for a responder and will be at least 28 days.  The duration of 
response is only calculated for a patient who meets the primary efficacy endpoint.  
 Duration of hematopoietic response (days) defined as the time period from the 
first time hemoglobin increases at least ≥ 2 g/dL from baseline to the last time 
there is hemoglobin  ≥ 2 g/dL increase from baseline.  Duration of response is 
only calculated for a responder and will be at least 28 days.  The duration of 
response is only calculated for a patient who meets the primary efficacy endpoint. 
 Duration of hematopoietic response (days) defined as the time period from the 
first time hemoglobin concentration ≥ 11 g/dL to the last time there is hemoglobin 
concentration ≥ 11 g/dL.  Duration of response is only calculated for a responder 
and will be at least 28 days.  The duration of response is only calculated for a 
patient who meets the primary efficacy endpoint.  
 Duration of hematopoietic response (days) defined as the time period from the 
first time to achieve at least  ≥ 1 g/dL, ≥ 2 g/dL and/or hemoglobin concentration 
≥ 11 g/dL to the last time there is the same response.  
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 Time to achieve hematopoietic response (days) defined as the time from first dose 
of ACE-011/placebo to the first time a hemoglobin result at least ≥ 1 g/dL 
increase from baseline and maintained for a period of at least 28 consecutive days. 
 Time to achieve hematopoietic response (days) defined as the time from first dose 
of ACE-011/placebo to the first time a hemoglobin result at least ≥ 2 g/dL 
increase from baseline and maintained for a period of at least 28 consecutive days. 
 Time to achieve hematopoietic response (days) defined as the time from first dose 
of ACE-011/placebo to the first time hemoglobin concentration ≥ 11 g/dL and 
maintained for a period of at least 28 consecutive days. 
 Time to achieve hematopoietic response (days) defined as the time period the first 
time hemoglobin increases at least ≥ 1 g/dL, ≥ 2 g/dL from baseline and/or 
hemoglobin concentration ≥ 11 g/dL for a period of at least 28 consecutive days.   
 Proportion of patients receiving red blood cell (RBC) transfusions and/or ESAs in 
each dose group as well as within each cycle of each ACE-011/placebo dose 
level. 
 Objective tumor response rate for each dose level using RECIST criteria v1.1. 
 Progression-Free Survival is defined as the time from the start date of current 
chemotherapy regimen into the study to the first observation of documented 
disease progression or death due to any cause.  If the patient has not progressed or 
died at the time of final analysis, PFS will be censored at the time of last tumor 
assessment.   
7.3 
Safety Analysis Endpoints  
The safety analysis endpoints include: 
 Incidence of adverse events. 
 Change and shift from baseline in clinical laboratory parameters including iron 
studies, nutritional tests, coagulation, serum chemistry, hematology, LH, FSH, 
testosterone, progesterone, and estradiol, and urinalysis, and 12-lead ECG. 
7.4 
Exploratory Analysis Endpoints  
 Change or percent change in serum bone biomarkers (OC, BSAP, P1NP, CTX, 
TRACP-5b), urine bone biomarker (uNTX), bone mineral density (DXA scans of 
lumbar spine and hip) from baseline. 
 Incidence of skeletal related events (SREs). 
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 Change in the FACT-Fatigue.  
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8.0 
DETERMINATION OF SAMPLE SIZE 
With an anticipated dropout rate of 20%, a sample size of 30 patients per dose level is 
estimated to achieve at least 80% power with 2 sided significance level of 0.05 to 
differentiate targeted response rate of p1=0.45 from null hypothesis p0=0.20. An 
additional 15 patients will be enrolled to the placebo group for safety comparison. A total 
of 105 patients will be randomized to three ACE-011 dose groups (0.1, 0.3, and 0.5 
mg/kg) and placebo with a ratio of 2:2:2:1. 
 
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9.0 
INTERIM ANALYSIS 
There is no planned interim analysis for this study.   
 
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10.0 
METHODS OF ANALYSIS AND PRESENTATION 
10.1 
General Principles 
A blind data review of tables, appendices, and figures presented with surrogate treatment 
codes will be conducted prior to database freeze. This review will assess the accuracy and 
completeness of the study database, patient evaluability (including definition of analysis 
populations), and appropriateness of the planned statistical methods. 
10.1.1 Analysis Data Sets 
The data from all centers that participate in this protocol will be combined for the 
analysis. Missing data will not be imputed in any of the analysis. 
Derived analysis data sets will be produced as appropriate from the case report form 
(CRF) data and laboratory data (including central lab, ECG, bone biomarker, anti-drug 
antibody test, and DXA)  to assist with analysis and summary of both efficacy and safety 
variables. Derived data sets will identify observations selected according to the study 
window convention described in section 10.1.3. For details regarding the derived 
variables and derived analysis data sets, see the Study Derived Database and Technical 
Programming Specifications document. 
10.1.2  Definition of Study Day 1 and Baseline 
Study Day 1 is defined as the date of the first dose of ACE-011/placebo administered on 
or after the date of randomization. Other study days are defined relative to Study Day 1, 
and are numbered as …, -2, -1, 1, 2, …, with Day 1 defined as Study Day 1 and Day -1 
defined as the day prior to Study Day 1. The baseline value for a variable is defined as 
the last observation collected on or before Study Day 1, prior to the first dose of ACE-
011/ Placebo (including a screening value, if necessary).  
10.1.3 Study Dates and Visit Windows 
Durations (e.g., treatment duration) will be measured in days and calculated as: End Date 
– Start Date + 1. All scheduled study visit days will be defined relative to Study Day 1.  
A windowing convention will be used to determine the analysis value for a given study 
visit and will be applicable for all by-visit summaries.  
The visit window convention will be used for the analyses of efficacy and safety 
laboratory variables, as well as vital signs, ECG, FACT-Fatigue, DXA, and LH, FSH, 
Testosterone, Progesterone and Estradiol.  
For efficacy variables, the visit windows are based on the windows defined in the 
protocol Schedule of Events. For safety variables, visit windows are exhaustive.  
 
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One or more results for a particular efficacy or safety variable may be obtained in the 
same visit window. In such an event, the result with the date closest to the scheduled visit 
date will be used.  
10.1.4  Analysis Considerations 
All confidence intervals, statistical tests, and resulting p-values will be reported as 
2-sided and will be assessed at the 0.05 significance level. Unless otherwise specified, no 
Type 1 error adjustments for multiple comparisons will be made.  
Alternative methods of analysis may be considered prior to unblinding should some of 
the underlying model assumptions not be met (e.g. normality, missing values and lost to 
follow-up). The reason for any changes to the planned approach and methods will be 
fully documented. 
10.1.5  Table and Appendix Presentation 
Frequency distributions (number and percentage of patients) will be used to summarize 
categorical variables. When count data are presented, the percentage will be suppressed 
when the count is zero in order to draw attention to the non-zero counts. Unless otherwise 
specified, the denominator for percentages will be the number of patients in a given 
ACE-011/placebo group within the population of interest. Descriptive statistics (number 
of patients with non-missing values, mean, median, SD, minimum, and maximum) will 
be used to summarize continuous variables unless otherwise noted. 
In summary tables for categorical data, all categories will be presented if they are 
specified on the CRF (e.g., discontinuation reason), or if categories are ordered intervals 
(e.g., age groups), regardless of whether or not a patient is found in a given category. For 
other categorical data (e.g., adverse events and medications), only categories with at least 
1 patient will be presented. 
When no data are available for a table or appendix, an empty page with the title will be 
produced with suitable text (e.g., “There are no observations for this table/appendix.”). 
Means and medians will be presented to 1 more decimal place than the recorded data. 
Standard deviations (SDs) and standard errors (SEs, if applicable) will be presented to 
2 more decimal places than the recorded data. Minimum and maximum values will be 
presented using the same number of decimal places as the recorded data. Confidence 
intervals will be presented using the same number of decimal places as the parameter 
estimate (e.g., mean). Percentages will be presented to 1 decimal place. 
All p-values will be rounded to 3 decimal places. If a p-value is less than 0.001, it will be 
reported as “<0.001”. If a p-value is greater than 0.999, it will be reported as “>0.999”. 
The tables will be accompanied by data appendices sorted by treatment, study center, and 
patient number. Patients are uniquely identified by a concatenation of study center 
number and patient number. All data available from the CRFs along with some derived 
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variables will be listed. For relevant dates, the actual day relative to start of ACE-011/ 
placebo will also be listed. Dates will be presented in the format of “DDMONYYYY.”  
10.1.6  Analysis Software 
SAS® Version 8.2 or higher (Cary, NC: SAS Institute) will be used for all statistical 
analyses. 
10.2 
Analysis Sets 
The following 4 analysis sets will be used: the Randomized Set, the modified Intent-To-
Treat Set (MITT), the Safety Set, and the Per Protocol Set (PP). 
The Randomized Set includes all enrolled patients who have been randomized.  
The modified Intent-To-Treat Set includes all randomized patients who received at least 
one dose of ACE-011/placebo. 
The Safety Set includes all patients who received at least one dose of ACE-011/placebo. 
The Per Protocol Set includes all patients randomized who have confirmed chemotherapy 
induced anemia, received at least one dose of ACE-011/ placebo and on study (treatment) 
for at least 2 months (57 days). 
The number and percentage of patients in each analysis set will be summarized in Table 
14.1.1.  
10.3 
Patient Disposition  
Patient disposition will be summarized (frequency, percentage) by dose groups or 
placebo and overall for each patient sample, as will incidence of discontinuation of 
investigational drug, reason for discontinuation of investigational drug, incidence of 
discontinuation of study follow-up and reason of discontinuation of study follow-up. 
Overall disposition summaries will be presented in Table 14.1.1. Disposition information 
will be listed in Appendix 16.2.1 
A summary of patients enrolled by sites will be provided in Table 14.1.2. 
Inclusion/Exclusion criteria and randomization details will be listed in Appendices 16.2.2 
and 16.1.7, respectively. 
10.4 
Demographic and Baseline Characteristics 
Demographic and baseline characteristics will be listed and summarized by dose groups 
or placebo and overall.  Demographic and baseline characteristics include age (years), 
race, ethnicity, height (cm), weight (kg), body mass index (BMI) (kg/m2), breast cancer 
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history such as stage of breast cancer at diagnosis, histological subtype at diagnosis, 
histological grade, molecular subtype, estrogen and progesterone receptor status, HER-
2/neu status and sites of metastatic breast cancer. Summaries of demographic and 
baseline characteristics will be based on the MITT Set.  
Age in years is calculated as the integer part of the formula (Date of informed consent – 
Date of Birth + 1) /365.25 and will be summarized using descriptive statistics. 
The number and percentage of patients in each race category (American Indian or Alaska 
Native, Asian, Black, Native Hawaiian or Other Pacific Islander, White and Other) will 
be presented. 
The number and percentage of patients in each ethnicity category (Hispanic or Latino and 
Others) will be presented. 
BMI will be calculated using weight and height collected at Screening as follows: 
[(weight in kg) / ((height in cm) / 100)2]. 
These data will be listed in Appendices 16.2.4.1 and 16.2.4.2 and summarized in Tables 
14.1.3.1 and 14.1.3.2. 
10.5 
Medical History 
Summaries of medical history will be based on the MITT Set. No inferential statistics 
will be presented. 
Medical history will consist of any significant conditions or diseases including relevant 
surgical, therapeutic and diagnostic procedures that started prior to first dosing (Day 1).  
Medical history will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA, Version 11.1) coding system. Each diagnosis is mapped to a lower level term, 
and then to a preferred term, which is then mapped to a system organ class. 
The number and percentage of patients with any reported medical history will be 
summarized for each system organ class and preferred term in Tables 14.1.4. For the 
tables, if a patient reports the same preferred term multiple times, then that preferred term 
will be counted only once for that patient. Similarly, if a patient reports multiple 
conditions within the same system organ class, then that system organ class will be 
counted only once for that patient in the tables. System organ classes and preferred terms 
will be sorted in decreasing frequency based on the total number of reports. Medical 
history will be presented in Appendix 16.2.4.3. 
10.6 
Concomitant Diagnostic, Surgical, and Therapeutic Procedures 
Any diagnostic, surgical, and therapeutic procedures that are conducted during the study 
i.e., from Day 1 to Day 281/Termination visit, will be considered as concomitant 
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procedures. Concomitant diagnostic, surgical, and therapeutic procedures will be listed in 
Appendix 16.2.4.4.1.  
10.7 
Prior and Concomitant Medications 
Summaries of prior and concomitant medications will be based on the MITT Set. No 
inferential statistics will be presented. 
Any medication that was taken within 28 days prior to Day 1 and through 90 days from 
the last dose of ACE-011/placebo will be recorded in the CRF as prior and concomitant 
medication.   
Prior and concomitant medications will be coded using the World Health Organization 
Drug dictionary (Version March 2009) and classified into the default anatomical 
therapeutic chemical classification system (ATC) code provided by the system (the first 
ATC code by alphabetic order). The level 2 code will be used for analyses. 
Prior and concomitant medication will be summarized by dose groups or placebo and 
overall in Table 14.1.5. The table will present the number and percentage of patients by 
preferred term within each class sorted by decreasing frequency based on the total 
number of reports. The total number and percentage of patients receiving at least 1 
medication will also be presented. Prior and concomitant medications will be listed in 
Appendix 16.2.4.5.   
10.8 
Prior and Current Chemotherapy for Breast Cancer 
Summaries of prior chemotherapy agents and current chemotherapy agents for breast 
cancer will be based on the MITT Set. No inferential statistics will be presented. 
Any chemotherapy agents that were stopped at or prior to Screening will be considered 
prior chemotherapy. Chemotherapy agents taken at any time from Screening through Day 
281/Termination visit will be considered current chemotherapy. 
Prior and current chemotherapy agents will be coded using the World Health 
Organization Drug dictionary (Version March 2009) and classified into the default 
anatomical therapeutic chemical classification system (ATC) code provided by the 
system (the first ATC code by alphabetic order). The level 2 code will be used for 
analyses. 
Prior chemotherapy agents will be summarized by dose groups or placebo and overall in 
Table 14.1.6.1. Current chemotherapy agents will be summarized by dose groups or 
placebo and overall in Table 14.1.6.2. The tables will present the number and percentage 
of patients by preferred term within each class sorted by decreasing frequency based on 
the total number of reports. The total number and percentage of patients receiving at least 
1 chemotherapy agent will also be presented. Prior and current chemotherapy agents will 
be listed in Appendices 16.2.4.6.1 and 16.2.4.6.2 respectively.   
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10.9 
Prior Radiation Therapy 
Any radiation therapy prior to Day 1 will be recorded in the CRF. Radiation therapy will 
be summarized by dose groups or placebo and overall in Table 14.1.7. The table will 
present the number and percentage of patients by body sites. The total number and 
percentage of patients receiving at least 1 radiation therapy will also be presented. Prior 
radiation therapy will be listed in Appendix 16.2.4.7.   
10.10 Investigational Drug Exposure and Dose Modification 
ACE-011/placebo will be administered as a SC injection at the clinical site by the study 
staff, approximately every 28 days, on days 1, 29, 57, and 85 of the treatment period. 
The summaries of drug exposure and dose modification will be based on the Safety Set. 
No inferential statistics will be presented. 
The number of doses received (i.e., 1 – 4), skipped and/or modified (i.e., 0 – 3) during the 
study will be summarized in Table 14.1.8.1 using frequencies and percentages for each 
dose group. The total dosage received, which is defined as the sum of dosage received 
during the treatment period will be summarized using descriptive statistics for each dose 
group.  
The local hemoglobin values and blood pressure values will be evaluated on each ACE-
011/placebo dosing day (Appendix 16.2.5.2).  The hemoglobin values 28 days prior to 
each ACE-011/placebo dosing day and blood pressure will be reviewed and evaluated for 
dose modifications.  The rules for dosing modifications have been specified in protocol 
section 9.5.2.2. A patient may have up to 3 dose reductions in the study. The total number 
of dose modifications (i.e., 0, 1, 2 and 3) and reason of dose modification at Days 29, 57 
and 85 will be summarized by dose groups or placebo and overall (all three doses 
together) in Table 14.1.8.2.  
The investigational drug exposure and dose modification will be listed in Appendix 
16.2.5.1. 
10.11 Efficacy Analysis 
10.11.1  Primary Efficacy Analysis 
The primary efficacy endpoint is the hematopoietic response rate at each dose level or 
placebo.  It is defined as the proportion of patients who have a hematopoietic response of 
an increase in hemoglobin of ≥ 1 g/dL for 28 consecutive days during the treatment 
period including up to 2 months after the last dose of ACE-011/placebo, in the absence of 
any RBC transfusions and/or ESAs. The ACE-011/placebo treatment period is defined as 
the time period from the time of first ACE-011/placebo dose to up to 2 months after the 
last dose of ACE-011/placebo treatment.  To be considered as a responder, all 
hemoglobin measurements during a 28 consecutive day period or longer must have an 
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increase of ≥ 1 g/dL from baseline. If RBC transfusions and/or ESAs are required, no 
hemoglobin measurements within 28 days of the RBC transfusion of ESA administration 
will be used to determine the hemoglobin response.  
Primary efficacy analysis will be based on the PP Set.  Primary efficacy analysis will also 
be conducted on the MITT Set as supportive to the PP based analysis.  Patients who do 
not receive ACE-011/placebo will be excluded from primary efficacy analysis.  Patients 
who discontinue the ACE-011/placebo treatment prematurely will be counted as non-
responder in the calculation of response rate unless the patients can be determined as 
responder using available hemoglobin measurements.     
An exact 95% confidence interval (CI) for the response rate for each dose level or 
placebo as well as overall (all three doses levels analyzed together) will be provided to 
assess whether 95% CI of response rate contains null hypothesis response rate, p0=0.20 
(Clopper and Pearson, 1934).  The response rate and 95% CI will also be provided for 
patients with chemotherapy on weekly basis versus those with chemotherapy on a less 
frequent basis for each dose level or placebo as well as overall (all three doses levels 
analyzed together).  
An exploratory analysis with the Kaplan Meier approach will be considered to account 
for those patients who discontinue the ACE-011/placebo treatment prematurely if the 
drop out rate is greater than 20%.  Exploratory analysis of comparing hematopoietic 
response rates between active and placebo will be performed using Fisher’s exact test.  
Due to the nature of the study (phase 2 dose determination study), no multiplicity 
adjustment will made for the multiple comparisons.  
Primary efficacy analysis of hematopoietic response in the PP Set and MITT Set will be 
based on central lab hemoglobin values and summarized in Table 14.2.1.1 and Table 
14.2.1.2 respectively. The values of hemoglobin and hematocrit will be listed in 
Appendix 16.2.6.1. 
10.11.2  Secondary Efficacy Analyses 
All secondary efficacy analyses will be conducted under both MITT and PP analysis sets. 
The following secondary efficacy endpoints will be analyzed in the SAP.  
 Proportion of patients achieving an increase in hemoglobin of ≥ 2 g/dL for 28 
consecutive days during the treatment period and up to 2 months after the last 
dose of ACE-011/placebo in the absence of any RBC transfusions and/or ESAs. 
 Proportion of patients achieving hemoglobin concentration ≥ 11 g/dL for 28 
consecutive days during the treatment period and up to 2 months after the last 
dose of ACE-011/placebo in the absence of any RBC transfusions and/or ESAs. 
 Proportion of patients achieving an increase in hemoglobin of ≥ 2 g/dL and/or 
hemoglobin concentration ≥ 11 g/dL for 28 consecutive days during the treatment 
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period and up to 2 months after the last dose of ACE-011/placebo in the absence 
of any RBC transfusions and/or ESAs. 
For the above endpoints, patients who discontinue the ACE-011/placebo treatment 
prematurely will be counted as non-responder in the calculation of response rate unless 
the patients can be determined as responder using the available hemoglobin 
measurements. An exact 95% confidence interval (CI) for the response rate for each dose 
level as well as overall (all three doses levels analyzed together) will be provided 
(Clopper and Pearson, 1934).  The response rate and 95% CI will also be provided for 
patients with chemotherapy on weekly basis versus those with chemotherapy on a less 
frequent basis for each dose level as well as overall (all three doses levels analyzed 
together). P–value will be calculated based on Fisher’s exact test to compare the response 
rate between each dose level and placebo. No multiplicity adjustment will made for the 
multiple comparisons. The results will be presented in Tables 14.2.2.1 – 14.2.2.6. 
 Duration of hematopoietic response (days) defined as the time period the first 
time hemoglobin increases at least ≥ 1 g/dL from baseline to the last time there is 
hemoglobin  ≥ 1 g/dL increase from baseline.  
 Duration of hematopoietic response (days) defined as the time period the first 
time hemoglobin increases at least ≥ 2 g/dL from baseline to the last time there is 
hemoglobin  ≥ 2 g/dL increase from baseline.   
 Duration of hematopoietic response (days) defined as the time period the first 
time hemoglobin concentration ≥ 11 g/dL to the last time there is hemoglobin 
concentration  ≥ 11 g/dL.   
 Duration of hematopoietic response (days) defined as the time period the first 
time hemoglobin increases at least ≥ 1, ≥ 2 g/dL and/or  hemoglobin 
concentration ≥ 11 g/dL from baseline to the last time when the same response is 
maintained.  
For the above endpoints, duration of response is only calculated for a responder and will 
be at least 28 days.  The duration of response is only calculated for a patient who meets 
the primary efficacy endpoint. Duration of hematopoietic response in days will be 
summarized by each dose group or placebo as well as overall (all three doses together) 
using descriptive statistics in Tables 14.2.2.7 and 14.2.2.8. 
 Time to achieve hematopoietic response (days) defined as the time from first dose 
of ACE-011/placebo to the first time a hemoglobin result at least ≥ 1 g/dL 
increase from baseline and maintained for a period of at least 28 consecutive days. 
 Time to achieve hematopoietic response (days) defined as the time from first dose 
of ACE-011/placebo to the first time a hemoglobin result at least ≥ 2 g/dL 
increase from baseline and maintained for a period of at least 28 consecutive days. 
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 Time to achieve hematopoietic response (days) defined as the time from first dose 
of ACE-011/placebo to the first time hemoglobin concentration ≥ 11 g/dL and 
maintained for a period of at least 28 consecutive days. 
 Time to achieve hematopoietic response (days) defined as the time period the first 
time hemoglobin increases at least ≥ 1, ≥ 2 g/dL and/or  hemoglobin 
concentration ≥ 11 g/dL and maintained for a period of at least 28 consecutive 
days. 
For the above endpoints, patients who die before the event was reached will be right 
censored at the date of death. Patients who discontinue the study or who are lost to follow 
up and for whom the event was not reached before premature discontinuation will be 
right censored at the last date of follow up. Patients who complete the required follow up 
but do not reach the event will also be right censored at the last date of follow up. Time to 
achieve hematopoietic response after the first dose of ACE-011/placebo will be analyzed 
using Kaplan-Meier method to estimate the survival curve and median time to event. The 
95% Confidence Interval (CI) for the estimated median time will be based on the sign test 
(Brookmeyer and Crowley 1982).   Time to hematopoietic response will be summarized 
in Tables 14.2.2.9 and 14.2.2.10 and plotted in Figures 14.2.2.9.1 – 14.2.2.9.5 and 
Figures 14.2.2.10.1 – 14.2.2.10.5. 
 Proportion of patients receiving red blood cell (RBC) transfusions and/or ESAs in 
each dose group as well as within each cycle of each ACE-011 dose level.  
The RBC transfusion and ESA will be captured and coded in the Concomitant 
Medication page. The treatment cycles are defined as from Day 1 to prior to Day 29, Day 
29 to prior to Day 57, Day 57 to prior to Day 85 and Day 85 to prior to Day 141. For each 
treatment cycle and overall for all treatment cycles, the number and percentage of 
patients who have received any RBC transfusion, any ESA, and any RBC transfusion 
and/or ESA will be presented by dose groups or placebo as well as overall (all three doses 
together) in Tables 14.2.2.11 and 14.2.2.12. 
 Objective tumor response rate for each dose level using RECIST criteria v1.1.  
The objective tumor response evaluated using RECIST criteria will be recorded at Days 
64 and 113. The tumor (both target and non-target) responses will be summarized in 
Tables 14.2.2.13 and 14.2.2.14 for dose groups or placebo and overall (all three doses 
together). The unscheduled tumor response evaluations will not be summarized in the 
tables but be presented in Appendix 16.2.6.2. The tumor lesions assessed by CT/MRI 
scans recorded at Screening, Days 64 and 113 and Unscheduled will be presented in 
Appendix 16.2.6.3. 
 Progression-Free Survival (PFS) is defined as the time from the start date of 
current chemotherapy regimen to the first observation of documented disease 
progression or death due to any cause.  If the patient has not progressed or died at 
the time of end of follow-up, PFS will be censored at the time of last tumor 
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assessment.  The number and percentage of patients who have progressed, died 
and censored as well as the median PFS (95% CI) will be presented in Tables 
14.2.2.15 and 14.2.2.16. The median PFS will be estimated using Kaplan – Meier 
method and the 95% CI will be calculated using the sign test (Brookmeyer and 
Crowley 1982). 
10.12 Safety and Exploratory Analyses  
10.12.1 Adverse Events 
All adverse events will be summarized using the Safety Set. No inferential statistics will 
be provided. 
An adverse event (AE) is any untoward medical occurrence in a patient administered a 
pharmaceutical product, which does not necessarily have a causal relationship with the 
treatment.  An AE can be any unfavorable and unintended sign (e.g., including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of 
the investigational drug, whether or not it is considered to be investigational drug related.  
This includes any newly occurring event or previous condition that has increased in 
severity or frequency since the administration of investigational drug (treatment-
emergent). 
A treatment-emergent adverse event will be defined as any adverse event, regardless of 
relationship to investigational drug occurring after ACE-011/placebo administration up to 
90 days from the last dose of ACE-011/placebo.   
Adverse events with missing onset dates will be considered treatment-emergent. If an 
onset date or end date is partial, the event will be considered treatment-emergent unless 
the partial date eliminates the possibility that the event is treatment-emergent. 
Specifically, if a day is missing, the month and year will be used to determine treatment 
emergence.  If a day and month is missing, the year will be used to determine treatment 
emergence. 
All adverse events will be coded using the MedDRA (Version 11.1) coding system. In 
this dictionary, each diagnosis is mapped to a lower level term, and then to a preferred 
MedDRA term, which is then mapped to system organ class. 
Adverse events will be summarized by dose groups or placebo and overall (three doses 
levels combined). The following sections describe the summaries that will be presented. 
10.12.1.1  Incidence of Adverse Events 
A high-level summary of treatment-emergent adverse events will be presented in 
Table 14.3.1.1. This table will include the number and percentage of patients who have 
experienced any treatment-emergent adverse event and any treatment-emergent adverse 
events that lead to investigational drug discontinuation. The table will also present the 
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event count of each CTCAE grade and related or not related to investigational drug by 
dose groups or placebo and overall (three doses levels combined).  
Treatment-emergent adverse events will be presented by system organ class and preferred 
term in Table 14.3.1.2. The table will include only one occurrence of a preferred term per 
patient. If a patient reports the same preferred term multiple times, then that preferred 
term will be counted only once for that patient. Similarly, if a patient reports multiple 
adverse events within the same system organ class, then that system organ class will be 
counted only once for that patient.   System organ class terms and preferred terms will be 
sorted in decreasing frequency based on the total number of adverse event reports.  All 
adverse events will be presented in Appendix 16.2.7.1. 
10.12.1.2  Relationship of Adverse Events to Investigational drug 
An overview of treatment-emergent adverse events by relationship to investigational drug 
will be presented in Tables 14.3.1.3.1. The overview presents by the relationship with the 
investigational drug (none, unlikely, possibly, probably and definitely) the number of 
treatment-emergent adverse events and the number and percentage of patients who have 
experienced at least one treatment-emergent adverse event. 
Drug-related adverse events will be defined as any adverse events that are considered by 
the investigator to be either possibly, probably, or definitely related to investigational 
drug. A summary of treatment-emergent adverse events related to investigational drug 
will be presented by system organ class and preferred term in Table 14.3.1.3.2. 
A patient is counted once for most related event if the patient reports more than one 
event. If relationship to investigational drug is missing, no imputation will be 
implemented for the missing relationship (Appendix 16.2.7.1). 
10.12.1.3  CTCAE Grade of Adverse Events 
An overview of treatment-emergent adverse events by CTCAE grades will be presented 
in Table 14.3.1.4.1. The overview presents by the CTCAE grades (1-5) the total number 
of treatment-emergent adverse events and the number and percentage of patients who 
have experienced at least one treatment-emergent adverse event. 
The grades 3, 4 and 5 AEs will be summarized by system organ class and preferred term 
in Table 14.3.1.4.2. A patient is counted once for most severe event if the patient reports 
more than one event. 
10.12.1.4  Adverse Events Leading to Treatment Discontinuation 
All treatment-emergent adverse events collected with an investigational drug action taken 
as “Permanently Discontinued” will be presented by system organ class and preferred 
term in Table 14.3.1.5. 
10.12.1.5  Serious Adverse Events 
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All treatment-emergent SAEs will be presented in Table 14.3.1.6 and Appendix 16.2.7.2. 
Treatment-Emergent serious adverse event is defined as any serious adverse event that 
starts on or after date of first dose through Day 281/Termination visit. If a patient reports 
the same SAE preferred term multiple times, then that preferred term will be counted 
only once for that patient. Similarly, if a patient reports multiple SAEs within the same 
system organ class, then that system organ class will be counted only once for that 
patient.  If a patient reports multiple occurrences of the same SAE, only the most related 
occurrence will be presented.   
10.12.1.6  Skeletal Related Events 
Skeletal Related Events (SREs) are defined as pathologic fracture, radiation therapy to 
bone, surgery to bone, or spinal cord compression that starts on or after the date of first 
dose through Day 281/Termination visit.  
The overall number of SREs reported in both AE and Concomitant Diagnostic, Surgical, 
and Therapeutic Procedures (CP) pages will be summarized in Table 14.3.2 by dose 
groups or placebo and overall (three doses levels combined). The number of patients with 
at least one SRE will be summarized in this table as well. In addition, the number and 
percentage of patients within each SRE category (i.e., pathologic fracture, radiation 
therapy to bone, surgery to bone, and spinal cord compression) will also be summarized 
in Table 14.3.2. All SREs in AE and CP pages will be presented respectively in 
Appendices 16.2.7.1 and 16.2.4.4.1. A summary of all SREs will be listed in Appendix 
16.2.4.4.2.  
10.12.2  Clinical Laboratory Evaluations 
Clinical laboratory evaluations will be assessed using the Safety Set. No inferential 
statistics will be presented. 
All iron studies, nutritional tests, coagulation studies, serum chemistry, hematology, 
urinalysis and LH, FSH, testosterone, progesterone, and estradiol will be sent to the 
central laboratory. Central laboratory results will be used for assessment of the study 
outcomes. Hemoglobin and hematocrit will be also evaluated by the local laboratory in 
the evaluation of ACE-011/placebo dose modifications. Urine pregnancy test will be 
conducted in local laboratories. 
Baseline is defined as the last nonmissing value prior to the first dose of ACE-
011/placebo. Change from baseline in continuous safety laboratory variables will be 
summarized by dose groups or placebo and overall (three doses levels combined) as 
described below. Conventional units will be reported for all analytes.  
In addition, shift tables will be presented showing the number of patients with low, 
normal, or high values at baseline and each post-baseline visit according to the central 
laboratories’ reference ranges. 
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For the relationship to normal reference range and shift table summaries, if a patient has 
multiple tests available in a particular visit window, the most abnormal result will be 
selected for summary (if applicable). All descriptive statistics will be based on data 
selected according to the window convention outlined in Section 10.1.3. 
Laboratory tests with character results that cannot be analyzed by change from baseline 
or shift table analysis will be listed in their respective data appendices 16.2.8.1 – 16.2.8.8.  
10.12.2.1  Iron Studies 
Iron studies will be collected at Screening, Days 1, 29, 57, 85 and 281. Baseline is 
defined as the last nonmissing value prior to the first dose of ACE-011/placebo. 
Table 14.3.3.1.1 will present descriptive statistics of iron studies for baseline, each post-
baseline visit, and change from baseline to each post-baseline visit. Table 14.3.3.1.2 will 
present the shift from baseline to each post-baseline visit. The following laboratory tests 
will be included:  
 serum iron (mcg/dL) 
 total iron binding capacity (TIBC) (mcg/dL) 
 transferrin(g/L) 
 serum ferritin (ng/dL) 
For all parameters, mean values (±SE) over time will be graphed in Figures 14.3.3.1.3.1 – 
14.3.3.1.3.4. Appendix 16.2.8.1 will list all iron studies values for all patients. 
10.12.2.2 Nutritional Tests 
Nutritional tests include serum folate (ng/mL) and vitamin B12 (pg/mL). Vitamin B12 
will be collected only at Screening. Serum folate will be collected at Screening, Days 36, 
113 and 281. Baseline is defined as the last nonmissing value prior to the first dose of 
ACE-011/placebo. Table 14.3.3.2.1 will present descriptive statistics of nutritional tests 
for baseline, each post-baseline visit, and change from baseline to each post-baseline 
visit. Table 14.3.3.2.2 will present the shift from baseline to each post-baseline visit. For 
serum folate, mean values (±SE) over time will be graphed in Figure 14.3.3.2.3. 
Appendix 16.2.8.2 will list all nutritional tests values for all patients. 
10.12.2.3  Coagulation  
Coagulation profile will be collected at Screening, Days 1, 8, 15, 22, 29, 36, 43, 57, 64, 
71, 85, 99, 113, 141 and 281. Baseline is defined as the last nonmissing value prior to the 
first dose of ACE-011/placebo. Table 14.3.3.3.1 will present descriptive statistics of 
coagulation for baseline, each post-baseline visit, and change from baseline to each post-
baseline visit. Table 14.3.3.3.2 will present the shift from baseline to each post-baseline 
visit. The following laboratory tests will be included:  
 prothrombin time (PT) (sec) 
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 partial thromboplastin time (PTT) (sec) 
 fibrinogen (mg/dL) 
For all parameters, mean values (±SE) over time will be graphed in Figures 14.3.3.3.3.1 – 
14.3.3.3.3.3. Appendix 16.2.8.3 will present coagulation profile for all patients. 
10.12.2.4  Hematology 
Hematology will be collected at every visit including Screening, Days 1, 8, 15, 22, 29, 
36, 43, 57, 64, 71, 85, 99, 113, 141, 169, 197, 225, 253 and 281. Baseline is defined as 
the last nonmissing value prior to the first dose of ACE-011/placebo. Peripheral blood 
smear will be conducted only on dosing days (i.e., Days 1, 29, 57, and 85) and Day 281. 
Reticulocyte will be done on days 1, 8, 15, 22, 29, 36, 57, 64, 85, and at the termination 
visit. Table 14.3.3.4.1 will present descriptive statistics of hematology values for 
baseline, each post-baseline visit, and change from baseline to each post-baseline visit. 
Table 14.3.3.4.2 will present the shift from baseline to each post-baseline visit. The 
following laboratory tests will be included:  
 red blood cell (RBC) count (106/mm3) 
 monocytes (K/mm3) 
 hemoglobin (g/dL) 
 lymphocytes (K/mm3) 
 hematocrit (%) 
 mean corpuscular volume (fl) 
 platelet count (103/mm3) 
 mean corpuscular hemoglobin (pg) 
 white blood cell (WBC) 
count (103/mm3) 
 mean corpuscular hemoglobin 
concentration (g/dL) 
 total neutrophils (103/mm3) 
 erythropoietin (mIU/mL) 
 eosinophils (K/mm3) 
 reticulocyte (absolute count) 
 basophils (K/mm3) 
 reticulocyte (%) 
For all parameter, mean values (±SE) over time will be graphed in Figures 14.3.3.4.3.1 – 
14.3.3.4.3.16. Appendix 16.2.8.5 will list all hematology values for all patients. 
10.12.2.5  Serum Chemistry 
Serum chemistry will be collected at visits including Screening, Days 1, 8, 15, 22, 29, 36, 
43, 57, 64, 71, 85, 99, 113, 141 and 281. Baseline is defined as the last nonmissing value 
prior to the first dose of ACE-011/placebo. Table 14.3.3.5.1 will present descriptive 
statistics of serum chemistry for baseline, each post-baseline visit, and change from 
baseline to each post-baseline visit. Table 14.3.3.5.2 will present the shift from baseline 
to each post-baseline visit. The following laboratory tests will be included:  
 blood urea nitrogen (mg/dL) 
 alkaline phosphatase (U/L) 
 calcium (mg/dL)  
 aspartate aminotransferase (AST) (U/L) 
 creatinine (mg/dL) 
 alanine aminotransferase (ALT) (U/L) 
 sodium (mEq/L) 
 chloride (mEq/L) 
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 potassium (mEq/L) 
 indirect bilirubin (mg/dL) 
 total bilirubin (mg/dL) 
 total protein (g/dL) 
 uric acid (mg/dL) 
 albumin (g/dL) 
 glucose (fasting) (mg/dL) 
 carbon dioxide (mEq/L) 
 phosphorus (mg/dL) 
 amylase (U/L) 
 lipase (U/L) 
 lactate dehydrogenase (LDH) (U/L) 
For all parameters, mean values (±SE) over time will be graphed in Figures 14.3.3.5.3.1 – 
14.3.3.5.3.20. Appendix 16.2.8.4 will present serum chemistry values for all patients. 
10.12.2.6  Urinalysis 
Urinalysis will be collected at Screening, Days 1, 85 and 281. Urinalysis laboratory 
parameters including protein, glucose, blood, ketone, leukocyte esterase and nitrite will 
be categorically summarized as shift from baseline to each post-baseline visit in 
Table 14.3.3.6.2. Urinalysis PH values and specific gravity will be presented in 
Table 14.3.3.6.1. Baseline is defined as the last nonmissing value prior to the first dose of 
ACE-011/placebo. Descriptive statistics for baseline, each post-baseline visit and change 
from baseline to each post-baseline visit will be presented. Microscopy results such as 
crystals, casts, WBCs, and red blood cells (if applicable) will not be summarized, only 
listed using categorical results provided directly by the laboratory (Appendix 16.2.8.6).  
Appendix 16.2.8.6 will include all urinalysis laboratory values for all patients. 
10.12.2.7  LH, FSH, Testosterone, Progesterone, and Estradiol  
The parameters of LH (mIU/mL), FSH (mIU/mL), testosterone (ng/dL), progesterone 
(ng/mL), and estradiol (pg/dl) will be evaluated at Screening, Days 1, 29, 57, 85, 113 and 
141. Baseline is defined as the last nonmissing value prior to the first dose of ACE-
011/placebo. Table 14.3.3.7.1 will present descriptive statistics for LH, testosterone, 
progesterone and estradiol for baseline, each post-baseline visit, and change from 
baseline to each post-baseline visit.  Table 14.3.3.7.2 will present descriptive statistics for 
FSH for baseline, each post-baseline visit, and change and percent change from baseline 
to each post-baseline visit. Table 14.3.3.7.3 will present the shift from baseline to each 
post-baseline visit. 
For all parameters as well as percent change from baseline in FSH, mean values (±SE) 
over time will be graphed in Figures 14.3.3.7.3.1 – 14.3.3.7.3.6. Appendix 16.2.8.8 will 
include all results for all patients. 
10.12.2.8  Local Hematology  
Local hematology will include hemoglobin and hematocrit that are collected at every visit 
from Screening to Day 281. These local lab results will be listed in Appendix 16.2.5.2. 
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10.12.2.9  Urine Pregnancy Test  
Urine pregnancy test will be conducted for females of child bearing potential only at 
dosing days (Days 1, 29, 57 and 85, prior to dosing) and Day 281.The urine pregnancy 
test will be listed in Appendix 16.2.9.5. 
10.12.3  Vital Signs 
Vital sign measurements (seated systolic and diastolic blood pressure in mmHg, heart 
rate in beats/minute, oral temperature in C, and weight in kg) will be collected at 
Screening, Days 1, 8, 15, 22, 29, 36, 43, 57, 64, 71, 85, 99, 113, 141 and 281. 
Measurements will be made prior to dosing on dosing days. Height in cm will be 
collected at Screening.  Height and weight at screening will be summarized with 
Demographics and Baseline Characteristics in Table 14.1.4. 
Vital signs will be summarized using the Safety Set. No inferential statistics will be 
presented. 
Baseline is defined as the last nonmissing value prior to the first dose of ACE-
011/placebo. Table 14.3.4 will display descriptive statistics for vital signs at baseline, 
each post-baseline visit, and change from baseline to each post-baseline visit by dose 
groups or placebo and overall (three doses levels combined). 
All vital sign measurements will be presented by patient in Appendix 16.2.9.1. 
10.12.4  Physical Examinations 
All physical examination results will be presented in Appendix 16.2.9.2.  
10.12.5  12-Lead ECGs 
Triplicate twelve-lead ECGs (3 minute intervals) will be performed at Screening, Days 1, 
8, 36, 64, 113 and 281. On Screening and Day 1, ECGs will be performed at two different 
time intervals (approximately 1 hour apart). On Day 1, ECGs are to be performed prior to 
dosing of ACE-011/placebo. ECG data will be interpreted by both local readers and 
central readers and the results will be presented separately. 
ECGs will be summarized using the Safety Set. The endpoints that will be collected 
include ventricular rate (beats/min), PR interval (msec), QRS duration (msec), QT 
interval (msec) and QTc interval.  
For each ECG parameter, the arithmetic mean will be calculated at each visit for all 
replicates. Baseline is defined as the last nonmissing mean value prior to the first dose of 
ACE-011/placebo. Descriptive statistics of mean ECG values will be presented for 
baseline, 8, 36, 64, 113 and 281 and change from baseline by dose groups or placebo and 
overall (three doses levels combined) in Tables 14.3.5.1 for local ECG and 14.3.5.3 for 
central ECG.   
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In addition, shift tables showing the number of patients with normal, non-clinically 
significant abnormal, or clinically significant abnormal ECG interpretation results from 
baseline to Days 8, 36, 64, 113 and 281 will be provided in Tables 14.3.5.2 for local 
ECG. For the ECG interpretation summaries, if a patient has multiple interpretations at a 
particular visit, the most significant result will be selected for summary (if applicable). 
For QTc (QTcB and QTcF) from central readers, baseline adjusted QTc (post-dose – 
baseline) at each post-dose visit for ACE-011/placebo patients will be calculated for each 
patient. Descriptive statistics of the baseline adjusted QTc data will be present for Days 8, 
36, 64, 113 and 281 by dose groups or placebo and overall (three doses levels combined) 
in Tables 14.3.5.4. In addition, the mean difference of the baseline adjusted QTc as well 
as its upper bound of one-sided 95% confidence interval will be calculated for each dose 
group and overall (three doses levels combined) comparing to the placebo. 
QTc interval (QTcB and QTcF) from the central readers will also be categorized as ≤ 450 
msec, > 450 but < 480 msec and ≥ 480 msec.  Table 14.3.5.5 presents the number and 
percentage of patients for each category for baseline, Days 8, 36, 64, 113 and 281 by dose 
groups or placebo and overall (three doses levels combined). 
Local and central ECG data will be presented in Appendices 16.2.9.3.1, 16.2.9.3.2, 
16.2.9.4.1 and 16.2.9.4.2. 
10.12.6  Anti-drug Antibody 
The results of anti-drug antibody will be listed in Appendix 16.2.8.10. 
10.13 Pharmacokinetic Analysis 
The PK analysis will be analyzed separately by the sponsor.  
10.14 Pharmacoeconomic Analysis 
Not applicable. 
10.15 Bone Biomarker Analysis 
Bone biomarkers (serum) including osteocalcin (OC), procollagen type 1 N-terminal 
propeptide (P1NP), serum bone specific alkaline phosphatase (BSAP), C-terminal type 1 
collagen telopeptide (CTX), tartrate-resistant acid phosphatase isoform-5b (TRACP-5b), 
and urine N-telopeptide (uNTX) will be collected prior to dosing on dosing days 1, 29, 57 
and  85, as well as Days 113, 141 and 281.  
Bone biomarker data will be summarized using the MITT Set. No inferential statistics 
will be presented. 
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Baseline is defined as the last nonmissing value prior to the first dose of ACE-
011/placebo. Table 14.3.6 will display descriptive statistics for each bone biomarker at 
baseline, each post-baseline visit, and change and percent change from baseline to each 
post-baseline visit by treatment group. 
For each parameters as well as percent change from baseline, mean values (±SE) over 
time will be graphed in Figures 14.3.6.1 – 14.3.6.12. All bone biomarker data will be 
presented by patient in Appendix 16.2.8.7. 
10.16 Quality of Life Analysis 
FACT-Fatigue questionnaire (version 4, Appendix) will be administered at Screening, 
prior to dosing on Days 1, 29, 57 and 85 and Day 281. FACT-Fatigue subscale has 13 
Likert scale items with response categories of “Not at all”, “A little bit”, “Somewhat”, 
“Quite a bit” and “Very much” coded as 0, 1, 2, 3 and 4. The total score of the subscale 
will be calculated by summing up all items with range from 0 – 52. The scoring 
algorithm is listed as below: 
1. Reverse coding for items HI7, HI12, An1, An2, An3, An4, An8, An12, An14, 
An15 and An16 by subtracting the response from “4” to reflect the higher score 
means better quality of life,  
2. Sum individual items to obtain a score,  
3. Multiply the sum of the item scores by the number of items in the subscale (i.e., 
13), then divide by the number of items answered.  This produces the subscale 
score. 
The total score requires more than 50% of the items are answered (i.e., a minimum of 7 
of 13 items). The total score will be considered as missing when there are less than 50% 
item endorsed. 
Baseline FACT-Fatigue total score is defined as the last nonmissing value prior to the 
first dose of ACE-011/placebo. Descriptive statistics for the total score will be presented 
for baseline, Days 29, 57, 85 and 281 and change from baseline by treatment group in 
Table 14.3.7.   
FACT-Fatigue total score will be summarized using the MITT Set. 
FACT-Fatigue item data will be presented in Appendix 16.2.9.7. 
10.17 DXA Analysis 
Bone Mineral Density (BMD) of lumbar spine and hip will be assessed using DXA scan 
at Screening, Days 113 and 281. The analyzed parameters include BMD (g/cm2) for spine 
regions L1-L4 and hip total.  
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CONFIDENTIAL 
Baseline is defined as the last nonmissing value prior to the first dose of ACE-
011/placebo. Tables 14.3.8.1 and 14.3.8.2 will display descriptive statistics for each 
parameter at baseline, each post-baseline visit, change from baseline and percent change 
from baseline to each post-baseline visit by treatment group. 
BMD will be summarized using the MITT Set. Percent change from baseline in BMD 
will be compared to placebo group using ANOVA Dunnett’s test. 
The BMD and percent change from baseline for spine regions and hip total will be 
graphed by mean values (±SE) over time in Figures 14.3.8.3.1 - 14.3.8.3.4. DXA data 
will be presented by patient in Appendices 16.2.8.9.1 and 16.2.8.9.2. 
10.18 Changes in the Statistical Analysis Plan from the Protocol Analysis Plan 
The statistical analysis plan does not deviate from the analysis specified in the protocol. 
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11.0 
REFERENCES 
1. Brookmeyer R, Crowley J. A confidence interval for the median survival time.
Biometrics. 1982;38:29-41.
2. Clopper C.,  Pearson E. S. The use of confidence or fiducial limits illustrated in the
case of the binomial. Biometrika  1934; 26: 404-413.
3. Functional Assessment of Chronic Illness, FACT-Fatigue Version 4.
http://www.facit.org/qview/qlist.aspx. 2003.
4. Hosmer DW, Lemeshow S. Applied Survival Analysis. New York: Wiley 1999.
5. ICH Topic E3: Structure and Content of Clinical Study Reports (CPMP/ICH/137/95 –
adopted December 1995).
6. ICH Topic E9: Statistical Principles for Clinical Trials (CPMP/ICH/363/96 - adopted
March 1998).
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APPENDIX 
 FACT-Fatigue Subscale 
Item 
Number 
Item Description 
HI7 
I feel fatigued. 
HI12 
I feel weak all over. 
An1 
I feel listless (“washed out”). 
An2 
I feel tired. 
An3 
I have trouble starting things because I am tired. 
An4 
I have trouble finishing things because I am tired. 
An5 
I have energy. 
An7 
I am able to do my usual activities. 
An8 
I need to sleep during the day. 
An12 
I am too tired to eat. 
An14 
I need help doing my usual activities. 
An15 
I am frustrated by being too tired to do the things I want to do. 
An16 
I have to limit my social activity because I am tired. 
 
 
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