Conditions: Advanced Adult Hepatocellular Carcinoma
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 21
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate the safety and tolerability of dalantercept plus sorafenib in patients with advanced hepatocellular carcinoma (HCC) to determine the recommended dose level of dalantercept in combination with sorafenib.

Detailed description:
The initial design of the study was a dose escalating approach in which dalantercept in combination with sorafenib, would be administered at increasing dose levels among 3 cohorts of subjects with HCC in order to determine the Maximum Tolerated Dose (MTD) of the combination. Once the MTD was determined, a forth expansion cohort of subjects would be enrolled at the MTD to assess safety. A total of up to 38 subjects were planned.

The initial cohort (Cohort 1) enrolled 5 subjects at a dalantercept dose level of 0.6 mg/kg once every 3 weeks (Q3W) in combination with sorafenib (400 mg PO once daily). Following an assessment of safety/tolerability by a Safety Review Team, it was recommended to de-escalate the dalantercept dose for Cohort 2 to 0.4 mg/kg Q3W in combination with sorafenib (400 mg PO once daily); 6 subjects were enrolled.

The 0.4 mg/kg dose level was determined to be the MTD, and an additional 10 subjects were enrolled at that dose level in the expansion cohort (Cohort 3).

A formal Statistical Analysis Plan was initially planned for this study. However, due to its early termination, only cursory descriptive statistics were carried out on the available data; no formal SAP was prepared.

Arms:
arm 1: Cohort 1: Participants received dalantercept 0.6 mg/kg by subcutaneous (SC) injection once every 3 weeks plus sorafenib 400 mg orally (PO) once daily arm 2: Cohort 2: Participants will receive dalantercept 0.4 mg/kg SC injection once every 3 weeks plus sorafenib 400 mg PO once daily arm 3: Cohort 3: Participants will receive dalantercept 0.4 mg/kg SC injection once every 3 weeks plus sorafenib 400 mg PO once daily

Interventions: intervention 1: Dalantercept plus sorafenib
Intervention descriptions: intervention 1: Subcutaneous (SC) injection of dalantercept once every 3 weeks and oral sorafenib daily.

Protocol document:
Prot_SAP_001.pdf: 
Clinical Study Protocol      
 
 
 
 
 
 
 
 
 
 
 
Dalantercept (ACE-041) 
Study A041-05 
Revision Level: 02 
04 November 2016  
Acceleron Pharma Inc. 
Page 1 of 69 
CONFIDENTIAL 
 
CLINICAL STUDY PROTOCOL 
A Phase 1b, Open Label Study of Dalantercept plus Sorafenib in 
Patients with Advanced Hepatocellular Carcinoma 
 
 
 
 
    INVESTIGATIONAL PRODUCT: 
Dalantercept 
 
    PROTOCOL NUMBER: 
 A041-05 
 
 
SPONSOR: 
Acceleron Pharma Inc. 
 
128 Sidney Street 
 
Cambridge, MA 02139 USA 
 
 
Tel: 617-649-9200 
 
Fax: 617-649-9988 
 
   MEDICAL MONITOR:  
Matthew Sherman, MD 
 
 
Chief Medical Officer  
 
 
 
 
 
PROTOCOL DATE: 
08 November 2013 
 
AMENDMENT 01: 
23 April 2014 
 
AMENDMENT 02: 
04 November 2016 
 
 
 
 
 
 
 
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 (IRB)/Independent Ethics Committee (IEC).  Your acceptance of this document 
constitutes agreement that you will not disclose the information contained herein to others without written authorization from the 
sponsor. 


Clinical Study Protocol      
 
 
 
 
 
 
 
 
 
 
 
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Study A041-05 
Revision Level: 02 
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Page 2 of 69 
CONFIDENTIAL 
 
 
 
 
 
 
Signature Page 
 
Acceleron Pharma Approval 
 
 
 
 
 
 
 
 
 
 
Signature: 
 
 
 
 
 
Date: 
 
 
 
Name (print): 
 
 
 
 
 
 
 
 
 
Investigator Agreement: 
 
I have read the protocol and agree to conduct the study as outlined in the protocol.  The study 
will be conducted in accordance to current United States Food and Drug Administration 
(FDA) regulations, International Conference of Harmonization (ICH) Guidelines, Good 
Clinical Practices (GCP), the Declaration of Helsinki, and local ethical and legal 
requirements. 
 
 
 
Signature: 
 
 
 
Date: 
 
 
 
Name (print): 
 
 
 
 
 
 
 
 
 
 
 
 
Institution Name and Address: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Clinical Study Protocol      
 
 
 
 
 
 
 
 
 
 
 
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Study A041-05 
Revision Level: 02 
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Acceleron Pharma Inc. 
Page 3 of 69 
CONFIDENTIAL 
PROCEDURES IN CASE OF EMERGENCY 
Table 1: Emergency Contact Information 
Role in Study 
Name 
Contact Information 
Medical Monitor 
Matthew Sherman, MD 
Acceleron Pharma Inc. 
128 Sidney Street  
Cambridge, MA 02139 
Office Tel: 617-649-9282 
Cell Tel: 617-584-5023 
Fax: 617-649-9988 
Pharmacovigilance 
Drug Safety Hotline 
Covance Inc. 
206 Carnegie Center 
Princeton, NJ 08540  
Tel: 888-724-4908 
Fax: 888-887-8097 
 


Clinical Study Protocol      
 
 
 
 
 
 
 
 
 
 
 
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Study A041-05 
Revision Level: 02 
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CONFIDENTIAL 
1. 
PROTOCOL SYNOPSIS 
Name of Sponsor/Company: Acceleron Pharma Inc., 128 Sidney Street, Cambridge, MA 02139 
Name of Investigational Product: Dalantercept (also known as ACE-041) 
Name of Active Ingredient: Dalantercept is a recombinant fusion protein consisting of the 
extracellular domain (ECD) of human activin receptor-like kinase 1 (ALK1) linked to the Fc 
(hinge, CH2 and CH3 domains) portion of human immunoglobulin G1 (IgG1).   
Title of Study: A phase 1b, open label study of dalantercept plus sorafenib in patients with 
advanced hepatocellular carcinoma 
Study Center(s): Up to 20 centers  
Phase of Development: 1b 
Objectives: 
Primary: 
• Evaluate the safety and tolerability of dalantercept plus sorafenib in patients with 
advanced hepatocellular carcinoma (HCC) to determine the recommended phase 2 
dose level of dalantercept in combination with sorafenib  
Secondary: 
• Evaluate the pharmacokinetic (PK) profiles of dalantercept and sorafenib when used in 
combination 
• Evaluate the preliminary activity of dalantercept plus sorafenib in patients with 
advanced HCC as defined by response rates per RECIST v1.1, time to progression 
(TTP), progression free survival (PFS), disease control rate (DCR), and overall 
survival (OS)Explore the association of the expression of BMP9/10, ALK1 and/or 
other relevant pharmacodynamic (PD) markers in archived or recent tumor biopsy 
with tumor response and/or other assessments of clinical response 
• Explore association of serum pharmacodynamic (PD) biomarkers with assessments of 
response 
Study Design, Dosage and Administration:  
This is an open label, multi-center phase 1b study to evaluate the safety, tolerability, PK and PD, 
and preliminary activity of dalantercept plus sorafenib in patients with advanced HCC.   
The dose level of dalantercept for the first cohort will be 0.6 mg/kg administered subcutaneously 
(SC) every 3 weeks (Q3W) plus sorafenib 400 mg orally (PO) once daily (QD).  
Dose escalation:  
The dose escalation portion will include up to three planned cohorts of a minimum of 3 patients 


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Study A041-05 
Revision Level: 02 
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Acceleron Pharma Inc. 
Page 5 of 69 
CONFIDENTIAL 
each to determine the maximum tolerated dose (MTD) of the combination.  Patients may require 
dose modification(s) of dalantercept or sorafenib as indicated per protocol or prescribing 
information, respectively.   
At least three patients must complete the Day 22 visit at each dalantercept dose level with review 
of data through Day 22 by the Safety Review Team (SRT) prior to escalation to the next higher 
dose level.  The SRT may recommend adding additional patients, for a total of up to 6 patients, to 
the current dose level for further evaluation, escalating to an intermediate dose level or 
discontinuing escalation. 
The planned dose escalation for dalantercept and sorafenib is outlined below. 
Planned Starting Dose Regimen Per Cohort 
Dose Cohort 
Dalantercept 
Sorafenib 
Number of 
Patients 
1 
0.6 mg/kg Q3W 
400 mg QD 
3-6 
2 
0.9 mg/kg Q3W 
400 mg QD 
3-6 
3 
0.9 mg/kg Q3W 
400 mg BID 
3-6 
Expansion 
TBD 
TBD 
up to 20 
Total (planned) 
 
 
up to 38 
Expansion cohort:   
Once the MTD or maximum tested dose level has been determined by the SRT and Sponsor, up to 
a total of 20 patients may be enrolled at or below the MTD to further evaluate the safety, 
tolerability, and PK profile of dalantercept plus sorafenib.  The SRT will meet after a minimum of 
10 patients have been evaluated for a minimum of 21 days after the first dose of 
dalantercept/sorafenib (Day 22) to review safety data.  The SRT may recommend adding up to an 
additional 10 patients to the current dose level for further evaluation or to an intermediate dose 
level. 
Duration of Treatment:  
The total duration of participation in the study will vary between patients.  There will be a 14-day 
screening period, a treatment period lasting for as long as patients are eligible to remain on-study, 
a final visit approximately 1 month after the last dose of dalantercept and follow-up for 1 year 
from first dose for patient survival.   
If a patient has a positive anti-drug antibody (ADA) result at the last visit, the patient may be 
asked to return for additional ADA testing every three months, until a negative result is obtained 
or the result is considered to be stabilized.  


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Diagnosis and Main Criteria for Eligibility 
Inclusion Criteria: 
1.  Age ≥ 18 years. 
2.  Histologically confirmed (from either a recent or archival biopsy), locally advanced 
(no presence of distant metastases, unresectable and not eligible for transplant) or 
metastatic HCC. 
3.  Child-Pugh Score A (5-6) (Appendix 1). 
4.  At least one target lesion that has not been treated with local therapy and is measurable 
by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 (Appendix 2).  If there 
is a lesion within the field of local therapy and has shown ≥ 20% in size since post 
treatment assessment, this can be classified as a target lesion. 
5.  Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 (Appendix 3). 
6.  Life expectancy of at least 12 weeks.  
7.  Able to tolerate oral therapy. 
8.  Clinical laboratory values that meet the following criteria within 72 hours prior to study 
day 1: 
•  
Hematology (in the absence of hematopoietic growth factor support): 
o Absolute neutrophil count (ANC) ≥ 1,000/µL (≥ 1.0 x 109/L). 
o Hemoglobin ≥ 9 g/dL (≥ 90 g/L). 
o Platelet count ≥ 60,000 /µL (≥ 60 x 109/L) without transfusion support 
30 days prior to cycle 1 day 1 unless required for biopsy for study 
eligibility provided their pre-transfusion platelet count was at least 
60,000 /µL.  
• Creatinine ≤ 1.5 x ULN or measured or calculated creatinine clearance, using the 
Cockcroft-Gault formula, (Appendix 4) ≥ 60 mL/min. 
• Total bilirubin ≤ 1.5 x upper limit of normal (ULN).  Patients with known 
Gilbert’s Syndrome may have bilirubin levels up to 3.0 mg/dL. 
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 5 x ULN. 
• PT/INR ≤ 1.5 x ULN. 
• Serum albumin ≥ 2.8 g/dL (≥ 28 g/L). 
• Urinary protein < 2+ by urine dipstick or urinalysis. If ≥ 2+, then patient may be 
enrolled if 24-hour urine protein < 2 g/24hr. 
9.  Females of child bearing potential (defined as sexually mature women who have not 
undergone hysterectomy or bilateral oophorectomy, or are not naturally postmenopausal 
≥ 24 consecutive months) must have negative urine or blood pregnancy test prior to 
enrollment and use adequate birth control methods (abstinence, oral contraceptives, 


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Study A041-05 
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CONFIDENTIAL 
barrier method with spermicide, or surgical sterilization) during study participation.  
Males must agree to use a latex condom during any sexual contact with females of 
child-bearing potential while participating in the study and for 12 weeks following the 
last dose of dalantercept, even if he has undergone a successful vasectomy.  Patients must 
be counseled concerning measures to be used to prevent pregnancy and potential 
toxicities prior to the first dose of dalantercept. 
10.  Signed written informed consent. 
Exclusion Criteria: 
1.  Mixed tumor histology (e.g., hepatocellular carcinoma plus cholangiocarcinoma) or 
fibrolamellar variant tumors.  
2.  Prior solid organ or allogeneic bone marrow transplantation. 
3.  Prior systemic therapy for metastatic disease. 
4.  Adjuvant therapy < 6 months prior to study day 1.   
5.  Prior treatment with dalantercept or other agent targeting the ALK1 pathway. 
6.  Prior treatment with sorafenib or other RAF/VEGF targeted therapies. 
7.  Hepatic radiation, chemoembolization, and radiofrequency ablation < 4 weeks prior to 
study day 1.  
8.  Palliative radiation therapy to metastatic sites of disease < 2 weeks prior to study day 1.  
9.  Interferon therapy < 4 weeks prior to study day 1.  
10. Uncontrolled Hepatitis B despite appropriate therapy.  
11. Clinically significant pulmonary, endocrine, neurologic, hematologic, gastrointestinal 
(GI), autoimmune, psychiatric or genitourinary disease unrelated to HCC that in the 
judgment of the investigator should preclude treatment with dalantercept or sorafenib. 
12. Known HIV infection.  
13. Clinically significant cardiovascular risk including: 
• Ejection fraction (EF) ≤ 50%.  
• Significant history of congestive heart failure (CHF) defined as New York Heart 
Association (NYHA) class II-IV (Appendix 5). 
• Hospitalization for CHF (any NYHA class) within 6 months of study day 1.   
• Active coronary artery disease [e.g., myocardial infarction (MI), uncontrolled 
angina], peripheral vascular disease, cerebrovascular disease [e.g., transient 
ischemic attack (TIA), stroke], bypass surgery, angioplasty, or vascular stenting 
within 12 months prior to study day 1.  Worsening symptoms attributable to 
cardiac or vascular disease or new findings on cardiac evaluation (e.g. clinical, 
stress test, etc.) within 3 months prior to study day 1. 
• Known deep vein thrombosis (DVT) within 6 months of study day 1 (with the 


Clinical Study Protocol      
 
 
 
 
 
 
 
 
 
 
 
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Study A041-05 
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CONFIDENTIAL 
exception of portal vein thrombosis).  
• Significant arrhythmia or electrophysiologic disease including placement of 
implantable cardioverter defibrillator (ICD), atrial fibrillation with uncontrolled 
rate or prolonged QTc interval > 450 ms.  
• Uncontrolled hypertension defined as systolic blood pressure (BP) ≥ 150 mm Hg 
or diastolic BP ≥ 95 mm Hg.  Patients with a history of hypertension must be 
well-controlled (BP < 150/90 mmHg) upon study entry using a stable regimen of 
anti-hypertensive therapy. 
14. Clinically significant active pulmonary risk including pulmonary hypertension and 
pulmonary edema within 12 months of study day 1 or pulmonary embolism within 
6 months of study day 1. 
15. Known CNS metastasis. 
16. Known active GI bleeding, as evidenced by hematemesis, hematochezia, or melena 
within 3 months prior to study day 1 without evidence of resolution documented by 
endoscopy or colonoscopy. 
17. Known bleeding diathesis including clinically significant platelet disorders or active 
hemoptysis defined as bright red blood of ≥ 1/2 teaspoon (2.5 mL) in any 24 hour period 
within 6 months prior to study day 1.  For clinically significant epistaxis within 4 weeks 
prior to study day 1, no risk of further bleeding must be clearly documented. 
18. Known history of hereditary hemorrhagic telangiectasia (HHT).  
19. History of another primary cancer, with the exception of:  
•  Curatively resected non-melanoma skin cancer. 
•  Curatively treated cervical carcinoma in situ.  
•  Other primary solid tumor with no known active disease in the opinion of the 
investigator that will not affect patient outcome in the setting of current HCC 
diagnosis. 
20. Major surgery within 4 weeks prior to study day 1.  Patients must have recovered 
completely from any previous surgery prior to study day 1.   
21. Active infection requiring parenteral antibiotic therapy within 1 month prior to study day 
1 or systemic antibiotics within 2 weeks of study day 1.  
22. Anti-coagulation therapy (e.g., clopidogrel, dabigatran, warfarin, and heparin) or 
prophylactic aspirin > 81 mg within one week prior to study day 1.  Low dose aspirin 
(≤ 81 mg) for cardiovascular prophylaxis is permitted unless the investigator deems the 
patient is at a significant risk for bleeding. 
23. Concomitant treatment with potent CYP3A4 inducers (carbamazepine, dexamethasone, 
felbamate, omeprazole, phenobarbital, phenytoin, amobarbital, nevirapine, primidone, 
rifabutin, rifampin, St. John’s wort) is not allowed and should be discontinued 2 weeks 
prior to study day 1.  


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24. Persistent peripheral edema within 2 weeks prior to study day 1. 
25. History of recurrent ascites requiring paracentesis within 4 weeks of study day 1.  
26. History of severe (defined as ≥ grade 3, using the National Cancer Institute Common 
Toxicity Criteria for Adverse Events, version 4.0 [NCI-CTCAE] v4 (Appendix 6) current 
minor version) allergic or anaphylactic reaction or hypersensitivity to recombinant 
proteins or excipients (10 mM Tris buffered saline) in the investigational agent.   
27. Pregnant or lactating female patients.  
Assessments for Evaluation: 
Safety: Patient safety will be assessed by monitoring AEs using the NCI-CTCAE v4 current 
minor version, physical examinations, vital signs (including weight), clinical laboratory tests, 
ECHO, ECG and ADA testing.   
Preliminary Activity: Response to treatment with dalantercept plus sorafenib will be determined 
according to RECIST v1.1 evaluating response rates, time to progression (TTP), progression free 
survival (PFS), disease control rate (DCR), and overall survival (OS). Patients will be assessed for 
efficacy using data from tumor response assessments as well as evaluation of PD biomarkers in 
blood and tissue. 
Statistical Methods: 
Determination of Sample Size: There is no formal sample size calculation for this study.  A 
standard dose escalation of 3-6 patients will be implemented for dose escalation and up to 
20 patients may be enrolled in the expansion to further evaluate safety, tolerability, and the PK 
profile of this combination.  
The Safety Analysis Set (SAF) will be used for all safety analyses and will consist of all patients 
who received any study drug.   
The Pharmacokinetics (PK) population will consist of all patients who have received at least 
1 dose of dalantercept plus sorafenib and have sufficient PK samples collected and assayed. 
Primary Safety Analysis  
The safety analyses will be performed on the SAF population.  Adverse event incidence rates will 
be tabulated by System Organ Class and preferred term and without regard to causality.  The 
frequency of occurrence of overall toxicity, categorized by toxicity grades, will be summarized.  
Shift tables and change from baseline will be summarized by analyte for laboratory panels.  
Treatment-emergent laboratory findings will be summarized.  Change from baseline and shift 
tables may be presented for vital sign and ECG parameters. 
Interim Analysis  
There are no planned interim analyses. 


Clinical Study Protocol      
 
 
 
 
 
 
 
 
 
 
 
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CONFIDENTIAL 
2. 
SCHEDULE OF EVENTS 
Schedule of Events1 
 
Screening2 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 54 
Cycle 64 
Final 
Visit5 
Follow 
Up15 
C1D13 
C1D8 
C1D15 
C2D13 
C2D8 
C3D13 
C3D8 
C4D13 
C4D8 
C5D13 
C6D13 
Day -14 
Day 1 
Day 8 
(± 2d) 
Day 15 
(± 2d) 
Day 22 
(± 2d) 
Day 29 
(± 2d) 
Day 43 
(± 3d) 
Day 50 
(± 3d) 
Day 64 
(± 3d) 
Day 71 
(± 3d) 
Day 85 
(± 3d) 
Day 106 
(± 3d) 
Informed consent17 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor biopsy 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test 
 X7 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination12 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
 
Vital signs (including weight) 
X 
X 
X 
X 
X  
X 
X  
X 
X 
X 
X 
X  
X  
 
ECOG performance status 
X 
X 
 
 
 
 
X 
 
 
 
X 
 
X 
 
Hematology/serum chemistry8 
 X8 
X8 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Coagulation 
X8 
X8 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
 
Thyroid Function9 
 X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis and Urine Chemistry8 
 X8 
X8 
 
 
X 
 
X 
 
X 
 
 
X4 
X 
 
Alpha-fetoprotein (AFP) 
X 
X 
 
 
 
 
X 
 
 
 
X 
 
X 
 
PD blood biomarkers 
 
X 
 
 
X 
X 
X 
 
X 
 
X 
 
X 
 
PK blood sample collection16 
 
X16 
X 
X 
X 
X16 
X 
 
 
 
 
 
 
 
Anti-drug antibody (ADA) 
 
X 
 
 
 
 
X 
 
 
 
 
X4 
 X10 
X10 
ECHO scan6 
 X2 
 
 
 
 
 
 
 
X 
 
 
 
X6 
 
ECG (12-lead)6 
X 
 
 
 
 
 
 
 
X 
 
 
 
X6 
 
Tumor response assessment scan11 
 X2 
 
 
 
 
 
X 
 
 
 
X 
 
X5 
 
Monitoring of AEs and concomitant 
medications 
X13 
X14 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Dalantercept administration 
 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
 
 
Sorafenib administration  
 
Continuous daily dosing 
 
 
Survival Follow-up 
 
 
 
 
 
 
 
 
 
 
 
 
 
X15 
 
 
 


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1   All visit day windows should be determined relative to the date of the previous dose of dalantercept except for tumor assessments (see footnote 11).  Actual visit days (e.g., day 1, day 8, 
day 15) may be different than planned due to windows on visits and potential dosing delays. 
2   All screening procedures should be performed within 14 days prior to study day 1.  ECHO and tumor response assessment scans obtained for clinical purposes within 28 days prior to 
study day 1 may be used as the baseline image for this study and do not need to be repeated.   
3   Perform all assessments prior to dosing dalantercept plus sorafenib and review for potential dose modifications.  All AEs and abnormal laboratory or other findings that might require 
modification of dosing (see Section 11.5) should be reviewed prior to dosing to ensure that the patient is still eligible to receive dalantercept. Assessments performed on C1D1 prior to 
dosing will be considered baseline.   
4   If the patient has stable or responding disease at the end of 6 cycles of treatment, repeat the procedures performed for cycles 5 and 6 until the patient completes cycle 14 (C7D1=C5D1, 
C8D1=C6D1, etc.).  NOTE: after cycle 6, ADA and urinalysis only need to be repeated once every 4 cycles (C10D1, C14D1, etc.). If the patient has stable or responding disease at the 
end of 14 cycles of treatment, please refer to Section 3. Schedule of Events (Cycle ≥15) 
5   Patients who terminate from the study should complete the Final Visit.  The Final Visit should occur approximately 30 days after the last dose of dalantercept ± 10 days.  The tumor 
response assessment at the Final Visit should only be performed to assess progression if progression has not already been confirmed by a previous tumor response assessment scan.  
6   ECHO scans for ejection fraction and presence or absence of pericardial effusion unless additional testing is clinically indicated.  ECHO scans may be performed up to 5 days prior to a 
scheduled visit. A complete cardiac evaluation including ECG and ECHO should be performed if determined to be clinically necessary even if it is an unscheduled time point.  Cardiac 
evaluation should be included at the Final Visit for early termi nation patients if determined to be clinically necessary. 
7   Urine or blood pregnancy test required for patients of child bearing potential only. 
8   Baseline hematology, chemistry, coagulation and urinalysis may be collected up to 72 hours prior to dosing.  If the screening visit is within 72 hours prior to study day 1, hematology, 
chemistry, coagulation and urinalysis do not need to be repeated.  This includes the following:  
Hematology - complete blood count (CBC) with differential and reticulocyte count; CBC includes red blood cells (RBCs), white blood cells (WBCs), platelets, hemoglobin, hematocrit, 
mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), and mean corpuscular hemoglobin concentration (MCHC);  
Chemistry - albumin, alkaline phosphatase (ALP), ALT, AST, blood urea nitrogen (BUN), calcium, chloride, carbon dioxide (CO2), creatinine, glucose, lactate dehydrogenase (LDH), 
serum osmolality, phosphorus, potassium, sodium, total bilirubin, total protein, amylase, and lipase;  
Coagulation - PT, INR;  
Urine by urinalysis or dipstick analysis - pH, specific gravity, protein, glucose, ketones, blood, leukocyte esterase, and nitrite with microscopic examination if indicated;   
Urine Chemistry - osmolality and sodium.    
9   Thyroid function includes the following: free thyroxine (T4) and thyroid stimulating hormone (TSH). 
10 If the patient has a positive ADA result at their last assessment, the patient may be asked to return approximately every three months for additional testing, until a negative result is 
obtained or the result is considered stabilized. 
11 Tumor response assessment scans may be performed up to 5 days prior to a scheduled visit (except screening and final visit which have wider windows).  Tumor response assessment scans must 
be reviewed prior to dosing the next cycle of treatment.  Tumor response assessment scans should be performed every 6 weeks regardless of dalantercept or sorafenib dosing delays.  
 12 A full physical exam [skin (including telangiectasias), head, eyes, ears, nose, throat and neck, lymph nodes, cardiovascular, respiratory, gastrointestinal, musculoskeletal (including 
edema), and  neurological is required at screening, C1D1, C1D8, C2D1, C3D1, C4D1,C5D1,C6D1 and the final visit.  A targeted physical exam requiring assessment of the respiratory, 
cardiovascular and musculoskeletal (including edema) body systems is required at all other time points including beyond cycle 6.  If clinically indicated, additional assessment of other 
body systems should occur. 
13 Concomitant medications taken within 28 days prior to study day 1 will be collected. 
14 Adverse events will be collected after the first dose administration.  Non-serious AEs prior to dosing on study day 1 will be collected as medical history. 
15  All patients should be contacted every 3 months (± 2 weeks) for up to 1 year from the date of first dose for survival 
16  PK blood sample collection should be performed pre-dose for dalantercept and sorafenib at all time points.  In addition, PK blood samples should be collected between 1-3 hours and 4-6 hours 
post dalantercept and sorafenib dosing at C1D1 visit and between 1-3 hours and 4-6 hours post sorafenib dosing at C2D8 visit. 
17 Informed consent must be obtained within 28 days prior to C1D1 and prior to any study specific procedures. 


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3. 
SCHEDULE OF EVENTS (CYCLES ≥ 15) 
Schedule of Events1 
 
Cycle 152 
Cycle 162 
Final Visit4 
C15D13 
C16D13 
Day 295 
(± 3d) 
Day 316 
(± 3d) 
Physical examination5 
X 
 
X 
Vital signs (including weight) 
X 
X  
X  
Hematology/serum chemistry6 
X 
X 
X 
ECHO scan7 
 
 
X 
ECG (12-lead)7 
 
 
X 
ADA8 
X2 
 
X8 
Tumor response assessment scan9 
X2 
 
X4 
Alpha-fetoprotein (AFP) 
X2 
 
 
Monitoring of AEs and concomitant medications 
X 
X 
X 
Dalantercept administration 
X 
X 
 
Sorafenib administration 
Continuous daily dosing 
 
1 All visit day windows should be determined relative to the date of the previous dose of dalantercept except for tumor assessments (see footnotes 2 and 9).  Actual visit days (e.g., day 1, day 8, day 15) 
may be different than planned due to windows on visits and potential dosing delays. 
2 If the patient has stable or responding disease at the end of 14 cycles of treatment repeat, the procedures performed for cycles 15 and 16 until the patient is taken off study (C17D1=C15D1, 
C18D1=C16D1, etc.).  NOTE: after cycle 15, tumor assessments, ADA, and AFP only need to be repeated once every 4 cycles (C19D1, C23D1, C27D1, etc.).  
3 Perform all assessments prior to dosing dalantercept plus sorafenib and review for potential dose modifications.  All AEs and abnormal laboratory or other findings that might require modification of 
dosing (see Section 11.5) should be reviewed prior to dosing to ensure that the patient is still eligible to receive dalantercept.   
4 Patients who terminate from the study should complete the final visit.  The final visit should occur approximately 30 days after the last dose of dalantercept ± 10 days.  The tumor response assessment 
at the final visit should only be performed to assess progression if progression has not already been confirmed by a previous tumor response assessment scan.  
5 A full physical exam [skin (including telangiectasias), head, eyes, ears, nose, throat and neck, lymph nodes, cardiovascular, respiratory, gastrointestinal, musculoskeletal (including edema), and  
neurological is required at screening, C1D1, C1D8, C2D1, C3D1, C4D1,C5D1,C6D1 and the final visit.  A targeted physical exam requiring assessment of the respiratory, cardiovascular and 
musculoskeletal (including edema) body systems is required at all other time points including beyond cycle 6.  If clinically indicated, additional assessment of other body systems should occur. 
6  Hematology - complete blood count (CBC) with differential; CBC includes red blood cells (RBCs), white blood cells (WBCs), platelets, hemoglobin, hematocrit;  
  Chemistry - albumin, alkaline phosphatase (ALP), ALT, AST, blood urea nitrogen (BUN), chloride, carbon dioxide (CO2), creatinine, glucose, lactate dehydrogenase (LDH), potassium, total 
bilirubin, total protein, and sodium. Amylase and lipase only if clinically indicated. 
7 A complete cardiac evaluation including ECG and ECHO should be performed if determined to be clinically necessary even if it is an unscheduled time point.  Cardiac evaluation should be included 
at the Final Visit for early termination patients if determined to be clinically necessary.. 
8 If the patient has a positive ADA result at their last assessment, the patient may be asked to return approximately every three months for additional testing, until a negative result is obtained or the 
result is considered stabilized. 
9  Tumor response assessment scans may be performed up to 5 days prior to a scheduled visit (except final visit which have wider windows).  Tumor response assessment scans must be reviewed prior 
to dosing the next cycle of treatment.  Tumor response assessment scans should be performed every 12 weeks regardless of dalantercept or sorafenib dosing delays


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4. 
TABLE OF CONTENTS 
1. 
PROTOCOL SYNOPSIS .............................................................................................4 
2. 
SCHEDULE OF EVENTS .........................................................................................10 
3. 
SCHEDULE OF EVENTS (CYCLES ≥ 15) ..............................................................12 
4. 
TABLE OF CONTENTS ...........................................................................................13 
5. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................17 
6. 
ETHICS ......................................................................................................................21 
6.1. 
Institutional Review Board .........................................................................................21 
6.2. 
Ethical Conduct of the Study ......................................................................................21 
6.3. 
Patient Information and Consent ................................................................................21 
6.4. 
Patient Data Protection ...............................................................................................21 
7. 
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE .................22 
8. 
INTRODUCTION AND STUDY RATIONALE ......................................................23 
8.1. 
Overview of Hepatocellular Carcinoma .....................................................................24 
8.2. 
Summary of Nonclinical Studies ................................................................................25 
8.2.1. 
Pharmacology Studies ................................................................................................25 
8.2.2. 
Toxicology Studies .....................................................................................................25 
8.3. 
Summary of Clinical Experience ................................................................................26 
8.4. 
Potential Risks of Human Use of Dalantercept ..........................................................27 
8.5. 
Potential Risks of Human Use of Sorafenib ...............................................................29 
9. 
TRIAL OBJECTIVES ................................................................................................30 
10. 
OVERALL STUDY DESIGN AND PLAN ...............................................................31 
10.1. 
Study Design ...............................................................................................................31 
10.2. 
Discussion of Study Design ........................................................................................32 
10.3. 
Selection of Study Population ....................................................................................32 
10.3.1. 
Inclusion Criteria ........................................................................................................32 
10.3.2. 
Exclusion Criteria .......................................................................................................34 
10.4. 
Patient Withdrawal Criteria ........................................................................................36 
10.5. 
Patient Replacement Criteria ......................................................................................36 
11. 
TREATMENT OF PATIENTS ..................................................................................37 
11.1. 
Treatments Administered ............................................................................................37 


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11.1.1. 
Continuation of Treatment ..........................................................................................37 
11.1.2. 
Progressive Disease ....................................................................................................37 
11.2. 
Concomitant Medications ...........................................................................................37 
11.3. 
Randomization ............................................................................................................38 
11.4. 
Treatment Compliance ................................................................................................38 
11.5. 
Dose Modifications .....................................................................................................38 
11.5.1. 
Dose Modifications of Dalantercept ...........................................................................38 
11.5.2. 
Dose Modifications of Sorafenib ................................................................................42 
11.5.3. 
Fluid Management Therapy ........................................................................................42 
11.6. 
Safety Review Team (SRT) ........................................................................................43 
11.6.1. 
Dose-Limiting Toxicity (DLT) Definition .................................................................43 
11.6.2. 
Expansion Cohort .......................................................................................................44 
12. 
STUDY PROCEDURES ............................................................................................45 
12.1. 
Written Informed Consent ..........................................................................................45 
12.2. 
Safety Assessments .....................................................................................................45 
12.2.1. 
Clinical Laboratory Tests ...........................................................................................45 
12.2.2. 
Other Safety Assessments ...........................................................................................45 
12.3. 
Pharmacokinetic, Pharmacodynamic Assessments and Biopsies ...............................46 
12.3.1. 
Pharmacokinetic Assessments ....................................................................................46 
12.3.2. 
Pharmacodynamic Blood Biomarkers ........................................................................46 
12.3.3. 
Tumor Biopsy .............................................................................................................46 
12.4. 
Tumor Response Assessment .....................................................................................46 
12.4.1. 
Tumor Assessments ....................................................................................................46 
13. 
STUDY SCHEDULE .................................................................................................47 
13.1. 
Screening ....................................................................................................................47 
13.2. 
Dosing Days and Interim Visits ..................................................................................47 
13.2.1. 
Final Visit ...................................................................................................................48 
13.2.2. 
Follow-up ....................................................................................................................48 
13.3. 
Discontinuation of Study ............................................................................................49 
14. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................50 
14.1. 
Study Drug ..................................................................................................................50 
14.2. 
Study Drug Packaging and Labeling ..........................................................................50 


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14.3. 
Study Drug Storage .....................................................................................................50 
14.4. 
Study Drug Preparation ..............................................................................................50 
14.5. 
Administration ............................................................................................................50 
14.6. 
Study Drug Accountability .........................................................................................50 
14.7. 
Study Drug Handling and Disposal ............................................................................51 
15. 
ASSESSMENT OF SAFETY .....................................................................................52 
15.1. 
Adverse Event Definitions ..........................................................................................52 
15.2. 
Pregnancy and In Utero Drug Exposure .....................................................................53 
15.3. 
Severity .......................................................................................................................53 
15.4. 
Relationship to Study Drug ........................................................................................53 
15.5. 
Documentation and Methods of Reporting of Adverse Events by Investigator .........54 
15.5.1. 
Documentation of Serious Adverse Events ................................................................54 
15.6. 
Reporting Period and Monitoring of Patients with Adverse Events ...........................55 
15.7. 
Notification about Serious Adverse Events ................................................................55 
15.7.1. 
Safety Reporting to Health Authorities, Independent Ethics Committees 
Institutional Review Boards and Investigators ...........................................................55 
16. 
STATISTICS ..............................................................................................................57 
16.1. 
Analysis Populations ..................................................................................................57 
16.2. 
Statistical Plan ............................................................................................................57 
16.3. 
Safety Analysis ...........................................................................................................57 
16.4. 
Activity Analysis ........................................................................................................57 
16.5. 
Pharmacokinetics Analysis .........................................................................................57 
16.6. 
Determination of Sample Size ....................................................................................57 
16.7. 
Interim Analysis ..........................................................................................................58 
16.8. 
Deviation from Original Analysis Plan ......................................................................58 
17. 
SOURCE DOCUMENTATION AND INVESTIGATOR FILES .............................59 
17.1. 
Study Monitoring ........................................................................................................59 
17.2. 
Audits and Inspections ................................................................................................59 
18. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................59 
18.1. 
Data Quality Control and Quality Assurance .............................................................59 
18.1.1. 
Investigator Responsibility .........................................................................................59 
18.1.2. 
Protocol Modifications ...............................................................................................59 


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19. 
CONFIDENTIALITY ................................................................................................60 
20. 
PUBLICATION POLICY ..........................................................................................60 
21. 
PROTOCOL AMENDMENTS ..................................................................................60 
22. 
DATA HANDLING AND RECORDKEEPING .......................................................61 
22.1. 
Case Report Form Completion ...................................................................................61 
22.2. 
Retention of Records ..................................................................................................61 
23. 
REFERENCES ...........................................................................................................62 
24. 
APPENDICES ............................................................................................................64 
24.1. 
Appendix 1: Child-Pugh Classification of Severity of Liver Disease ........................64 
24.2. 
Appendix 2: RECIST v1.1 ..........................................................................................65 
24.3. 
Appendix 3: ECOG Performance Status ....................................................................66 
24.4. 
Appendix 4: Cockcroft-Gault formula for Estimation of Creatinine 
Clearance ....................................................................................................................67 
24.5. 
Appendix 5: New York Heart Association - Classification of Heart Failure .............68 
24.6. 
Appendix 6: National Cancer Institute (NCI) Common Terminology Criteria 
for Adverse Events (CTCAE) .....................................................................................69 
 


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5. 
 LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Term 
Definition 
ADA 
Anti-drug antibody 
AE 
Adverse event 
AFP 
Alpha-fetoprotein 
ALK1 
Activin receptor-like kinase1 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
AST 
Aspartate aminotransferase 
AUC 
Area under the curve 
BID 
Twice per day 
BMP 
Bone morphogenetic protein 
BP 
Blood pressure 
BUN 
Blood urea nitrogen 
C1D1 
Cycle 1 Day 1 
CBC 
Complete blood count 
CFR 
Code of federal regulations 
CHF 
Congestive heart failure 
CL/F 
Apparent clearance 
Cmax 
Maximum concentration 
CNS 
Central nervous system 
CO2 
Carbon dioxide 
CR 
Complete response 
CRA 
Clinical research associate 
CRF 
Case report form 
CRO 
Contract research organization 
CT scan 
Computed tomography scan 
DCE-MRI 
Dynamic contrast-enhanced magnetic resonance imaging 
DCR 
Disease control rate 


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Term 
Definition 
DLT 
Dose limiting toxicity 
DVT 
Deep venous thrombosis 
ECD 
Extracellular domain 
ECG 
Electrocardiogram 
ECHO 
Echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EF 
Ejection fraction 
FDA 
Food and Drug Administration 
FDG 
Fluorodeoxyglucose 
FGF 
Fibroblast growth factor 
GCP 
Good Clinical Practice 
GI 
Gastrointestinal 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
HED 
Human equivalent dose 
HHT 
Hereditary hemorrhagic telangiectasia 
HIV 
Human immunodeficiency virus 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Council on Harmonisation 
ICD 
Implantable cardioverter-defibrillator 
IRB 
Institutional Review Board 
LDH 
Lactate dehydrogenase 
LV 
Left ventricular 
LVEF 
Left ventricular ejection fraction 
MCH 
Mean corpuscular hemoglobin 
MCHC 
Mean corpuscular hemoglobin concentration 
MCV 
Mean corpuscular volume 
MI 
Myocardial infarction 
MRI 
Magnetic resonance imaging 


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Term 
Definition 
MTD 
Maximum tolerated dose 
NCI-CTCAE 
National Cancer Institute-Common Terminology Criteria for 
Adverse Events 
NOAEL 
No observed adverse effect level 
NSCLC 
Non-small cell lung cancer 
NYHA 
New York Heart Association 
OS 
Overall survival 
PD 
Pharmacodynamic 
PET-CT 
Positron emission tomography-computed tomography 
PFS 
Progression free survival 
PHI 
Protected health information 
PK 
Pharmacokinetic 
PO 
Orally 
PT/INR 
Prothrombin time/international normalized ratio 
Q3W 
Every 3 weeks 
QD 
Once daily 
RAF 
Rapidly Accelerated Fibrosarcoma 
RBC 
Red blood cell 
RCC 
Renal cell carcinoma 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
Serious adverse event 
SAF 
Safety Analysis Set 
SAP 
Statistical analysis plan 
SC 
Subcutaneous 
SCCHN 
Squamous cell carcinoma of the head and neck 
SD 
Stable disease 
SDV 
Source data verification 
SOC 
System organ class 
SRT 
Safety review team 
SUSAR 
Suspected, unexpected serious adverse reaction 


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Term 
Definition 
T1/2 
Elimination half- life 
T4 
Thyroxine 
TGF-β 
Transforming growth factor β 
TK 
Toxicokinetic 
TKI 
Tyrosine kinase inhibitor 
Tmax 
Time to maximum concentration 
TSH 
Thyroid stimulating hormone 
TTP 
Time to tumor progression 
ULN 
Upper limit of normal 
VEGF 
Vascular endothelial growth factor 
Vz/F 
Apparent volume of distribution 
WBC 
White blood cell 
 


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6. 
ETHICS 
6.1. 
Institutional Review Board 
The investigator will submit this protocol, any protocol modifications, and the patient informed 
consent form (ICF) to be used in this study to the appropriate institutional review board (IRB) for 
review and approval.  A letter confirming IRB approval of the protocol and ICF as well as a 
statement that the IRB is organized and operates according to Good Clinical Practice (GCP) and 
the applicable laws and regulations, must be forwarded to the sponsor prior to the enrollment of 
patients into the study.  A copy of the approved ICF will also be forwarded to the sponsor.  
Appropriate reports on the progress of the study will be made to the IRB and the sponsor by the 
principal investigator in accordance with applicable governmental regulations and in agreement 
with the policy established by the sponsor. 
6.2. 
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.   
6.3. 
Patient Information and Consent 
A signed ICF 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 
(CFR), 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 (or designee).   
6.4. 
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 case report form (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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7. 
INVESTIGATORS AND STUDY ADMINISTRATIVE 
STRUCTURE 
Acceleron Pharma is the sponsor for this trial.  The sponsor or designee will serve as the medical 
monitor for the study.  The sponsor or designee will manage the conduct of the trial and provide 
clinical monitoring, data management, biostatistics, and report writing.  Clinical research 
associates (CRAs) will monitor each study center on a periodic basis and verify source 
documentation for each patient.  The sponsor’s regulatory representative will be responsible for 
timely reporting of serious adverse events (SAEs) to United States regulatory authorities as 
required. 
Prior to trial initiation, the investigator will provide the sponsor with a fully executed and signed 
Food and Drug Administration (FDA) Form 1572 and a Financial Disclosure Form.  Financial 
Disclosure Forms will also be completed by all sub-investigators listed on the Form 1572 who 
will be involved directly in the treatment or evaluation of patients enrolled in this trial. 


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8. 
INTRODUCTION AND STUDY RATIONALE 
Dalantercept (also known as ACE-041) is a novel biologic anti-angiogenesis agent that inhibits 
signaling through activin receptor-like kinase 1 (ALK1).  ALK1 is a type I receptor in the 
transforming growth factor-β (TGF-β) superfamily that is selectively expressed on the surface of 
activated endothelial cells during development or in response to injury or disease.  ALK1 binds 
with high affinity to the ligands bone morphogenetic proteins (BMP) 9 and BMP10.  Signaling 
through ALK1 requires binding of ligand and simultaneous engagement of a type II receptor 
(ActRIIB, ActRIIA or BMPRII) which results in phosphorylation of the intracellular Smad 1/5/8 
cascade which activates proangiogenic transcription factors such as Id1 and Id3.1-3  Endoglin 
(CD105), an accessory receptor to ALK1 and may facilitate signaling by acting as a ligand 
chaperone but is not required for ALK1 signaling and has no known intracellular signaling 
activity.  Dalantercept is a recombinant fusion protein consisting of the extracellular domain 
(ECD) of human ALK1 linked to the Fc (hinge, CH2 and CH3 domains) portion of human 
immunoglobulin G1 (IgG1) and acts as a ligand trap by binding to BMP9 and BMP10. 
Multiple lines of evidence characterize the BMP9/ALK1/SMAD 1/5/8 pathway as playing a 
pivotal role in the maturation phase of angiogenesis which leads to the development of functional 
vasculature.4   The processes involved in vascular maturation include vessel stabilization via 
incorporation of pericytes and other stromal cells which are commonly downstream of the 
proliferative stage processes which are driven by vascular endothelial growth factor (VEGF) and 
other proangiogenic factors.  Furthermore, ALK1 expression is normally low in established 
blood vessels but elevated in neovascular endothelium during tumor growth or wound healing 
which is in contrast to the VEGF/VEGFR axis which is constitutively expressed in new and 
established blood vessels and in other tissues.5   In addition, the BMP9/BMP10/ALK1 pathway 
regulates development of lymphatic vessels6,  which has implications for metastatic spread of 
tumor cells through lymphatic vasculature.7  Thus targeting the ALK1 and VEGF pathways 
simultaneously may result in more effective angiogenic blockade and delay tumor progression in 
a variety of cancers.  
Dalantercept has demonstrated robust anti-angiogenic activity in tumor model studies, and has 
demonstrated preliminary anti-tumor activity in a completed Phase 1 study in advanced solid 
tumor patients.  In support of this therapeutic strategy, experiments were conducted in mouse 
xenograft renal cell carcinoma (RCC) models combining VEGF receptor tyrosine kinase 
inhibitor (TKI), sunitinib, with dalantercept which demonstrated additive tumor growth delay 
beyond either agent alone and curtailed sunitinib resistance.  In an ongoing randomized Phase 2 
study combining axitinib, a VEGF receptor TKI, with dalantercept in patients with advanced 
RCC, safety and preliminary activity of the combination have been observed in the first two 
cohorts of patients all of whom had prior VEGF and in some cases mammalian target of 
rapamycin (mTOR) directed therapies.  
In addition to demonstrating efficacy in RCC models, dalantercept was tested in an HCC 
xenograft model using the human BEL-7402 hepatocellular carcinoma cell line.  In mice with 
established BEL-7402 tumors, treatment with dalantercept as a single agent therapy 
demonstrated significant inhibition of tumor growth such that treated tumors were 25% the size 
of vehicle treated control mice (p ≤ 0.001) after 35 days of treatment.  The only targeted agent 


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currently approved for the treatment of advanced HCC is sorafenib, a VEGF receptor TKI and 
multi-kinase inhibitor.  Therapeutic responses to sorafenib are short lived and few options exist 
outside of a clinical trial. ALK1 has been detected in the vasculature of many human tumor types 
including hepatocellular carcinoma (HCC).8  BMP9 expression occurs predominantly in the 
liver.  Based upon immunohistochemical testing conducted at Acceleron Pharma and published 
results from the human protein atlas (www.proteinatlas.org), BMP9 expression appears elevated 
in HCC compared to unaffected liver in human and mouse tissue.  In addition to its role in ALK1 
mediated angiogenesis, BMP9 has been shown to induce epithelial to mesenchymal transition 
leading to cell migration and invasiveness in the HCC HepG2 model.9,10  Furthermore, HepG2 
cells produce BMP9 as an autocrine growth factor that directly supports the proliferative and 
survival capacity of these tumor cells.10     
In summary, the BMP9/ALK1/SMAD 1/5/8 pathway is a novel target in angiogenesis and may 
play an important role in the malignant progression of HCC.  Given the limited efficacy of 
sorafenib and growing incidence of HCC, there is a critical need for more effective therapies.  
We hypothesize dalantercept can be combined safely with sorafenib and will augment the 
therapeutic response to sorafenib in HCC by enhancing angiogenic blockade and inhibiting 
BMP9 induced cellular proliferation. 
8.1. 
Overview of Hepatocellular Carcinoma 
Hepatocellular carcinoma (HCC) most commonly develops in the setting of chronic liver disease 
and affects a diverse group of patients including those with hereditary and metabolic syndromes, 
auto-immune disease, viral hepatitis B and C and alcoholism.  In 2013, it is estimated there will 
be 30,640 new cases of HCC diagnosed and 21,670 deaths due to the disease in the US.11 
Moreover, HCC is the 5th leading cause of cancer mortality in US men.  Globally, HCC is the 7th 
leading cause of cancer and the 3rd leading cause of cancer mortality.12  
Historically, systemic treatment options for patients with advanced HCC remained limited to 
toxic chemotherapy regimens which were relatively ineffective in prolonging survival.  The most 
active chemotherapy agent in HCC is doxorubicin which is associated with a 4% response rate 
and survival of approximately 8 months.13  The exploration of growth factors in HCC has 
implicated VEGF and angiogenesis as a critical component in the malignant progression of the 
disease and has encouraged the development and investigation of novel anti-angiogenic agents.14  
Sorafenib is an oral multi-targeted tyrosine kinase inhibitor of VEGFR-1, 2, 3, PDGF, Raf, and 
other kinases.15  In the international phase 3 study entitled “Sorafenib HCC Assessment 
Randomized Protocol” (SHARP trial), 602 subjects with advanced HCC (Child-Pugh Class A 
cirrhosis) who had received no prior systemic therapy were randomized to sorafenib 400 mg 
twice daily or placebo.  The overall response to sorafenib was only 2%.  However, the disease 
control rate 43% vs. 32% and overall survival 10.7 vs. 7.9 months (hazard ratio: 0.69, p < 0.001) 
were significantly better with sorafenib compared to placebo.  The median TTP was 5.5 months 
with sorafenib and 2.8 months with placebo (p < 0.001).16 
Based upon the modest activity of sorafenib, several clinical studies have been conducted to 
explore additional VEGF and other targeted agents in comparison to sorafenib or after sorafenib 
failure.  Combinations with sorafenib have also been explored with epidermal growth factor 
receptor (EGFR) TKI, erlotinib.  To date, none of these approaches has resulted in meaningful 


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improvements in time to progression or overall survival compared to sorafenib monotherapy.17 
Importantly, there is growing interest in targeting the ALK1 pathway in HCC, as shown by 
recent or ongoing studies with TRC105 (anti-endoglin antibody) and PF-03446962 (anti-ALK1 
antibody).  There has been clinical activity reported in a completed phase I study with 
PF-03446962 in patients with HCC who were intolerant to or progressed on sorafenib.  Of the 24 
patients in this cohort the disease control rate at 12 weeks was 29% and median TTP was 3 
months.18  
8.2. 
Summary of Nonclinical Studies 
8.2.1. 
Pharmacology Studies 
Signaling through the ALK1 receptor is important in vascular development and pathological 
angiogenesis.  Activation of the ALK1 pathway helps regulate endothelial cell sprouting after 
initiation of angiogenesis by various growth factors.19  The data from studies designed to 
evaluate the inhibition of angiogenesis in response to known angiogenic growth factors such as 
vascular endothelial growth factor (VEGF) or fibroblast growth factor (FGF) demonstrate that 
blocking signaling through the ALK1 receptor by the use of a soluble receptor [dalantercept or 
RAP-041 (murine ortholog of dalantercept)] can inhibit angiogenesis initiated by a variety of 
factors.  In oncology models, RAP-041 has demonstrated inhibition of tumor progression in 
xenograft models of breast cancer (MDA-MB-231, MCF-7), lung cancer (Calu-6) and renal cell 
carcinoma Cell (A498) head and neck cancer (FaDu, CCL-30), as well as in genetic models of 
pancreatic cancer (RIP1 Tag2),20 breast cancer (mouse mammary tumor virus) and multiple 
myeloma (5T2MM).  Dalantercept has also shown efficacy as both a single agent and in 
combination with sunitinib using renal cell carcinoma xenograft models.  In the subcutaneously 
implanted A498 kidney carcinoma cell line dosing of dalantercept inhibited tumor growth similar 
to sunitinib treated mice.  Importantly combination therapy with both dalantercept and sunitinib 
inhibited tumor growth to a greater extent than either agent alone.  In a second xenograft model, 
subcutaneously implanted 786-O kidney adenocarcinoma cells were also treated with 
dalantercept alone or in combination with sunitinib.  In this model dalantercept did not 
demonstrate single agent efficacy.  In this model it is known that tumors treated with sunitinib 
develop rapidly develop resistance and continue to grow.  Combination therapy with dalantercept 
reduced tumor growth to a greater extent than single agent sunitinib and continued to show 
tumor inhibition even when the tumors treated with sunitinib alone began to develop resistance 
and progressed further.21  Overall, these data provide a rationale for the clinical development of 
dalantercept as an anti-angiogenic therapy in combination with VEGF pathway targeted therapy. 
8.2.2. 
Toxicology Studies 
Dalantercept has been evaluated in two species, rats and monkeys, for toxicological effects and 
pharmacokinetic (PK) properties following single and repeated subcutaneous (SC) injections. 
Single-dose SC injections up to a high dose of 100 mg/kg were well tolerated in both rats and 
monkeys.  Repeat-dose toxicity studies were conducted in both rats and monkeys for 3 months; 
both studies included male and female animals, a recovery period, and toxicokinetic (TK) 
evaluations.  Dalantercept dose levels were 10, 30 and 100 mg/kg in the rat study, and 3, 10 and 
30 mg/kg in the monkey study.  Dose administration was weekly, which ensured continuous 


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exposure to dalantercept, based on serum half-lives of approximately 3 days in rats and 
approximately 5 days in monkeys. 
Subcutaneous administration of dalantercept at ≥ 30 mg/kg resulted in edema and fluid in the 
thoracic and abdominal cavities that contributed to the death of moribund animals.  The most 
significant findings were observed in the heart.  In the 3-month rat study, heart weights were 
increased at ≥ 30 mg/kg, with histological findings of myocardial degeneration/necrosis, LV 
hypertrophy, atrial dilation and mononuclear cell infiltration.  These effects resolved by the end 
of the one month recovery period.  In the 3-month monkey study, increases in heart weight were 
observed at 30 mg/kg.  By echocardiogram (ECHO) there was increased LV mass in animals 
dosed at 10 and 30 mg/kg in addition to increased left atrial (LA) area at 30 mg/kg.  Both effects 
were substantially or completely reversed after one month of recovery.  The increased heart 
weight in monkeys did not correlate with any microscopic changes or increases in serum markers 
of heart muscle damage.  Electrocardiography (ECG) and ejection fraction (EF) were normal. 
The highest dose level in the 3-month rat toxicity study was 100 mg/kg with a no observed 
adverse effect level (NOAEL) of 10 mg/kg, while the highest dose level in the 3-month monkey 
toxicity study was 30 mg/kg with a NOAEL of 10 mg/kg.  The two NOAEL values corresponded 
to a human equivalent dose (HED) of 1.6 mg/kg (rat data) and 3.2 mg/kg (monkey data).   
8.3. 
Summary of Clinical Experience 
A Phase 1, open-label, multiple dose, dose escalation study (A041-01)22 of dalantercept has been 
conducted in patients with advanced solid tumors or relapsed/refractory multiple myeloma.  A 
total of 37 patients with advanced solid tumors were enrolled.  The first 25 patients were enrolled 
in 7 dose-escalating cohorts (0.1 to 4.8 mg/kg SC with a treatment cycle of 3 weeks), followed 
by 12 patients who were enrolled in an expansion cohort at a dose of 1.6 mg/kg (11 patients) or 
0.8 mg/kg (1 patient).  Based on the cumulative safety data observed at the 1.6 mg/kg and higher 
dose levels, the recommended phase 2 dose was selected as 1.2 mg/kg.   
Tumor response was evaluated using the Response Evaluation Criteria in Solid Tumors 
(RECIST) v1.1.  Patients must have had a baseline and at least one post-treatment tumor 
response assessment to be evaluable; 29 patients met these criteria for the analysis.   
Antitumor activity as evident by partial response or prolonged stable disease was observed in 
9 of 29 evaluable patients at dose levels ranging from 0.2 to 4.8 mg/kg; 1 patient with squamous 
cell carcinoma of the head and neck (SCCHN) involving the base of the tongue had a partial 
response by Cycle 9 at a dose level of 0.4 mg/kg, and 8 patients had prolonged periods of stable 
disease (SD) for at least 3 months after the first dose across a range of dose levels (0.2 to 
4.8 mg/kg), including 3 patients with non-small cell lung cancer (NSCLC), 1 patient each with 
neuroendocrine carcinoid, SCCHN, granulosa cell tumor, small bowel mucinous 
adenocarcinoma, and colorectal adenocarcinoma.  
Tumor metabolic activity was evaluated using fluorodeoxyglucose (FDG) positron emission 
tomography-computed tomography (PET-CT) scan.  Tumor metabolic activity decreased from 
baseline in 17 (63%) of 27 evaluable patients.  Seven out of the 8 patients with prolonged stable 
disease were evaluable for FDG PET-CT.  All 7 of these patients had a reduction in metabolic 


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activity.  In addition, the patient with a partial response had a 44% reduction in metabolic 
activity.   
Tumor blood flow was evaluated using dynamic contrast-enhanced magnetic resonance imaging 
(DCE-MRI).  Analysis by DCE-MRI found that 71% (10 out of 14) of patients with evaluable 
DCE-MRI data showed reduced tumor blood flow (Ktrans) at day 15 compared to baseline.  Nine 
out of 11 patients with evaluable data from both DCE-MRI and RECIST data showed reductions 
in Ktrans at day 15 compared to baseline.  Six patients with stable disease had evaluable 
DCE-MRI data and 5 had decreases in Ktrans.  Three patients with prolonged stable disease 
(≥ 3 months) were evaluable for DCE-MRI and all 3 patients had a reduction in Ktrans. 
A Phase 2, open-label study A041-03 of dalantercept is currently being conducted in patients 
with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN).  The first 
two patients received 80 mg however, due to the general co-morbidities of this heavily 
pre-treated patient population, the protocol was amended to a lower weight based dose of 
0.6 mg/kg.  Thirteen patients were enrolled at this dose level which demonstrated a generally 
safe toxicity profile.  A second amendment increased the dose level to 1.2 mg/kg and an 
additional 31 patients were enrolled.  In total, forty-six patients have been enrolled and 
enrollment has ended. The primary endpoint in this study is objective response rate.  
Study A041-04 is a two-part, multi-center, randomized, placebo-controlled, double-blind, phase 
2 study to evaluate safety, tolerability, efficacy, PK and PD of dalantercept in combination with 
axitinib in patients with advanced RCC.  The study will enroll up to 44 patients in the dose 
escalation, open label phase of the study (Part 1) and approximately 130 patients in the 
randomized, double-blind, placebo-controlled phase of the study (Part 2) for a total of up to 
approximately 174 patients.  The primary endpoint in this study is progression free survival.  
Two additional studies with dalantercept at 1.2 mg/kg as monotherapy in ovarian and 
endometrial cancer are ongoing under investigator-sponsored IND(s) conducted by the 
Gynecologic Oncology Group (GOG).  Acceleron is responsible for providing dalantercept drug 
product for these studies.  
8.4. 
Potential Risks of Human Use of Dalantercept 
Dalantercept is designed to bind to the protein ligands BMP9 and BMP10 to inhibit their 
interaction with the ALK1 receptor, thus blocking a cell signaling process involved in 
angiogenesis.  Effects on other organ systems, including erythropoiesis, may also be related to 
ALK1 or BMP9/10 inhibition. 
The most frequently observed AEs ( ≥ 10% patients) in the dalantercept monotherapy clinical trials 
(A041-01 and A041-03) as of September 10, 2013 were fatigue, peripheral edema, headache, anemia, 
dyspnea, nausea, constipation, vomiting, anorexia, pyrexia, abdominal pain, cough, dehydration, 
epistaxis, hyponatremia, telangiectasia, diarrhea, hypotension, insomnia, arthralgia, back pain, 
dizziness and pleural effusion.  
In the actively accruing two-part Phase 2 RCC A041-04 study with the combination of 
dalantercept plus axitinib, as of September 10, 2013, the most frequently observed AEs (≥ 20% 
of patients, n=10) regardless of causality, have included dysphonia, fatigue, diarrhea, arthralgia, 
constipation, hypertension, blood alkaline phosphatase increased, blood creatinine increased, 


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chills, cough, dizziness, headache, hyperkalemia, muscle spasm, nausea, thrombocytopenia and 
vomiting.  
In the completed Phase 1 study, serious AEs considered related to dalantercept included 
congestive heart failure (1 patient at 1.6 mg/kg and 1 patient at 4.8 mg/kg), fluid overload 
(2 patients at 1.6 mg/kg), fatigue (1 patient at 1.6 mg/kg), and left ventricular dysfunction 
(1 patient at 0.4 mg/kg).  Three of these patients (2 patients with CHF and 1 with LV 
dysfunction) had a prior history of coronary artery disease.  Although dyspnea and other signs 
typical of heart failure were reported, serial echocardiograms did not show a trend for worsening 
of LV ejection fraction in the majority of patients receiving dalantercept.  
In the Phase 2 SCCHN study (A041-03), dalantercept-related SAEs to date have included 
2 events of pleural effusion (1 patient at 0.6 mg/kg, 1 patient at 1.2 mg/kg), one event each of 
pulmonary edema and tracheal obstruction occurring in one patient receiving 1.2 mg/kg.   
In the GOG sponsored endometrial carcinoma study, serious adverse events possibly related to 
dalantercept reported to date include 2 patients with ascites, 1 patient each with   gastric 
hemorrhage, rectal fistula, pleural effusion, vomiting, anemia and dyspnea.  The gastric 
hemorrhage was a fatal event which occurred in a patient with a prior history of small bowel 
obstruction and radiation fibrosis.  
In the GOG sponsored ovarian carcinoma study, serious adverse events possibly related to 
dalantercept reported to date occurred in 1 patient and include hypokalemia, anorexia, 
dehydration, and creatinine increase.  
Across studies, peripheral edema and weight gain events have responded to diuretic therapy.  A 
possible explanation of these events may be the effect of dalantercept on capillary or lymphatic 
vessels which may lead to fluid leakage and result in fluid overload.  Serial ECHO data from the 
completed phase 1 and ongoing studies do not show a trend for a decline in LV ejection fraction 
in the majority of patients treated with dalantercept.   
In summary, the safety data to date suggest that patients with significant bleeding and/or 
cardiovascular risks should be excluded from participating in studies with dalantercept.  The 
volume-related events such as peripheral edema, weight gain, pleural effusion, and pulmonary 
edema, across the studies appear to be least common when dalantercept is administered at doses 
≤ 1.6 mg/kg. 
The effects of dalantercept on reproduction and development are not fully known.  Although no 
histopathological effects were seen in reproductive organs in 3-month toxicology studies in 
monkeys and rats, use of adequate birth control measures should be required in dalantercept 
studies and dalantercept should not be administered to pregnant or nursing women. 
As with all biologics, there is the potential for the development of anti-drug antibodies that can 
be associated with altered drug clearance and/or hypersensitivity reactions.  No specific anti-drug 
antibodies were detected in the Phase 1 study.  Anti-drug antibody formation should be 
monitored in selected clinical studies.   
A comprehensive review of dalantercept, as well as details regarding the information 
summarized above, is provided in the Investigator’s Brochure (IB).  The most recent version of 
the dalantercept IB should be reviewed prior to initiating the study. 


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8.5. 
Potential Risks of Human Use of Sorafenib 
The most common side effects observed in at least 20% of patients which were considered 
related to sorafenib include fatigue, weight loss, rash/desquamation, hand-foot skin reaction, 
alopecia, diarrhea, anorexia, nausea and abdominal pain.  For additional risks associated with 
patients taking sorafenib, please refer to the sorafenib prescribing information (see Nexavar® 
[sorafenib] prescribing information, Warnings and Precautions). 
 


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9. 
TRIAL OBJECTIVES  
Primary: 
• Evaluate the safety and tolerability of dalantercept plus sorafenib in patients with 
advanced hepatocellular carcinoma (HCC) to determine the recommended phase 2 
dose level of dalantercept in combination with sorafenib  
Secondary: 
• Evaluate the pharmacokinetic (PK) profiles of dalantercept and sorafenib when used 
in combination 
• Evaluate the preliminary activity of dalantercept plus sorafenib in patients with 
advanced HCC as defined by response rates per RECIST v1.1, time to progression 
(TTP), progression free survival (PFS), disease control rate (DCR), and overall 
survival (OS). Explore the association of the expression of BMP9/10, ALK1 and/or 
other relevant pharmacodynamic (PD) markers in archived or recent tumor biopsy 
with tumor response and/or other assessments of clinical response 
• Explore association of serum pharmacodynamic (PD) biomarkers with assessments of 
response 


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10. 
OVERALL STUDY DESIGN AND PLAN 
10.1. 
Study Design  
This is an open label, multi-center phase 1b study to evaluate the safety, tolerability, PK and PD, 
and preliminary activity of dalantercept plus sorafenib in patients with advanced HCC.   
The dose level of dalantercept for the first cohort will be 0.6 mg/kg administered subcutaneously 
(SC) every 3 weeks (Q3W) plus sorafenib 400 mg orally (PO) once daily (QD).   
Dose Escalation 
The dose escalation portion will include up to three planned cohorts of a minimum of 3 patients 
each to determine the maximum tolerated dose (MTD) of the combination.  Patients may require 
dose modification(s) of dalantercept or sorafenib as indicated per protocol or prescribing 
information, respectively.   
At least three patients must complete the Day 22 visit at each dalantercept dose level with review 
of data through Day 22 by the Safety Review Team (SRT) prior to escalation to the next higher 
dose level.  The SRT may recommend adding additional patients, for a total of up to 6 patients, 
to the current dose level for further evaluation, escalating to an intermediate dose level or 
discontinuing escalation.  The following general dose escalation rules will apply: 
1. Dalantercept starting dose level is 0.6 mg/kg in combination with sorafenib starting dose 
level of 400 mg QD. 
2. Dalantercept will be escalated to a maximum dose level of 0.9 mg/kg plus sorafenib 
400 mg QD. 
3. Once the maximum tolerated dose level of dalantercept is determined, sorafenib will be 
escalated to 400 mg BID. 
4. After the MTD level of the combination is determined in the dose escalation portion, an 
additional 10-20 patients will be added in the expansion portion.  
5. If the dalantercept starting dose level of 0.6 mg/kg is not tolerated, there will be one dose 
level de-escalation to 0.4 mg/kg. 
The planned dose escalation for dalantercept and sorafenib is outlined below in Table 2.  
Table 2: 
Planned Starting Dose Regimen Per Cohort 
Dose Cohort 
Dalantercept 
Sorafenib 
Number of 
Patients 
1 
0.6 mg/kg Q3W 
400 mg QD 
3-6 
2 
0.9 mg/kg Q3W 
400 mg QD 
3-6 
3 
0.9 mg/kg Q3W 
400 mg BID 
3-6 
Expansion 
TBD 
TBD 
up to 20 
Total (planned) 
 
 
up to 38 


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Expansion Cohort 
Once the MTD or maximum tested dose level has been determined by the SRT and Sponsor, up 
to a total of 20 patients may be enrolled at or below the MTD to further evaluate the safety, 
tolerability, and PK profile of dalantercept plus sorafenib.  The SRT will meet after a minimum 
of 10 patients have been evaluated for a minimum of 21 days after the first dose of 
dalantercept/sorafenib (Day 22) to review safety data.  The SRT may recommend adding up to 
an additional 10 patients to the current dose level for further evaluation or to an intermediate 
dose level. 
Duration of Treatment 
The total duration of participation in the study will vary for each patient.  There will be a 14-day 
screening period, a treatment period lasting for as long as patients are eligible to remain 
on-study, a final visit approximately 1 month after the last dose of dalantercept and follow-up for 
for 1 year from first dose for patient survival. 
If a patient has a positive anti-drug antibody (ADA) result at the last visit, the patient may be 
asked to return for additional ADA testing every three months, until a negative result is obtained 
or the result is considered to be stabilized. 
10.2. 
Discussion of Study Design 
Dalantercept is a novel anti-angiogenic agent that inhibits the BMP9/ALK1/Smad 1/5/8 
signaling cascade involved in blood vessel maturation and stabilization.  In addition to its role in 
angiogenesis, BMP9 may directly stimulate HCC cellular proliferation based on in vitro data. In 
an Acceleron mouse xenograft study using the human BEL-7402 HCC cell line, single agent 
therapy with dalantercept significantly inhibited tumor growth when dosed at 15 mg/kg three 
times per week for 5 weeks. Preclinical, Phase 1 and early Phase 2 clinical data support the 
development of dalantercept in combination with VEGF pathway inhibitors to maximize growth 
inhibition in tumors that are sensitive to anti-angiogenic agents.  Importantly, the dalantercept 
side effect profile to date is mostly non-overlapping with the toxicity profiles of VEGF TKI 
therapies including sorafenib. Ongoing studies targeting the ALK1 pathway in HCC are 
underway and support further development of combination approaches in this challenging and 
underserved disease.  Thus we propose to investigate the safety, tolerability, and PK profile of 
the novel combination of dalantercept with sorafenib, a VEGF and multi-kinase TKI, in the 
treatment of patients with newly diagnosed advanced HCC utilizing a dose escalation of 
sorafenib and dalantercept followed by an expansion.    
10.3. 
Selection of Study Population 
10.3.1. 
Inclusion Criteria 
1. Age ≥ 18 years. 
2.  Histologically confirmed (from either a recent or archival biopsy), locally advanced (no 
presence of distant metastases, unresectable and not eligible for transplant) or metastatic 
HCC. 
3.  Child-Pugh Score A (5-6) (Appendix 1). 


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4.  At least one target lesion that has not been treated with local therapy and is measurable 
by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 (Appendix 2).  If there 
is a lesion within the field of local therapy and has shown ≥ 20% in size since post 
treatment assessment, this can be classified as a target lesion. 
5.  Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 (Appendix 3). 
6.  Life expectancy of at least 12 weeks.  
7.  Able to tolerate oral therapy. 
8.  Clinical laboratory values that meet the following criteria within 72 hours prior to study 
day 1: 
•  Hematology (in the absence of hematopoietic growth factor support): 
o Absolute neutrophil count (ANC) ≥ 1,000/µL (≥ 1.0 x 109/L). 
o Hemoglobin ≥ 9 g/dL (≥ 90 g/L). 
o Platelet count ≥ 60,000 /µL (≥ 60 x 109/L) without transfusion support 
30 days prior to cycle 1 day 1 unless required for biopsy for study eligibility 
provided their pre-transfusion platelet count was at least 60,000 /µL.  
• Creatinine ≤ 1.5 x ULN or measured or calculated creatinine clearance, using the 
Cockcroft-Gault formula, (Appendix 4) ≥ 60 mL/min. 
• Total bilirubin ≤ 1.5 x upper limit of normal (ULN).  Patients with known 
Gilbert’s Syndrome may have bilirubin levels up to 3.0 mg/dL. 
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) 
≤ 5 x ULN. 
• PT/INR ≤ 1.5 x ULN. 
• Serum albumin ≥ 2.8 g/dL (≥ 28 g/L). 
• Urinary protein < 2+ by urine dipstick or urinalysis. If ≥ 2+, then patient may be 
enrolled if 24-hour urine protein < 2 g/24hr. 
9.  Females of child bearing potential (defined as sexually mature women who have not 
undergone hysterectomy or bilateral oophorectomy, or are not naturally postmenopausal 
≥ 24 consecutive months) must have negative urine or blood pregnancy test prior to 
enrollment and use adequate birth control methods (abstinence, oral contraceptives, 
barrier method with spermicide, or surgical sterilization) during study participation.  
Males must agree to use a latex condom during any sexual contact with females of 
child-bearing potential while participating in the study and for 12 weeks following the 
last dose of dalantercept, even if he has undergone a successful vasectomy.  Patients 
must be counseled concerning measures to be used to prevent pregnancy and potential 
toxicities prior to the first dose of dalantercept. 
10. Signed written informed consent. 
 


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10.3.2. 
Exclusion Criteria 
1. Mixed tumor histology (e.g. hepatocellular carcinoma plus cholangiocarcinoma) or 
fibrolamellar variant tumors.  
2. Prior solid organ or allogeneic bone marrow transplantation. 
3. Prior systemic therapy for metastatic disease. 
4. Adjuvant therapy < 6 months prior to study day 1.   
5. Prior treatment with dalantercept or other agent targeting the ALK1 pathway. 
6. Prior treatment with sorafenib or other RAF/VEGF targeted therapies. 
7. Hepatic radiation, chemoembolization, and radiofrequency ablation < 4 weeks prior to 
study day 1.  
8. Palliative radiation therapy to metastatic sites of disease < 2 weeks prior to study day 1.  
9. Interferon therapy < 4 weeks prior to study day 1.  
10. Uncontrolled Hepatitis B despite appropriate therapy.  
11. Clinically significant pulmonary, endocrine, neurologic, hematologic, gastrointestinal 
(GI), autoimmune, psychiatric or genitourinary disease unrelated to HCC that in the 
judgment of the investigator should preclude treatment with dalantercept or sorafenib. 
12. Known HIV infection.  
13. Clinically significant cardiovascular risk including: 
• Ejection fraction (EF) ≤ 50%.  
• Significant history of congestive heart failure (CHF) defined as New York Heart 
Association (NYHA) class II-IV (Appendix 5). 
• Hospitalization for CHF (any NYHA class) within 6 months of study day 1.   
• Active coronary artery disease [e.g., myocardial infarction (MI), uncontrolled 
angina], peripheral vascular disease, cerebrovascular disease [e.g., transient 
ischemic attack (TIA), stroke], bypass surgery, angioplasty, or vascular stenting 
within 12 months prior to study day 1.  Worsening symptoms attributable to 
cardiac or vascular disease or new findings on cardiac evaluation (e.g. clinical, 
stress test, etc.) within 3 months prior to study day 1. 
• Known deep vein thrombosis (DVT) within 6 months of study day 1 (with the 
exception of portal vein thrombosis).  
• Significant arrhythmia or electrophysiologic disease including placement of 
implantable cardioverter defibrillator (ICD), atrial fibrillation with uncontrolled 
rate or prolonged QTc interval > 450 ms.  
• Uncontrolled hypertension defined as systolic blood pressure (BP) ≥ 150 mm Hg 
or diastolic BP ≥ 95 mm Hg.  Patients with a history of hypertension must be 


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well-controlled (BP < 150/90 mmHg) upon study entry using a stable regimen of 
anti-hypertensive therapy. 
14. Clinically significant active pulmonary risk including pulmonary hypertension and 
pulmonary edema within 12 months of study day 1 or pulmonary embolism within 6 
months of study day 1. 
15. Known CNS metastasis. 
16. Known active GI bleeding, as evidenced by hematemesis, hematochezia, or melena 
within 3 months prior to study day 1 without evidence of resolution documented by 
endoscopy or colonoscopy. 
17. Known bleeding diathesis including clinically significant platelet disorders or active 
hemoptysis defined as bright red blood of ≥ 1/2 teaspoon (2.5 mL) in any 24 hour period 
within 6 months prior to study day 1.  For clinically significant epistaxis within 4 weeks 
prior to study day 1, no risk of further bleeding must be clearly documented. 
18. Known history of hereditary hemorrhagic telangiectasia (HHT).  
19. History of another primary cancer, with the exception of:  
• Curatively resected non-melanoma skin cancer. 
• Curatively treated cervical carcinoma in situ. 
• Other primary solid tumor with no known active disease in the opinion of the 
investigator that will not affect patient outcome in the setting of current HCC 
diagnosis. 
20. Major surgery within 4 weeks prior to study day 1.  Patients must have recovered 
completely from any previous surgery prior to study day 1.   
21. Active infection requiring parenteral antibiotic therapy within 1 month prior to study day 
1 or systemic antibiotics within 2 weeks of study day 1.  
22. Anti-coagulation therapy (e.g., clopidogrel, dabigatran, warfarin, and heparin) or  
prophylactic aspirin > 81 mg within one week prior to study day 1.  Low dose aspirin 
(≤ 81 mg) for cardiovascular prophylaxis is permitted unless the investigator deems the 
patient is at a significant risk for bleeding. 
23. Concomitant treatment with potent CYP3A4 inducers (carbamazepine, dexamethasone, 
felbamate, omeprazole, phenobarbital, phenytoin, amobarbital, nevirapine, primidone, 
rifabutin, rifampin, St. John’s wort) is not allowed and should be discontinued 2 weeks 
prior to study day 1.  
24. Persistent peripheral edema  within 2 weeks prior to study day 1. 
25. History of recurrent ascites requiring paracentesis within 4 weeks of study day 1.  
26. History of severe (defined as ≥ grade 3, using the National Cancer Institute Common 
Toxicity Criteria for Adverse Events, version 4.0 [NCI-CTCAE] v4 (Appendix 6) current 
minor version) allergic or anaphylactic reaction or hypersensitivity to recombinant 
proteins or excipients (10 mM Tris buffered saline) in the investigational agent.   


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27. Pregnant or lactating female patients.  
10.4. 
Patient Withdrawal Criteria 
Patients will be informed that they have the right to withdraw from study treatment or from the 
study at any time for any reason without prejudice to their medical care.   
Patients may be withdrawn from study treatment for any of the following reasons:  
• Patient’s request 
• Patient’s unwillingness or inability to comply with the protocol 
• Withdrawal of consent 
• Pregnancy 
• Progression of disease  
• Use of prohibited medications 
• Medical reason, at the discretion of the investigator and/or the medical monitor 
• At the discretion of the sponsor (i.e. discontinuation of the study) 
In addition, patients may be withdrawn from the study for any of the following reasons: 
• Death 
• Lost to follow-up 
• Withdrawal of consent 
• At the discretion of the sponsor (i.e. discontinuation of the study) 
The reasons for withdrawal must be recorded in the patient’s CRF.  The investigator must notify 
the sponsor, the medical monitor and the contract research organization (CRO) immediately 
when a patient has been discontinued/withdrawn due to an Adverse Event (AE).   
The investigator must notify the sponsor and the CRO when a patient has been 
discontinued/withdrawn for reasons unrelated to the study or study drug (i.e., withdrawn consent, 
lost to follow-up).  
10.5. 
Patient Replacement Criteria 
Patients who discontinue prematurely from the study for reasons unrelated to the study or 
dalantercept (e.g., withdrawn consent) and prior to C2D1 may be replaced at the Sponsor’s 
discretion as required for the study to meet its objectives.  Data from the patients who are 
replaced will continue to be evaluated for safety.  
 


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11. 
TREATMENT OF PATIENTS 
11.1. 
Treatments Administered 
Once a patient is assigned to a cohort, the appropriate dose of dalantercept will be administered 
on study day 1 with the starting dose of sorafenib. Subsequent dalantercept doses will be 
administered once every 3 weeks with safety follow-up visits after each dose as outlined in the 
Schedule of Events (Section 2).  Patients should be observed for a minimum of 30 minutes 
following treatment with dalantercept.   
Patients will administer daily dosing of sorafenib, dispensed as per prescribing information 
(see Nexavar® [sorafenib] prescribing information, Dosage and Administration).  
Dose reductions for dalantercept or sorafenib may be required (see Section 11.5, Dose 
Modifications).    
11.1.1. 
Continuation of Treatment 
11.1.2. 
Progressive Disease   
Accumulating evidence indicates that the emergence of objective responses to anti-angiogenesis 
agents may follow delayed kinetics of weeks or months, and may be preceded by initial apparent 
radiological progression.  It is thus reasonable, in the absence of clinical deterioration, to 
continue to treat these patients until radiologic progression is both confirmed and found to have 
worsened at a subsequent imaging evaluation.23 
The initial tumor response assessment for all patients will occur prior to the C3D1 dosing visit.  
The decision to treat a patient with additional cycles of sorafenib plus dalantercept will be based 
on tumor response evaluation performed every 2 treatment cycles, prior to Day 1 of the next 
cycle. After cycle 14, tumor response evaluation will be performed every 4 treatment cycles. 
Patients with PD per RECIST v1.1 should be managed as follows:  
• PD at the end of Cycle 2: At the discretion of the treating physician in consultation with 
the sponsor medical monitor, the patient may continue dosing with the combination in the 
absence of clinical progression and the lack of any new measurable disease.  
• PD at the end of Cycle 4 or later:  If there is worsening PD (e.g., increase in target 
lesions, increase in non-target lesions, development of new lesions) in comparison to the 
end of Cycle 2 imaging, treatment will be discontinued and the patient will complete the 
final visit and enter follow-up. 
11.2. 
Concomitant Medications 
During screening and throughout the study, patients may take stable doses of medications for 
chronic conditions that are not specifically excluded by the protocol (see Section 10.3.1, 
Inclusion Criteria and Section 10.3.2, Exclusion Criteria).  Concomitant medications will be 
documented at all study visits beginning at screening and will include all medications taken 
within 28 days prior to study day 1.  


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• During the course of the study, concurrent therapy with any new prescription 
medication or dosage may be administered at the discretion of the investigator based 
upon clinical need.  If a patient requires treatment with any new medications that are 
specifically excluded by the eligibility criteria (Section 10.3.1, 10.3.2) or the 
sorafenib prescribing label (e.g., therapeutic anticoagulation medication, strong 
CYP3A4/5 inhibitors, strong CYP3A4/5 inducers, and any anti-cancer treatment 
other than dalantercept or sorafenib), the patient will be discontinued from the study.  
These patients should complete the final visit procedures and enter the follow-up 
period of the study.  The investigator should consult the medical monitor regarding 
any questions about whether a new medication or the dosage of an existing 
medication would require the patient to discontinue from the study.  Note that 
treatment with diuretics is expected for some patients during this study and such use 
should not be used to determine grading of hypertension.   
11.3. 
Randomization 
This is an open-label dose escalation study that does not require randomization. 
11.4. 
Treatment Compliance 
Each dose of dalantercept will be administered by SC injection(s) at the clinical site by the study 
staff and will be documented in the study record.   
Daily dosing of sorafenib will be the responsibility of each patient.  Drug accountability will be 
performed at each study visit by the study staff and recorded in the patient’s study record.  
11.5. 
Dose Modifications 
11.5.1. 
Dose Modifications of Dalantercept 
Patients will continue to receive the same dose level of dalantercept as they were assigned at 
study entry unless a dose modification is required to manage AEs.  Patients who experience 
dalantercept related AEs may continue treatment with dalantercept, provided that the AE can be 
managed (see below).   
Table 3 describes the management of related AEs and required dose modifications for 
dalantercept.  For any AE, including AEs not specifically mentioned in the table below, the 
investigator may decide to delay dosing or modify the dose level of dalantercept based on their 
clinical judgment.  If possible, these decisions should be discussed with the sponsor medical 
monitor prior to implementation.  If more than 1 AE occurs that would require a dose 
modification, upon resolution of all AEs to baseline or grade 1, dalantercept should be reduced 
two dose levels, or the patient should discontinue treatment.  If a patient has a repeating AE or an 
AE of similar nature that would require a dose modification, the patient should be dose reduced 
to the next dose level or the patient should discontinue treatment depending upon the nature of 
the AE and patient status.  The guidelines for management of AEs described in Table 3 are 
applicable to all scheduled visits as well as any unscheduled visits.  Refer to Table 4, 
Dalantercept Dose Level Modifications, for dose level reductions. 


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A dose delay of up to 3 weeks for dalantercept will be allowed for all AEs as outlined in Table 3.  
Adverse events must resolve as outlined in Table 3 prior to further dosing.  If a dose is delayed, 
the patient should resume the study with the next scheduled dosing cycle. 
If administration of dalantercept cannot be resumed within 3 weeks after the scheduled start of 
the next treatment cycle, the patient must be discontinued from the study and should complete 
the Final Visit.  Exemptions may be considered for those patients who are determined by the 
investigator to have received clinical benefit from treatment. 
For individual patients judged by the investigator to be at an unacceptable risk, despite not 
meeting the protocol-defined conditions for a dose modification, the investigator should consult 
with the sponsor’s medical monitor to decide whether to continue dosing at the same dose level, 
reduce the dose level, or discontinue the patient’s treatment with dalantercept. 


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Table 3: 
Management of Adverse Events Related to Dalantercept 
Adverse Event or Abnormal Finding 
Action 
Dalantercept Dose Modification 
Weight/Peripheral Edema Eventsa – If there is weight gain due to fluid retention or edema follow the weight management guidelines below. If a weight event occurs that is related to ascites, follow management of ascites 
guidelines below. Weight gain due to improvement in health, is not considered an adverse event or abnormal finding.  
1. 
≥ 3 to < 5% increase in weight from baseline or  grade 
1 peripheral edema 
• 
Administer therapya as needed to maintain approximate baseline 
weight or to reduce edema 
• 
Hold dalantercept treatment until weight returns to baseline 
(< 3% increase) or edema resolves 
1. 
Upon normalization of weight or resolution of edema, 
dalantercept should be restarted at the same dose 
level. 
2. 
≥ 5 to < 10% increase in weight from baseline 
(Grade 1) or grade 2 peripheral edema 
2. 
Upon normalization of weight or resolution of edema, 
dalantercept should be reduced one dose level.  
3. 
≥ 10% increase in weight from baseline (≥ Grade 2) or 
grade 3 peripheral edema 
• 
Administer therapya as needed to maintain approximate baseline 
weight or to reduce edema  
• 
Hold dalantercept treatment until weight returns to baseline 
(< 3% increase) or edema resolves 
• 
A complete cardiac evaluation including ECG, ECHO and any 
applicable laboratory tests should be performed if determined to be 
clinically indicated. 
3. 
Upon normalization of weight or normalization of 
edema, dalantercept should be reduced two dose 
levels. 
Pulmonary Events 
1. 
A new onset of signs or symptoms of pulmonary 
edema (Grade 1).  Signs and symptoms include but 
are not limited to shortness of breath, coughing up 
blood, end-inspiratory crackles, etc. 
• 
Administer therapya as needed.   
• 
Hold dalantercept treatment until resolution of AE(s). 
 
1. 
Upon resolution of AE(s), dalantercept should be 
reduced one dose level.  
2. 
≥ Grade 2 pulmonary edema  
• 
Administer therapya as needed.   
• 
Hold dalantercept treatment until resolution of AE(s). 
• 
A complete cardiac evaluation including, ECG, ECHO and any 
applicable laboratory tests should be performed if determined to be 
clinically necessary. 
2. 
Upon resolution of AE(s), dalantercept should be 
reduced two dose levels. 
3. 
Grade 1 pleural effusion 
• 
Administer therapy as needed. 
3. 
Reduce dalantercept one dose level. 
4. 
≥ Grade 2 pleural effusion 
• 
Administer therapy as needed. 
• 
Hold dalantercept treatment until resolution of AE to ≤ Grade 1. 
4. 
Upon resolution of AE, dalantercept should be 
reduced two dose levels. 
Cardiovascular Events 
1. 
Grade 2 ejection fraction decreased 
• 
Administer therapy as needed. 
• 
Hold dalantercept treatment until resolution of AE(s) or 
improvement of EF > 50%. 
• 
A cardiac evaluation including ECHO should be performed prior to 
starting next cycle. 
1. 
Upon resolution of AE(s) or improvement of EF 
> 50% dalantercept should be reduced one dose level 
and continue to follow repeat ECHO if determined to 
be clinically necessary. 


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Adverse Event or Abnormal Finding 
Action 
Dalantercept Dose Modification 
2. 
Grade 2 pericardial effusion detected on imaging 
• 
Administer therapy as needed. 
• 
Hold dalantercept treatment and repeat ECHO in three weeks. 
2. 
 If stable or resolved on repeat ECHO, reduce 
dalantercept one dose level.  If worsened, discontinue 
dalantercept. 
3.      ≥ Grade 3 cardiovascular eventb including grade 3 
pericardial effusion detected on ECHO 
• 
Discontinue further dalantercept treatment. 
Other Events 
1. 
≥ Grade 2 bleeding event, with the exception of Grade 
2 epistaxis 
• 
Discontinue further dalantercept treatment. 
2. 
 Any other event ≥ Grade 3 with the exception of 
> Grade 3 amylase and/or lipase or Grade 3 
hyponatremia in the absence of clinical symptoms  
• 
Hold dalantercept treatment until resolution of AE(s). 
 
2. 
Upon resolution of AE(s) to grade 1 or baseline, 
dalantercept should be reduced one dose level. 
3.  Grade 2 ascites: symptomatic, medical intervention 
indicated 
• 
If first occurrence of ascites, proceed with paracentesis at the 
discretion of the investigator. 
3. 
Upon resolution to at least grade 1, continue current 
dose of dalantercept. 
• 
If second occurrence of ascites, proceed with paracentesis at 
investigator discretion. 
3. 
Upon resolution to at least grade 1, dalantercept 
should be reduced one dose level. 
• 
> 2 occurrences, proceed with paracentesis at investigator discretion. 
3. 
Upon resolution to at least grade 1, reduce 
dalantercept one dose level with each additional 
occurrence.   
4. 
 Grade 3 ascites 
 
• 
If first occurrence of ascites, proceed with paracentesis. 
4. 
Upon resolution to at least grade 1, reduce 
dalantercept one dose level.  
• 
If second occurrence of ascites, proceed with paracentesis. 
4. 
Upon resolution to at least grade 1, dalantercept 
should be reduced two dose levels. 
• 
> 2 occurrences, proceed with paracentesis. 
4. 
Discontinue further dalantercept treatment. 
a Investigators can administer fluid management therapy as described in Section 11.5.3   
b Note that treatment with diuretics is expected for some patients during this study and should not be used to determine grading of hypertension. 
 


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Patients are allowed up to 3 dose modifications of approximately 25% each (Table 4) due to 
AEs.   
Table 4: 
Dalantercept Dose Level Modifications1 
Dose Modificationa 
Cohort 1 
(mg/kg) 
Cohorts 2 and 3 
(mg/kg) 
Starting dose level 
0.6 mg/kg 
0.9 mg/kg 
First dose reduction level  
0.45 mg/kg 
0.65 mg/kg 
Second dose reduction level  
0.35 mg/kg 
0.50 mg/kg 
Third dose reduction level 
0.25 mg/kg 
0.40 mg/kg 
Fourth dose reduction level  
Discontinue dalantercept treatment 
a If the starting dose level is de-escalated to 0.4 mg/kg, the dose modification levels will be 0.3 mg/kg, 0.2 mg/kg 
and 0.15 mg/kg. 
11.5.2. 
Dose Modifications of Sorafenib 
Patients enrolled in cohort 1 and 2 may have their dose of sorafenib increased to 400 mg BID,   
after the sponsor and the principal investigator have conducted a complete review of the 
individual patient’s safety data through Day 43 and the first on-study tumor assessment is 
evaluated. 
Over the course of treatment and at the discretion of the investigator, management of some 
adverse events such as hypertension, venous or arterial thromboembolic events, hemorrhage, 
gastric perforation or fistula, and proteinuria may require temporary dose interruption or 
permanent discontinuation and/or dose reduction of sorafenib (see Nexavar® [sorafenib] 
prescribing information, Warnings and Precautions).  If dose reduction from 400 mg BID is 
required, the recommended reduced dose is 400 mg QD or QOD.  Please refer to the labeling 
guidelines on the management of sorafenib related hand-foot skin reaction.  
In the event of a Grade 3 or greater toxicity, if it is deemed at the investigator’s discretion to be 
related to sorafenib, then sorafenib may be held or dose reduced until resolution of the toxicity or 
return to Grade 1 or baseline in keeping with the current labeling guidelines. 
Patients who require permanent discontinuation of sorafenib due to an adverse event related only 
to sorafenib may continue to receive treatment with dalantercept.  If patients requiring 
discontinuation of sorafenib have received < 2 doses of dalantercept plus sorafenib, they may be 
replaced (see Section 10.5).  The patients remaining on dalantercept not in combination with 
sorafenib will continue to follow the regular schedule of events (Section 2). 
11.5.3. 
Fluid Management Therapy 
11.5.3.1. Diuretics  
Use of diuretics is allowed to maintain approximate baseline weight in the instance of weight 
gain related to fluid events as described in Table 3.  Note that treatment with diuretics is 
expected for some patients during this study and such use should not be used to determine 


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grading of hypertension.  For ascites events that are deemed to be related to dalantercept, follow 
Table 3 outlining management of ascites.  
11.6. 
Safety Review Team (SRT) 
11.6.1. 
Dose-Limiting Toxicity (DLT) Definition  
A DLT is defined as any of the following events that are considered possibly or probably related 
to dalantercept and occur within 21 days after the first dose of dalantercept/sorafenib (Day 22):   
• Recurrent Grade 3 ascites event in a single patient despite optimal management of 
first event 
• Pulmonary edema grade 2 or higher 
• Bleeding grade 2 or higher with the exception of grade 2 epistaxis 
• Non-hematologic adverse event grade 3 or higher with the exception of grade 3 or 
higher amylase, lipase or grade 3 hyponatremia without symptoms, and grade 3 
nausea, vomiting, or diarrhea in the absence of appropriate prophylaxis 
• Grade 3 thrombocytopenia with associated bleeding 
• Grade 4 anemia or thrombocytopenia 
• Grade 4 neutropenia with fever 
Safety and DLTs will be evaluated by the SRT.  The SRT, which is comprised of a minimum of 
one study investigator, a Sponsor medical monitor, and a clinical investigator not participating in 
this study, will review safety data including AEs and serious adverse events (SAEs), laboratory 
results (including hematology and chemistry), and vital signs data through the Day 22 visit to 
assess the safety of a dose level prior to dose escalation.   
After a minimum of 3 patients have been evaluated for a minimum of 21 days after the first dose 
of dalantercept/sorafenib (Day 22), the SRT will consider dose escalation to the next dose cohort 
or adding additional patients, for a total of up to 6 patients, to the current dose cohort based in 
part upon the following dose escalation criteria: 
• If there are no DLTs, dose escalation to the subsequent dose level may proceed. 
• If 1 patient at a dose level experiences a DLT, additional patients may be enrolled at 
the current dose level for a total of up to 6 patients in the cohort. 
▪ If there are no further DLTs in the additional patients, dose escalation to 
the next dose level may proceed. 
• If a DLT occurs in ≥ 2 patients in any dose cohort of 3-6 patients, no further dose 
escalation will occur and a previous or lower intermediate dose level will be defined 
as the MTD.  Patients enrolled in this dose level cohort may continue to receive 
additional doses of dalantercept plus sorafenib at an appropriate dose level as outlined 
in Table 2. 
 


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11.6.2. 
Expansion Cohort 
Once the MTD or maximum tested dose level has been determined by the SRT and Sponsor, up 
to a total of 20 patients may be enrolled at or below the MTD to further evaluate the safety, 
tolerability, and PK profile of dalantercept plus sorafenib.  The SRT will meet after a minimum 
of 10 patients have been evaluated for a minimum of 21 days after the first dose of 
dalantercept/sorafenib (Day 22) to review safety data.  The SRT may recommend adding up to 
an additional 10 patients to the current dose level for further evaluation or to an intermediate 
dose level. 
If 4 out of 10 patients in the expansion cohort experience a DLT at any time during the first 21 
days after the first dose of dalantercept/sorafenib (Day 22) further enrollment in that expansion 
cohort will be discontinued.  The SRT may decide to cease enrollment if fewer than 4 out of 10 
patients experience a DLT if the nature of the event(s) is deemed a significant risk to patients for 
that dose level.  The next lower or an intermediate dose level may be recommended to enroll up 
to an additional 10 patients for assessment of safety following the same stopping rules. 


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12. 
STUDY PROCEDURES 
Please refer to Section 2, Schedule of Events for the schedule of procedures required for each 
visit.   
12.1. 
Written Informed Consent 
Patients will be required to sign an IRB/Independent Ethics Committee (IEC)-approved ICF 
prior to any study related procedures, including screening evaluations. 
12.2. 
Safety Assessments  
12.2.1. 
Clinical Laboratory Tests 
• Chemistry: Albumin, alkaline phosphatase (ALP), ALT, AST, blood urea nitrogen 
(BUN), calcium, chloride, carbon dioxide (CO2), creatinine, glucose, lactate 
dehydrogenase (LDH), serum osmolality, phosphorus, potassium, sodium, total 
bilirubin, total protein, amylase, and lipase. 
• Hematology: Complete blood count (CBC) with differential and reticulocyte count; 
CBC includes red blood cells (RBCs), white blood cells (WBCs), platelets, 
hemoglobin, hematocrit, mean corpuscular volume (MCV), mean corpuscular 
hemoglobin (MCH), and mean corpuscular hemoglobin concentration (MCHC).  
• Coagulation: PT, INR  
• Thyroid Function: Free thyroxine (T4) and thyroid stimulating hormone (TSH). 
• Urine tests by dipstick or urinalysis: pH, specific gravity, protein, glucose, ketones, 
blood, leukocyte esterase, and nitrite with microscopic examination if indicated.  
Urine Chemistry to include osmolality and sodium. 
• Alpha-fetoprotein (AFP) 
12.2.2. 
Other Safety Assessments  
Specific details regarding any testing to be performed by a central laboratory for this study will 
be located in the Study Reference Guide. 
• Physical examination: Full exam [skin (including telangiectasias, head, eyes, ears, 
nose, throat and neck, lymph nodes, cardiovascular, respiratory, gastrointestinal, 
musculoskeletal (including edema), and neurological] required at screening, Cycle 1 
Day 1 (C1D1), C1D8, C2D1, C3D1, C4D1, C5D1, C6D1, and the final visit.  A 
targeted exam [respiratory, cardiovascular and musculoskeletal (including edema) 
body systems] is required at all other visits beyond cycle 6 unless additional 
assessments are clinically indicated.  Findings at screening will be recorded on the 
medical history form.  Findings after C1D1 dosing will be recorded as AEs. 
• Vital signs: Including height, weight, systolic and diastolic BP, heart rate.  Height 
will be collected at screening only.   


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• Cardiac function testing: 12-lead ECG and ECHO scan (Ejection Fraction and 
presence or absence of pericardial effusion). 
• Anti-drug antibody and neutralizing antibody testing: As indicated. 
12.3. 
Pharmacokinetic, Pharmacodynamic Assessments and Biopsies 
Specific details regarding these assessments will be located in the Study Reference Guide. 
12.3.1. 
Pharmacokinetic Assessments  
Blood will be collected as outlined in the Schedule of Events (Section 2) to assess serum levels 
of dalantercept and sorafenib. 
12.3.2. 
Pharmacodynamic Blood Biomarkers 
Blood will be collected as outlined in the Schedule of Events (Section 2) to assess blood levels of 
PD biomarkers.   
12.3.3. 
Tumor Biopsy 
Patients will provide a sample of recent or archived biopsy of tumor tissue.  These recent or 
archived biopsies will be analyzed for expression of BMP9/10, ALK1 and other relevant 
markers.  
12.4. 
Tumor Response Assessment 
12.4.1. 
Tumor Assessments 
CT or MRI scans will be read at the investigational site and treatment response and disease 
progression will be assessed using RECIST v1.1 (Appendix 2).  Using local investigator 
assessments, it should be determined that a patient has not progressed before the next cycle study 
treatment is given unless continued treatment through first radiographic progression is justified 
(see Section 11.1.2). 
 


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13. 
STUDY SCHEDULE 
Please refer to Section 2, Schedule of Events for the schedule of procedures required for each 
visit.  All visit day windows should be determined relative to the date of the previous dose of 
dalantercept.  Actual visit days (e.g., day 1, day 8, day 15) may be different than planned due to 
windows on visits and potential dosing delays.      
13.1. 
Screening  
Signature of the current IRB-approved ICF should occur within 28 days prior to study day 1 and 
prior to initiation of any study-specific screening procedures.   
• All screening procedures should be performed within 14 days prior to study day 1.  
Echocardiogram and tumor response assessment scans obtained for clinical purposes 
within 28 days prior to study day 1 may be used as the baseline image for this study 
and do not need to be repeated.   
• The urine or blood pregnancy test is only required for patients of child-bearing 
potential. 
• Archived or recent tumor tissue sample(s) should be sent as soon as possible to the 
designated tissue sample vendor.  
• Concomitant medications taken within 28 days prior to study day 1 will be 
documented in CRF. 
• Screen failure information will be maintained to document specific information, 
including but not limited to, reason for failure.  
13.2. 
Dosing Days and Interim Visits 
• All screening and study day 1 procedure results required to confirm eligibility must 
be obtained and reviewed prior to dalantercept and sorafenib administration.  Patient 
eligibility for inclusion/exclusion criteria must be confirmed from these results, as 
applicable.   
• Baseline hematology, chemistry, coagulation and urinalysis may be collected up to 72 
hours prior to dosing.  If the screening visit occurs within 72 hours of study day 1, the 
hematology, chemistry, coagulation and urinalysis testing do not need to be repeated.   
• Any non-serious AEs that occur prior to dalantercept and sorafenib dosing on study 
day 1 should be recorded in the medical history CRF. 
• All AEs that occur after dalantercept and sorafenib dosing on study day 1 should be 
recorded in the AE CRF. 
• On subsequent dosing days, all AEs and abnormal laboratory or other findings that 
might require modification of dosing (see Section 11.5) should be reviewed prior to 
dosing to ensure that the patient is still eligible to receive additional doses of 
dalantercept or sorafenib.   


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• ECHO scans may be performed up to 5 days prior to a scheduled visit. 
• Tumor response assessment scans may be performed up to 5 days prior to a scheduled 
visit (except screening and final visit which have wider windows).  Tumor response 
assessment scans must be reviewed prior to dosing the next cycle of treatment.  
Tumor response assessment scans should be performed every 6 weeks regardless of 
dalantercept or sorafenib dosing delays.  
• PK blood sample collection should be performed pre-dose for dalantercept and 
sorafenib at all time points.  In addition, PK blood samples should be collected 
between 1-3 hours and 4-6 hours post dalantercept and sorafenib dosing at C1D1 and 
between 1-3 hours and 4-6 hours post sorafenib dosing at C2D8 visit.  
• The schedule of events outlines procedures through C6D1.  If patients have stable or 
responding disease and are able to continue beyond 6 cycles of treatment, the 
procedures outlined for cycle 5 and 6 should be repeated until the patient completes 
cycle 14 (i.e. C7D1=C5D1, C8D1=C6D1, etc.).  The only exception is that after cycle 
6, ADA and urinalysis are required once every 4 cycles instead of once every 2 cycles 
(i.e., C10D1, C14D1, etc.). 
• If the patient has stable or responding disease at the end of 14 cycles of treatment, the 
procedures outlined for cycles 15 and 16 should be repeated until the patient comes 
off study. Note: ADA collection continues on a schedule of once every 4 cycles 
starting at cycle 6 and tumor response scans only need to be repeated once every 4 
cycles (C19D1, C23D1, C27D1 etc.) starting at cycle 15. 
13.2.1. 
Final Visit 
• The final visit should occur when a patient discontinues from the study within 30 
days after the last dose of dalantercept (± 10 days). 
• The tumor response assessment scan does not need to be repeated at the final visit to 
assess progression if progression of disease was confirmed by a previous tumor 
response assessment scan. 
• If the patient has a positive ADA result at their last assessment, the patient may be 
asked to return approximately every 3 months for additional testing until a negative 
result is obtained, or the result is considered stabilized. 
13.2.2. 
Follow-up 
• After the final visit, patients will be contacted by phone or other appropriate method 
of communication approximately every 3 months (±2 weeks) for up to 1 year from 
date of first dose for survival.   
• Patients may also be asked to return to the clinic approximately once every 3 months 
for tumor response assessment scans if progression of disease has not previously been 
documented and/or every 3 months for additional ADA testing until a negative/stable 
result is obtained. 


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13.3. 
Discontinuation of Study 
The sponsor may terminate this study or a dose level after consultation with the investigator, the 
SRT, or at any time for safety or administrative reasons.  The sponsor will terminate the study if 
the occurrence of SAEs or other findings suggests unacceptable risk to the health of the patients.  


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14. 
STUDY DRUG MATERIALS AND MANAGEMENT 
14.1. 
Study Drug 
Dalantercept is a recombinant fusion protein consisting of the extracellular domain (ECD) of 
human activin receptor-like kinase 1 (ALK1) linked to the Fc (hinge, CH2 and CH3 domains) 
portion of human immunoglobulin G1 (IgG1).     
14.2. 
Study Drug Packaging and Labeling 
Dalantercept is supplied as a frozen liquid formulation at a concentration of 50 mg/mL in 10 mM 
Tris buffered saline (pH 7.5 ± 0.5) in 2 mL clear glass vials containing 1 mL of dalantercept.   
Please refer to the Nexavar® (sorafenib) prescribing information, Dosage and Administration, for 
how sorafenib is supplied.  
14.3. 
Study Drug Storage 
Dalantercept should be stored at  -65°C. 
Sorafenib should be stored at 25°C (77°F) in a dry place; excursions permitted to 15-30°C 
(59-86°F). 
14.4. 
Study Drug Preparation 
Please refer to the Study Reference Guide for detailed dalantercept drug handling, 
administration, and storage instructions.   
There is no preparation needed for sorafenib. 
14.5. 
Administration 
Dalantercept is to be administered by SC injection.  Each injection will not exceed 1.5 mL; 
multiple injections may be required to administer the required dose.  Each injection should be 
administered in alternating patterns in the upper and lower extremity regions. Please refer to the 
Study Reference Guide for detailed dalantercept drug handling, administration, and storage 
instructions.   
Sorafenib is to be administered PO and is available in a 200 mg tablet formulation.  Please refer 
to the Nexavar® (sorafenib) prescribing information, Dosage and Administration, for additional 
sorafenib administration information. 
14.6. 
Study Drug Accountability 
Accountability for dalantercept and sorafenib 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 dalantercept received, to whom it was dispensed (patient-by-patient 
accounting), and accounts of any dalantercept accidentally or deliberately destroyed or returned.  


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When possible all vials of dalantercept, both used and unused, should be saved for drug 
accountability purposes.  The used vials may be discarded, per the institution’s standard practice, 
after drug accountability assessment has been completed by the monitor.  If this method of drug 
accountability does not follow the institution’s standard practice, then the plans for performing 
accurate drug accountability should be documented and followed per institution.  The 
investigational site must maintain accurate records documenting sorafenib accountability. 
14.7. 
Study Drug Handling and Disposal 
Please refer to the Study Reference Guide for detailed dalantercept drug handling, 
administration, storage, and disposal instructions.   
Please refer to the prescribing information for Nexavar® (sorafenib), How Supplied/Storage and 
Handling for detailed drug handling, administration, storage, and disposal instructions. 


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15. 
ASSESSMENT OF SAFETY 
15.1. 
Adverse Event Definitions 
Adverse Event 
An AE is any untoward medical occurrence in a patient or clinical investigation patient 
administered a study drug, which does not necessarily have a causal relationship with this 
treatment.  An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of the study drug 
whether or not it is considered related to the study drug.  
Abnormal laboratory and other abnormal investigational findings (i.e., physical exam, ECG) 
should not be reported as AEs unless they are associated with clinical signs and symptoms, lead 
to treatment discontinuation or are otherwise considered clinically relevant by the investigator.  
In cases of surgical or diagnostic procedures, the condition/illness leading to such a procedure is 
considered as the AE rather than the procedure itself.  In case of a fatality, the cause of death is 
considered as the AE, and the death is considered as its outcome. 
Unexpected Adverse Events 
An unexpected AE is an AE that is not described in nature or severity in the IB. 
 
Events Not to Be Considered as Adverse Events 
Pre-existing medical conditions/signs/symptoms present before the screening period that do not 
worsen in severity or frequency during the study are defined as baseline medical conditions, and 
are not to be considered AEs. 
Serious Adverse Event 
A SAE is any AE, occurring at any dose level/regimen 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; however 
a hospitalization for an elective procedure will not be considered a SAE.  
• 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 


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home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, 
or the development of drug dependency or drug abuse.   
Events Not to Be Considered as Serious Adverse Events 
Elective hospitalizations to administer or to simplify study treatment or procedures are not 
considered as SAEs.  
15.2. 
Pregnancy and In Utero Drug Exposure 
The investigator will attempt to collect pregnancy information if a female patient or a male 
patient’s female partner becomes pregnant while the patient is participating in this study.  The 
pregnancy information will be recorded on the appropriate form and must be submitted to the 
sponsor within 2 weeks of learning of the pregnancy.  The patient or partner will be followed for 
the outcome of the pregnancy.  Information on the status of the mother and child will be 
forwarded to the sponsor or designee.  Generally, follow-up will be no longer than 6 to 8 weeks 
following the estimated delivery date.  Any premature termination of the pregnancy will be 
reported. 
15.3. 
Severity 
Investigators must evaluate the severity/intensity of AEs according to the NCI-CTCAE v4 
current minor version, preferentially using the graded scales.  If a particular AE’s 
severity/intensity is not specifically graded, the investigator should apply the general guidelines 
for determination of Grade 1 through Grade 5 as listed in the NCI-CTCAE v4 current minor 
version, cover page (reproduced below), using their best medical judgment: 
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living (preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc.). 
Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care activities of daily living 
(bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not 
bedridden). 
Grade 4: Life-threatening consequences; urgent intervention indicated. 
Grade 5: Death related to AE. 
15.4. 
Relationship to Study Drug 
Investigators must also assess the causal relationship of each AE to dalantercept and sorafenib.  
Factors for the assessment of causal relationship include, but are not limited to, temporal 
relationship between the AE and the administration of dalantercept or sorafenib, known side 
effects of dalantercept or sorafenib, medical history, concomitant therapy, course of the 
underlying disease and pertinent study procedures.  


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Probably: 
A causal relationship is clinically/biologically highly plausible and there is a 
plausible time sequence between onset of the AE and administration of 
dalantercept or sorafenib and there is a reasonable response on withdrawal. 
Possibly: 
A causal relationship is clinically/biologically plausible and there is a plausible 
time sequence between onset of the AE and administration of dalantercept or 
sorafenib. 
Unlikely: 
A causal relationship is improbable and another documented cause of the AE is 
most plausible.   
Not Related: A causal relationship can be definitively excluded and another documented cause 
of the AE is most plausible. 
15.5. 
Documentation and Methods of Reporting of Adverse Events by 
Investigator 
Patients will be evaluated and questioned generally for AEs during the course of the study, 
starting at the signing of the informed consent.  All non-serious AEs occurring after signing of 
the ICF until a patient is dosed on C1D1 are to be documented on the medical history CRF.  All 
AEs occurring after the C1D1 dose through 30 days after the last study drug administration (final 
visit) are to be documented on the AE CRF.   
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 changes in laboratory assessments, or other 
clinical findings as described in Section 15.1, are considered AEs and must be recorded on the 
AE CRF.  AEs are to be followed for resolution as described in Section 15.6.  
It is important that each AE report include a description of the event, duration (onset and 
resolution dates), severity, relationship with dalantercept, relationship with sorafenib, any other 
potential causal factors, any treatment given or other action taken (including dose modification 
or discontinuation of dalantercept or sorafenib) and outcome.  In addition, SAEs should be 
identified and the appropriate seriousness criteria documented.  Adverse events categorized as 
SAEs must also be documented using an SAE Report Form as described in Section 15.5.1. 
Specific guidance can be found in the CRF Completion Guidelines provided by the sponsor or 
designee.  
15.5.1. 
Documentation of Serious Adverse Events 
All SAEs that occur after the first study drug administration on C1D1 until 30 days (final visit) 
after the last study drug administration are to be documented on the AE CRF.  SAEs should not 
be reported for patients who are considered screen failures unless the event is deemed due to a 
protocol required procedure.  For all SAEs, an SAE form must be completed with as much 
information as possible and submitted within the time frame described in Section 15.7 
(Notification about Serious Adverse Events).   
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. 


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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. 
15.6. 
Reporting Period and Monitoring of Patients with Adverse Events 
All patients who took at least one dose of study drug should complete the final visit procedures.  
All AEs will be followed until clinical database lock (or stabilization/resolution if it occurs 
before database lock).  All SAEs will undergo active follow-up until resolved or the event 
becomes chronic or stable.  Follow-up data for SAEs obtained after clinical database lock will be 
incorporated into the dalantercept safety database. 
15.7. 
Notification about Serious Adverse Events 
If an SAE occurs during the reporting period, the investigator must immediately (i.e. within a 
maximum 24 hours after becoming aware of the event) inform the sponsor via the CRO by 
telephone, by fax or by e-mail. 
All written reports should be transmitted using the study specific SAE Report Form, which must 
be completed by the investigator following specific completion instructions.  Names, addresses, 
telephone and fax numbers for SAE reporting are located on the SAE Report Form and in the 
completion instructions provided in the Study Reference Manual.  When an SAE (or follow-up 
information) is reported by telephone, a written report must be sent immediately thereafter by fax 
or e-mail.  Reporting procedures and timelines for follow-up information are the same as for the 
initially reported SAE.  
Relevant pages from the CRF may be provided in parallel (i.e., medical history, concomitant 
therapy).  In all cases, the information provided in the SAE Report Form must be consistent with 
the data that are recorded in the corresponding sections of the CRF. 
The investigator/reporter must respond to any request for follow-up information or to any 
question the sponsor or designee may have on the SAE within the same timelines as described 
for initial reports.  This is necessary to permit a prompt assessment of the event by the sponsor 
and (as applicable) to allow the sponsor to meet regulatory timelines associated with expedited 
reporting obligations. 
Requests for follow-up will usually be made by the responsible CRA or Medical Monitor, or in 
exceptional circumstances by the Acceleron or CRO Pharmacovigilance representative who may 
contact the investigator directly to obtain clarification on a particularly critical event. 
15.7.1. 
Safety Reporting to Health Authorities, Independent Ethics Committees 
Institutional Review Boards and Investigators 
The sponsor will send appropriate safety notifications to Health Authorities in accordance with 
applicable laws and regulations. 
The investigator must comply with any applicable site-specific requirements related to the 
reporting of SAEs involving his/her patients to the IEC/IRB that approved the study. 


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In accordance with ICH/GCP guidelines, the sponsor will inform the investigator of “findings 
that could adversely affect the safety of patients, impact the conduct of the study, or alter the 
IRB’s approval/favorable opinion to continue the study.”  
The sponsor will inform the investigator of AEs that are both serious and unexpected and are 
considered to be related to dalantercept (“suspected unexpected serious adverse reactions” or 
SUSARs).  The investigator should place copies of these Safety Reports in the Investigator Site 
File.  National regulations with regard to Safety Report notifications to investigators will be 
followed. 
When specifically required by regulations and guidelines, the sponsor will provide appropriate 
Safety Reports directly to each site who is responsible for notifying their IRB and will maintain 
records of these notifications.  When direct reporting by the sponsor is not clearly defined by 
national or site-specific regulations, the investigator will be responsible for promptly notifying 
the concerned IRB of any Safety Reports and for filing copies of all related correspondence in 
the Investigator Site File. 
For studies covered by the European Union Clinical Trials Directive 2001/20/EC, the sponsor’s 
responsibilities regarding the reporting of SAEs/SUSARs will be carried out in accordance with 
that Directive and with the related Detailed Guidances. 
 


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16. 
STATISTICS 
16.1. 
Analysis Populations 
The Safety Analysis Set (SAF) will be used for all safety analyses and will consist of all patients 
who received any study drug.   
The Pharmacokinetics (PK) population will consist of all patients who have received at least 1 
dose of dalantercept plus sorafenib and have sufficient PK samples collected and assayed.  
16.2. 
Statistical Plan 
Details regarding the final data analysis will be discussed in a separate Statistical Analysis Plan 
(SAP). 
16.3. 
Safety Analysis 
The safety analyses will be performed on the SAF population.  Adverse event incidence rates 
will be tabulated by System Organ Class and preferred term and without regard to causality.  The 
frequency of occurrence of overall toxicity, categorized by toxicity grades, will be summarized.  
Shift tables and change from baseline will be summarized by analyte for laboratory panels.  
Treatment-emergent laboratory findings will be summarized.  Change from baseline and shift 
tables may be presented for vital sign and ECG parameters.   
16.4. 
Activity Analysis  
Response to treatment with dalantercept plus sorafenib will be determined according to RECIST 
v1.1 (Appendix 2) evaluating response rates, time to progression (TTP), progression free 
survival (PFS), disease control rate (DCR), and overall survival (OS).  Patients will be assessed 
for efficacy using data from tumor response assessments as well as evaluation of PD biomarkers 
in tissue and blood. 
16.5. 
Pharmacokinetics Analysis 
PK parameters, including but not limited to AUC, maximum concentration (Cmax), time to 
maximum concentration (tmax), elimination half-life (t½), apparent clearance (CL/F), and volume 
of distribution (Vz/F) will be assessed.  Additional analyses to explore the exposure/safety 
relationship of this combination may be performed.  For all PK analysis, the PK population will 
be used. 
16.6. 
Determination of Sample Size  
There is no formal sample size calculation for this study.  A standard dose escalation of 3-6 
patients will be implemented for dose escalation and up to 20 patients may be enrolled in the 
expansion to further evaluate safety, tolerability, and PK profile of the combination of 
dalantercept and sorafenib based on clinical considerations.    


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16.7. 
Interim Analysis 
There are no planned interim analyses. 
16.8. 
Deviation from Original Analysis Plan 
A formal SAP for the analysis and presentation of data from this study will be prepared before 
database lock.  Deviations from the statistical analyses outlined in this protocol will be indicated 
in this plan; any further modifications will be noted in the final clinical study report. 


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17. 
SOURCE DOCUMENTATION AND INVESTIGATOR FILES 
17.1. 
Study Monitoring 
The CRA 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 sites and their facilities.  During 
these visits, CRFs and other data related to the study will be reviewed and any discrepancies or 
omissions will be resolved.  The CRA will be given access to study relevant source documents 
(including medical records) for purposes of source data verification (SDV). 
17.2. 
Audits and Inspections 
The investigators and clinical sites will permit trial-related monitoring, audits, IRB review, and 
regulatory inspections as requested by FDA and the sponsor or designee.  In addition to CRFs, 
the clinical site will permit direct access to source data/documents (i.e., original medical records, 
laboratory reports, hospital documents, progress reports, signed ICFs, etc.).  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. 
18. 
QUALITY CONTROL AND QUALITY ASSURANCE 
18.1. 
Data Quality Control and Quality Assurance 
18.1.1. 
Investigator Responsibility 
The investigator is responsible for ensuring the study is conducted according to the protocol, 
CFRs, GCP, and applicable regulatory requirements.  The investigator’s responsibilities are 
outlined in these documents and must include the responsibility to obtain a signed informed 
consent prior to patient participation in the study. 
18.1.2. 
Protocol Modifications 
The investigator should not modify the protocol without agreement from the sponsor and prior 
review or approval by the IRB, unless an emergency situation requires protocol modification to 
ensure the safety of patients.  Any deviations from the protocol should be documented by the 
investigator or designee.  


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19. 
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 
authorities 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.  The patient’s medical information will only be released 
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 authorities, other 
investigators, corporate partners, or consultants as required. 
20. 
PUBLICATION POLICY 
All information concerning dalantercept 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 
persons involved in the study that need such information to assist in conducting the study, and 
then only on like terms of confidentiality and non-use. 
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 dalantercept, 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. 
21. 
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. 
In the event that the protocol needs to be modified immediately to eliminate an apparent hazard 
to a patient, the sponsor will implement the protocol change and subsequently amend the 
protocol and notify the regulatory authorities and/or the IRB, as appropriate. 
 


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22. 
DATA HANDLING AND RECORDKEEPING 
22.1. 
Case Report Form Completion 
Case report forms will be completed for each enrolled 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. 
22.2. 
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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23. 
REFERENCES 
1. Shi Y, Massague J. Mechanisms of TGF-beta signaling from cell membrane to the nucleus. 
Cell 2003;113:685-700. 
2. Brown MA, Zhao Q, Baker KA, et al. Crystal structure of BMP-9 and functional interactions 
with pro-region and receptors. J Biol Chem 2005;280:25111-8. 
3. David L, Mallet C, Keramidas M, et al. Bone morphogenetic protein-9 is a circulating 
vascular quiescence factor. Circ Res 2008;102:914-22. 
4. Oh SP, Seki T, Goss KA, et al. Activin receptor-like kinase 1 modulates transforming growth 
factor-beta 1 signaling in the regulation of angiogenesis. Proc Natl Acad Sci U S A 
2000;97:2626-31. 
5. Roodhart JM, Langenberg MH, Witteveen E, Voest EE. The molecular basis of class side 
effects due to treatment with inhibitors of the VEGF/VEGFR pathway. Curr Clin Pharmacol 
2008;3:132-43. 
6. Niessen K, Zhang G, Ridgway JB, Chen H, Yan M. ALK1 signaling regulates early postnatal 
lymphatic vessel development. Blood 2010;115:1654-61. 
7. Duong T, Koopman P, Francois M. Tumor lymphangiogenesis as a potential therapeutic 
target. J Oncol 2012;2012:204946. 
8. Hu-Lowe DD, Chen E, Zhang L, et al. Targeting activin receptor-like kinase 1 inhibits 
angiogenesis and tumorigenesis through a mechanism of action complementary to anti-VEGF 
therapies. Cancer Res 2011;71:1362-73. 
9. Qi Li XG, Honglei Weng, Shahrouz Ghafoory, Yan Liu, Teng Feng, Johanna Dzieran, Li Li, 
Iryna Iikavets, Marianna Kruithof- de Julio, Stefan Munker, Alexander Marx, Albrecht Piiper, 
Eduardo Augusto Alonso, Norbert Gretz, Chunfang Gao, Stefan Wölfl, Steven Dooley, Katja 
Breitkopf-Heinlein. BMP-9 induces EMT in hepatocellular carcinoma cells. Immunofl uorescent 
staining against BMP-9 (green) and E-cadherin (red) of a hepatocellular carcinoma section from 
TNF /cmyc bitransgenic mouse. Cancer Sci 2013 2013. 
10. Herrera B, Garcia-Alvaro M, Cruz S, et al. BMP9 is a proliferative and survival factor for 
human hepatocellular carcinoma cells. PLoS One 2013;8:e69535. 
11. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin 2012;62:10-29. 
12. Yang JD, Roberts LR. Hepatocellular carcinoma: A global view. Nat Rev Gastroenterol 
Hepatol 2010;7:448-58. 
13. Gish RG, Porta C, Lazar L, et al. Phase III randomized controlled trial comparing the 
survival of patients with unresectable hepatocellular carcinoma treated with nolatrexed or 
doxorubicin. J Clin Oncol 2007;25:3069-75. 
14. Zhu AX. Development of sorafenib and other molecularly targeted agents in hepatocellular 
carcinoma. Cancer 2008;112:250-9. 
15. Sampat KR, O'Neil B. Antiangiogenic therapies for advanced hepatocellular carcinoma. 
Oncologist 2013;18:430-8. 


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16. Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N 
Engl J Med 2008;359:378-90. 
17. Abou-Alfa GK, Venook AP. The antiangiogenic ceiling in hepatocellular carcinoma: does it 
exist and has it been reached? Lancet Oncol 2013;14:e283-8. 
18. Simonelli M ZP, Thomas M et al. . Phase I study of PF-03446962 (anti-ALK-1 mAb) in 
hepatocellular carcinoma (HCC). 2013. 
19. van Meeteren LA, Thorikay M, Bergqvist S, et al. Anti-human activin receptor-like kinase 1 
(ALK1) antibody attenuates bone morphogenetic protein 9 (BMP9)-induced ALK1 signaling and 
interferes with endothelial cell sprouting. J Biol Chem 2012;287:18551-61. 
20. Cunha SI, Pardali E, Thorikay M, et al. Genetic and pharmacological targeting of activin 
receptor-like kinase 1 impairs tumor growth and angiogenesis. J Exp Med 2010;207:85-100, 
S1-5. 
21. Wang X SN, Bhasin MK, Bahamon B, Zhan L, Signoretti S, Alsop D, Atkins MD, Pearsall, 
RS, Mier JW, Kumar R, Bhatt R. ALK1-Fc (ACE-041) Enhance VEGF Pathway Inhibition in 
Renal Cell Carcinoma. . In: AACR Annual Meeting 2012; 2012. 
22. Bendell JC, Gordon MS, Hurwitz HI, et al. Safety, pharmacokinetics, pharmacodynamics, 
and antitumor activity of dalantercept, an activin receptor-like kinase-1 ligand trap, in patients 
with advanced cancer. Clin Cancer Res 2014;20:480-9. 
23. Rosen MA, Schnall MD. Dynamic contrast-enhanced magnetic resonance imaging for 
assessing tumor vascularity and vascular effects of targeted therapies in renal cell carcinoma. 
Clin Cancer Res 2007;13:770s-6s. 
24. Child CG, Turcotte JG. Surgery and portal hypertension. Major Probl Clin Surg 1964;1:1-85. 
25. Pugh RN, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R. Transection of the 
oesophagus for bleeding oesophageal varices. Br J Surg 1973;60:646-9. 
26. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:228-47. 
27. Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern 
Cooperative Oncology Group. Am J Clin Oncol 1982;5:649-55. 
28. Gault MH, Longerich LL, Harnett JD, Wesolowski C. Predicting glomerular function from 
adjusted serum creatinine. Nephron 1992;62:249-56. 
29.  (American Heart Association Classes of Heart Failure.  Accessed at 
http://www.heart.org/HEARTORG/Conditions/HeartFailure/AboutHeartFailure/Classes-of-
Heart-Failure_UCM_306328_Article.jsp. 2011. 
 
 


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24. 
APPENDICES 
24.1. 
Appendix 1: Child-Pugh Classification of Severity of Liver Disease 
Parameter 
Points Assigned 
1 
2 
3 
Ascites 
Absent 
Slight 
Moderate 
Bilirubin (mg/dL) 
< 2 
2 to 3 
> 3 
Albumin (g/dL) 
> 3.5 
2.8 to 3.5 
< 2.8 
Prothrombin Time: 
seconds above control 
1 to 3 
INR: < 1.7 
4 to 6 
INR: 1.7 to 2.3 
> 6 
INR: > 2.3 
Encephalopathy 
None 
Grade 1 or 2 
Grade 3 or 4 
Total score of 5 to 6 is considered Grade A (well-compensated disease); 7 to 9 is Grade B 
(significant functional compromise); and 10 to 15 is Grade C (decompensated disease).24- 25  
 


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24.2. 
Appendix 2: RECIST v1.1 
RECIST Criteria-Response Evaluation26 
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 normalization of 
tumor 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 tumor 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). 
Please refer to the Study Reference Guide for details on RECIST v1.1. 


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24.3. 
Appendix 3: 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.27 
 
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 self-care but unable to carry out any work activities.  Up 
and about more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking 
hours 
4 
Completely disabled. Cannot carry on any self-care.  Totally confined to bed or chair 
5 
Dead 


Clinical Study Protocol      
 
 
 
 
 
 
 
 
 
 
 
Dalantercept (ACE-041) 
Study A041-05 
Revision Level: 02 
04 November 2016  
Acceleron Pharma Inc. 
Page 67 of 69 
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24.4. 
Appendix 4: Cockcroft-Gault formula for Estimation of Creatinine 
Clearance   
eCcr = (140 – Age) x Mass (kg) x (0.85 if Female) 
 
 
 
    72 x Serum Creatinine (mg/dL)  
Reference28 


Clinical Study Protocol      
 
 
 
 
 
 
 
 
 
 
 
Dalantercept (ACE-041) 
Study A041-05 
Revision Level: 02 
04 November 2016  
Acceleron Pharma Inc. 
Page 68 of 69 
CONFIDENTIAL 
24.5. 
Appendix 5: New York Heart Association - Classification of Heart 
Failure 
Class 1 – Class 1 heart failure – patients with cardiac disease but resulting in no limitation of 
physical activity.  Ordinary physical activity does not cause undue fatigue, palpitation, dyspnea 
or anginal pain.  
Class 2 – Class 2 heart failure – patients with cardiac disease resulting in slight limitation of 
physical activity.  They are comfortable at rest.  Ordinary physical activity results in fatigue, 
palpitation, dyspnea or anginal pain.  
Class 3 – Class 3 heart failure – patients with cardiac disease resulting in marked limitation of 
physical activity.  They are comfortable at rest.  Less than ordinary activity causes fatigue, 
palpitation, dyspnea or anginal pain.  
Class 4 – Class 4 heart failure – patients with cardiac disease resulting in inability to carry on 
any physical activity without discomfort.  Symptoms of heart failure or the anginal syndrome 
may be present even at rest.  If any physical activity is undertaken, discomfort increases.  
Reference29 
 


Clinical Study Protocol      
 
 
 
 
 
 
 
 
 
 
 
Dalantercept (ACE-041) 
Study A041-05 
Revision Level: 02 
04 November 2016  
Acceleron Pharma Inc. 
Page 69 of 69 
CONFIDENTIAL 
24.6. 
Appendix 6: National Cancer Institute (NCI) Common Terminology 
Criteria for Adverse Events (CTCAE)  
 
See http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE