Clinical trial NCT01264705
Conditions: Hepatocellular Carcinoma Liver Cancer
Keywords: Cirrhosis GI Cancer Hepatitis Oncology
Sponsor: University of Texas Southwestern Medical Center
Start date: 2011-01-01; Completion date: 2018-04-01
Enrollment: 47 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This is a non-randomized, open-label, single-institution phase I/II therapeutic trial of bavituximab and sorafenib in patients with advanced hepatocellular carcinoma (HCC). This study will be activated at the UT Southwestern Medical Center, comprised of The Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Hospitals-St. Paul and Parkland Memorial Hospital System. Advanced HCC is defined as disease that is not amenable to surgical resection or orthotopic liver transplantation or is metastatic in nature.

Detailed description:
The investigators are looking for men or women aged 18 years or older with hepatocellular carcinoma not suitable for surgical resection or hepatic transplantation. Prior locoregional therapy including but not limited to transarterial chemoembolization (TACE), radiofrequency ablation (RFA) or ethanol injection is allowed as long as the treatment was 4 weeks previous. Patients must be Child-Pugh A with no previous treatment with sorafenib or other vascular endothelial growth factor (VEGF) inhibitors.

Arms: arm 1: Cohort 1: Participants were administered Bavituximab:0.3 mg/kg weekly Sorafenib: 400mg PO twice daily arm 2: Cohort 2: Participants were administered Bavituximab:1.0 mg/kg weekly Sorafenib: 400mg PO twice daily arm 3: Cohort 3: Participants were administered Bavituximab:3.0 mg/kg weekly Sorafenib: 400mg PO twice daily
Interventions: intervention 1: bavituximab (0.3 mg/kg) and sorafenib intervention 2: bavituximab (1.0 mg/kg ) and sorafenib intervention 3: bavituximab (3.0 mg/kg) and sorafenib
Intervention descriptions: intervention 1: Bavituximab:0.3 mg/kg weekly Sorafenib: 400mg PO twice daily intervention 2: Bavituximab: 1.0 mg/kg weekly Sorafenib: 400mg PO twice daily intervention 3: Bavituximab: 3.0 mg/kg weekly Sorafenib: 400mg PO twice daily

Protocol documents:
Prot_SAP_000.pdf: 
A Phase I/II Study of Bavituximab and Sorafenib In Patients With Advanced 
Hepatocellular Carcinoma 
 
NCT01264705 
Version 18      07/05/2016 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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A Phase I/II Study of Bavituximab and Sorafenib In Patients With Advanced 
Hepatocellular Carcinoma 
UT Southwestern Medical Center Therapeutic Protocol 
Participating Institution: 
 
UT Southwestern Medical Center, Dallas, TX 
 
 
 
 
 
VA-North Texas, Dallas, TX 
 
 
 
 
 
 
Principal Investigator: 
 
Adam C. Yopp, M.D.  
 
 
Department:  
 
 
Surgery 
Participating Investigators:  
 
John C. Mansour, M.D.  
 
Surgery 
C. Glen Balch, M.D.  
 
Surgery 
Meelie Debroy, M.D. Surgery 
Juan Arenas, MD 
 
 
Surgery 
Yull Arriaga, M.D. 
 
 
Medicine 
Sirisha Karri, M.D.  Medicine 
William M. Lee, M.D.  
 
Medicine 
Chul Ahn, Ph.D. 
 
 
Biostatistics 
Muhammad Shaalan Beg, M.D.  
Medicine 
Takeshi Yokoo, MD Radiology 
Hao Zhu, MD  
 
 
Medicine 
Jonathan Dowell, MD  
 
Medicine 
 
 
Protocol Version History 
Version 1 
7/22/2010 
 
 
Version 2 
8/12/2010 
Version 3 
9/22/2010 
 
 
Version 4  
11/3/2010 
Version 5 
12/6/2010 
 
 
Version 6 
2/16/2011 
Version 7 
03/29/2011 
 
 
Version 8 
5/17/2011 
Version 9 
06/13/2011 
 
 
Version 10 
07/20/2011 
Version 11 
11/11/2011 
 
 
Version 12 
01/30/2012 
Version 13 
5/16/2012 
 
 
Version 14 
02/24/2013 
Version 15 
4/29/2013 
 
 
Version 16 
08/19/2013 
Version 17 
01/06/2014 
 
 
Version 18      07/05/2016 
 


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Table of Contents 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA 
 
 
 
4 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS 
 
 
 
 
9 
3.0 
BACKGROUND AND RATIONALE 
 
 
 
 
9 
3.1 
HEPATOCELLULAR CARCINOMA 
 
 
 
9 
3.2 
SCIENTIFIC BACKGROUND AND BAVITUXIMAB 
 
10 
 
3.2.1 NONCLINICAL STUDIES WITH MURINE 3G4  
11 
 
3.2.2 CHIMERIC 3G4 (BAVITUXIMAB)  
 
 
12 
 
3.2.3 NONCLINICAL STUDIES WITH CHIMERIC 3G4  
13
 
(BAVITUXIMAB) 
 
3.2.4 CLINICAL STUDIES WITH BAVITUXIMAB 
 
14 
3.3 
STUDY RATIONALE 
 
 
 
 
 
15 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
4.1 
DESIGN 
 
 
 
 
 
 
 
16 
4.2 
INTERVENTION 
 
 
 
 
 
 
 
 
4.2.1 PHASE I COMPONENT 
 
 
 
 
16 
4.2.2 PHASE II COMPONENT 
 
 
 
 
18 
 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS  
 
 
 
 
5.1 
BAVITUXIMAB 
 
 
 
 
 
 
20 
STORAGE CONDITIONS  
DRUG SUPPLY ACCOUNTABILITY 
5.2 
SORAFENIB TOSYLATE  
 
 
 
 
21 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY  
6.1 
SUBJECT INCLUSION CRITERIA  
 
 
 
22 
6.2 
SUBJECT EXCLUSION CRITERIA 
 
 
 
23 
7.0 
RECRUITMENT PLAN 
 
 
 
 
 
 
23 
8.0 
PRETREATMENT EVALUATION  
 
 
 
 
 
8.1 
PHASE I COMPONENT 
 
 
 
 
 
24 
8.2 
PHASE II COMPONENT 
 
 
 
 
 
25 
9.0 
TREATMENT/INTERVENTION PLAN 
9.1 
THERAPY (BAVITUXIMAB AND SORAFENIB)  
 
26 
9.2 
THERAPY (BAVITUXIMABAND SORAFENIB) TREATMENT 
PARAMETERS 
 
 
 
 
 
 
27 
9.3 
THERAPY (BAVITUXIMAB AND SORAFENIB) SUPPORTIVE 
GUIDELINES 
 
 
 
 
 
 
28 
9.4 
THERAPY (BAVITUXIMAB  AND SORAFENIB)  
DOSE DELAY AND MODIFICATIONS 
 
 
 
28 
10.0 
EVALUATION DURING TREATMENT/INTERVENTION 
 
29 
10.1 
CORRELATIVE STUDIES  
 
 
 
 
30 
11.0 
DOSE LIMITING TOXICITIES 
 
 
 
 
 
32 
12.0 
TOXICITIES/SIDE EFFECTS 
 
 
 
 
 
33 
12.1 
SORAFENIB  
 
 
 
 
 
 
33 


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12.2 
BAVITUXIMAB 
 
 
 
 
 
 
34 
13.0 
CRITERIA FOR THERAPEUTIC RESPONSE/ 
OUTCOME ASSESSMENT  
 
 
 
 
 
35 
13.1 
DEFINITIONS 
 
 
 
 
 
 
35 
13.1.1 MEASURABLE DISEASE  
 
 
 
35 
13.1.2 NON-MEASURABLE DISEASE 
 
 
 
36 
13.1.3 TARGET LESIONS  
 
 
 
 
36 
13.1.4 NON-TARGET LESIONS 
 
 
 
 
36 
13.2 
EVALUATION OF TARGET LESIONS 
 
 
 
36 
13.3 
EVALUATION OF NON-TARGET LESIONS 
 
 
37 
13.4 
EVALUATON OF BEST OVERALL RESPONSE  
 
37 
13.5 
GUIDELINES FOR EVALUATION OF MEASURABLE   
38 
DISEASE 
13.6 
CONFIRMATORY MEASUREMENT/DURATON OF 
 
38  
RESPONSE 
14.0 
CRITERIA FOR REMOVAL FROM STUDY 
 
 
 
39 
15.0 
BIOSTATISTICS 
 
 
 
 
 
 
 
39 
15.1 
SAMPLE SIZE CALCULATION 
 
 
 
 
39 
15.2 
SECONDARY ENDPOINTS 
 
 
 
 
40 
16.0 
DATA MANAGEMENT ISSUES 
16.1 
DATA AND SAFETY MONITORING 
 
 
 
41 
17.0 
PROTECTION OF HUMAN SUBJECTS 
 
 
 
 
41 
17.1 
PRIVACY 
 
 
 
 
 
 
 
42 
17.2 
ADVERSE EVENTS  
 
 
 
 
 
43 
 
18.0 
INFORMED CONSENT PROCEDURES 
 
 
 
 
44 
19.0 
Satellite Site Enrollment Process 
 
 
 
 
 
44 
20.0 
REFERENCES 
 
 
 
 
 
 
 
45 
21.0 
APPENDICES 
 
 
 
 
 
 
 
 
APPENDIX A 
ECOG PERFORMANCE SCORE 
 
 
48 
APPENDIX B  
CHILD-PUGH SCORE 
 
 
 
50 
APPENDIX C  
NYHA CLASSIFICATION  
 
 
51 
APPENDIX D 
SAMPLE INFORMED CONSENT  
 
52 
 
 
 
 
 
 
 


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1.0 
PROTOCOL SUMMARY AND/OR SCHEMA 
 
TITLE 
A Phase I/II Study of Bavituximab and 
Sorafenib In Patients With Advanced 
Hepatocellular Carcinoma 
STUDY OBJECTIVES 
Primary Objective: 
1) To determine the maximum tolerated 
dose of bavituximab in patients with 
advanced hepatocellular carcinoma 
treated with sorafenib. 
2) To determine the radiographic 
median time to progression in 
patients with advanced hepatocellular 
carcinoma treated with bavituximab 
and sorafenib. 
Secondary Objectives: 
1) Response rate, progression free-
survival and overall survival. 
2) Safety and tolerability as assessed by 
NCI CTC v4.0 of combination 
bavituximab and sorafenib. 
3) Correlation of treatment response 
with pre- and post-treatment tissue 
biopsies and serum biomarkers. 
 
STUDY DESIGN 
Single-arm, single-institution, non-
randomized, open-label phase I/II study. 
STUDY POPULATION 
Inclusion Criteria: 
1.  Patients must have a diagnosis of 
hepatocellular carcinoma by at least one 
criterion listed below: 
a. Histologically confirmed 
hepatocellular carcinoma 
b. Axial imaging consistent with liver 
cirrhosis and at least one solid liver lesion 
≥2 cm with early enhancement and 
delayed enhancement washout regardless 
of alpha-fetoprotein (AFP) levels. 
c. 
AFP ≥ 400 ng/ml and evidence of at 
least one solid liver lesion ≥ 2 cm 
regardless of specific imaging 
characteristics. 


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2. Locally advanced or metastatic disease. 
a.   Patients with locally advanced disease 
must have disease deemed to be 
unresectable or not eligible for hepatic 
transplantation by surgical oncologist or 
transplant physician 
3. Measurable disease, defined as lesions 
that can accurately be measured in at 
least one dimension (longest diameter to 
be measured) according to Response 
Evaluation Criteria in Solid Tumors 
(RECIST, version 1.1) at least 2 cm with 
conventional techniques or at least 1 cm 
with spiral computed tomography. 
4. Child-Pugh Score A or B7. 
5. Age ≥ 18 years. 
6. ECOG Performance Score of 0-2. 
7. Absolute neutrophil count ≥ 1,200 
cells/mm3. 
8. Platelet count ≥ 70,000 cells/mm3. 
9. Total Bilirubin ≤ 3.0 mg/dl. 
10. Hemoglobin ≥ 8.5 g/dl. 
11. INR ≤ 1.8 (therapeutic anticoagulation 
allowed as long as medically indicated.) 
12. Creatinine ≤ 1.5 times upper limit of 
normal. 
13. Women of childbearing potential must 
have a negative pregnancy test. 
14. No clinically significant episode of 
gastrointestinal bleeding within the 
previous 30 days. 
15. Men and women of childbearing 
potential must be willing to consent to 
using effective contraception while on 
treatment and for at least 3 months 
thereafter. 
16. At least 4 weeks since prior locoregional 
therapy including surgical resection, 
radiotherapy, hepatic arterial 
embolization or chemoembolization, 
radiofrequency ablation, percutaneous 
injection or cryoablation (treatment of 
target lesion only, non-target lesions can 
be treated with locoregional therapy).  
Provided the target lesion increased in 
size by 25% or more or the target lesion 


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was not treated with locoregional 
therapy. 
17. Greater than 4 weeks since interferon 
therapy. 
18. Greater than 4 weeks since and no 
concurrent use of rifampin or St John’s 
wort. 
19. Life expectancy > 12 weeks. 
20. Prior anti-viral therapy is allowed. 
21. Ability to understand informed consent 
and signing of written informed consent 
prior to initiation of protocol therapy. 
22. Non-English speaking patients will be 
enrolled. 
 
Exclusion Criteria: 
1. History of bleeding diathesis or 
coagulopathy. 
2. Symptomatic or clinically active brain    
metastases. 
3. Major surgery within previous 4 weeks. 
4. Clinically significant non-bleeding within 
previous 12 months. 
5. Concurrent hormone therapy (including 
hormone replacement therapy and anti-
estrogen). 
6. History of any condition requiring anti-
platelet therapy with the exception of 
general cardiovascular prophylaxis with 
aspirin. 
7. History of thromboembolic events 
(including both pulmonary embolisms 
and deep vein thrombosis not including 
tumor thrombus). 
8. Active infection. 
9. Patients who are pregnant or lactating. 
10. Hypersensitivity to IV contrast not 
suitable for pre-medication. 
11. Patients with known hypersensitivity to 
any of the components of bavituximab or 
sorafenib. 
12. Any other medical condition, including 
mental illness or substance abuse deemed 
by the investigators to likely interfere 
with a patient’s ability to sign informed 
consent, cooperate and participate in the 


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study or follow-up procedures.  
13. Patients with known human 
immunodeficiency virus (HIV). 
14. Significant history of cardiac diseases, 
including any of the following: 
a. LVEF < 40% by MUGA or myocardial 
scintigram. 
b. NYHA class III-IV congestive heart 
failure. 
c. Myocardial infarction within 
previous 6 months. 
d. Cardiac arrhythmias requiring anti-
arrhythmic therapy (other than beta 
blockers or digoxin). 
15. Evidence of poorly controlled 
hypertension (medically controlled 
hypertension is allowed provided blood 
pressure ≤ 150/90.) 
16. History of liver or renal transplantation. 
17. Prior adjuvant therapy with sorafenib or 
other Raf/MEK/RAS or VEGFR 
inhibitors. 
a. Other adjuvant therapy is allowed   
provided it was completed > 6 months 
prior to study and there is documented 
recurrence or progression of 
hepatocellular carcinoma. 
 
 
  
TOTAL EXPECTED NUMBER OF 
PATIENTS 
Phase I component- 9-18 patients 
Phase II component-38 patients 
PRE-, DURING AND POST-THERAPY 
TISSUE AND SERUM COLLECTION 
(Phase II component only) 
Serum samples will be drawn for 
measurement of angiogenic markers, alfa-
fetoprotein and inflammatory cytokines pre, 
during and post therapy.  When feasible core 
biopsies will be obtained for tissue banking 
for research purposes and for routine H&E 
staining, pre and during therapy. 
STUDY DRUG FORMULATIONS 
Bavituximab: supplied as a sterile, 
preservative-free solution with 10 mM 
acetate at pH 5.0 and diluted with 0.9% 
(w/v) saline to a final volume of 100 ml.  
Sorafenib: information per package insert. 


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ROUTE OF ADMINISTRATION 
Bavituximab: Intravenous (IV) 
Sorafenib: Oral 
 
DOSE REGIMEN 
Bavituximab: 0.3 mg/kg, 1.0 mg/kg or 3.0 
mg/kg IV over 90 minutes weekly. 
Sorafenib: Initial dose 200 mg PO twice 
daily to be escalated to the target dose of 400 
mg PO twice daily 
Phase I: Bavituximab and sorafenib are to be 
given for 1 cycle or 4 weeks. 
Phase II: Bavituximab and sorafenib are to 
be continued until disease progression or 
toxicity. 
EVALUATION CRITERIA 
Primary: 
Phase I: safety as measured by adverse 
events 
Phase II: efficacy as measured by time to 
progression using RECIST Version 1.1. 
 
Secondary: 
   Phase II:  
1. Safety and tolerability as assessed by 
NCI CTC v4.0 of this regimen in the 
phase II setting. 
2. Overall survival, response rate and 
progression-free survival. 
3. Correlation of serum and tissue 
markers of angiogenesis and immune 
response with treatment response. 
 
DURATION OF STUDY PERIOD 
Phase I: Patients will continue study 
treatment until 1 cycle of therapy. Phase II: 
Patients will continue study treatment until 
disease progression or toxicity. 
ANTICIPATED STUDY DATES 
Planned Start Date: February 2011 
Planned Recruitment Closure: February 
2013 
Planned End Date: February 2014 
 
 
 
 
 


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2.0 
OBJECTIVES AND SCIENTIFIC AIMS 
 
Primary Objectives: 
1. 
The primary objective of the Phase I component of this trial is to 
determine the maximum tolerated dose (MTD) of bavituximab up to 3.0 
mg/kg weekly in patients with hepatocellular carcinoma (not eligible for 
surgical resection or hepatic transplantation) treated with sorafenib. 
2. 
The primary objective of the Phase II component of this trial is to 
determine the median radiographic time to progression (from the date of 
first therapy to date of first documented progression) of patients with 
hepatocellular carcinoma (not eligible for surgical resection or hepatic 
transplantation) treated with sorafenib. 
Secondary objectives of the trial are to determine the: 
3. 
Safety and tolerability of combination bavituximab and sorafenib 
treatment in patients with hepatocellular carcinoma. 
4. 
Response rate, progression free-survival and overall survival. 
5. 
Correlation of treatment response with pre- and post-treatment tissue 
biopsies and serum angiogenic and phosphatidylserine biomarkers. 
 
3.0 
BACKGROUND AND RATIONALE 
 
3.1 
Hepatocellular Carcinoma 
 
Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and 
is responsible for more than 500,000 deaths annually. (1) Previously considered 
uncommon in Western countries, the incidence and mortality of HCC have 
increased three-fold in the United States over the past two decades. (2) Although 
complete resection or hepatic transplantation remains the most effective therapies 
for localized HCC, 50-70% of patients present with advanced disease not 
amenable to curative surgical approaches. (3,4) Disease that is diagnosed at an 
advanced stage or with progression after locoregional therapy has a dismal 
prognosis with a median overall survival of < 12 months mainly due to underlying 
liver dysfunction and suboptimal treatment options. (2) Ablative therapies are 
commonly used in this setting but are ineffective for large (>5 cm) or multifocal 
tumors, both commonly found in advanced disease. (5,6) Hepatic artery 
chemoembolization may have utility in patients with HCC but there are 
conflicting reports regarding its efficacy and in advanced disease a survival 
benefit has not been demonstrated. (7,8)  
 
Systemic Therapy for Advanced Hepatocellular Carcinoma 
 
The use of single agent systemic cytotoxic chemotherapy regimens including 


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irinotecan, gemcitabine or doxorubicin have historically demonstrated low 
response rates with little to no clinical efficacy. (9-11) Combination 
chemotherapy regimens using cytotoxic chemotherapeutic agents have fared no 
better with response rates ranging from 0% to 40% and limited clinical efficacy. 
A recent study compared single agent doxorubicin to a combination of cisplatin, 
interferon, doxorubicin and 5-fluorouracil (PIAF). Despite an improvement in 
response (10% for doxorubicin vs. 21% for PIAF) the study failed to show an 
improvement in survival (6.8 vs. 8.6 months, respectively; P=0.83). (12) 
 
The lack of appropriate traditional chemotherapeutic agents led to the 
investigation of molecular targeted agents, which have been shown to be 
efficacious in other tumor models.  Sorafenib, an oral multikinase inhibitor that 
blocks tumor cell proliferation by targeting the Raf/MEK/ERK signaling pathway 
and exerts an anti-angiogenic effect by targeting the tyrosine kinase receptors, 
VEGFR-2, VEGFR-3 and PDGF-, is the first biologically targeted agent to show 
efficacy in the treatment of advanced stage HCC. (13,14) In a phase III 
randomized controlled trial (SHARP trial), patients with advanced hepatocellular 
carcinoma (not eligible for surgical resection or transplantation) and preserved 
liver function (Child-Pugh A score) were randomly assigned to either systemic 
sorafenib or placebo. There was a significantly longer survival and radiologic 
time to progression (TTP) outcome in the cohort of patients that received 
sorafenib with little or no toxicity. Grade 3 drug relate events included diarrhea 
(8% in the sorafenib group vs. 2% in the placebo group), hand-foot skin reaction 
(8% vs. 1%), hypertension (2% vs. 1%) and abdominal pain (2% vs. 1%); there 
were no grade 4 drug-related adverse events in any of these categories in either 
study group.  Currently sorafenib is the only drug that has FDA approval for the 
systemic treatment of HCC.  Although sorafenib is the current standard of care for 
patients with advanced HCC, it prolonged radiologic time to progression less than 
3 months when compared to best supportive care: 5.5 months versus 2.8 months, 
respectively.  Overall survival was prolonged less than 3 months compared to best 
supportive care, 10.7 months versus 7.9 months, respectively. (14) Although 
systemic treatment with sorafenib shows statistically significant clinical efficacy, 
its overall benefit is modest. The complexity of HCC would appear to lend itself 
to escape mechanisms from the sorafenib-specific blockade of the RAF-MEK-
ERK and VEGFR/PDGF pathways, thereby promoting tumor proliferation and 
neo-angiogenesis through alternative means.  Such a mechanism would explain 
why certain patients fail to benefit from sorafenib therapy and provides the 
rationale for combining sorafenib with other chemotherapeutic agents.  
 
3.2 
Scientific background of bavituximab 
Anionic phospholipids are largely absent from the surface of resting mammalian 
cells under normal conditions.  Phosphotidylserine (PS), the most abundant 
anionic phospholipid of the plasma membrane, is tightly segregated to the internal 
leaflet of the plasma membrane in most cell types. In tumors, however, PS 
becomes exposed on the accessible outer surface of the vascular endothelium in 
response to oxidative stresses present in the tumor microenvironment. (15,16) PS 


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exposure on tumor vascular endothelium occurs in 15-40% of tested tumor 
models in the absence of cellular injury or exogenous agents and has not been 
demonstrated on blood vessels in non-tumor tissues regardless of the model used.  
The administration of cytotoxic chemotherapy or radiation therapy increases PS 
externalization presumably through the production of oxygen radicals and the 
subsequent translocase inhibition and scramblase activation. (17-22) 
3.2.1 Non-clinical studies with murine 3G4 
 
3G4, a novel murine IgG3 monoclonal antibody developed by Dr. Phillip Thorpe 
at UT Southwestern Medical Center, binds PS complexed with 2-glycoprotein 1 
mediating the binding of host effector cells to the tumor vascular endothelium. 
Murine 3G4 has demonstrated significant anti-tumor effects as a stand-alone 
therapy in various murine xenograft tumor models. (20) The growth of MDA-
MB-231 breast carcinoma, MDA-MB-435 breast carcinoma, Meth A 
fibrosarcoma and L540 Hodgkin lymphoma tumor xenografts was reduced by 
65%, 75%, 90% and 50%, respectively, compared to controls during treatment 
with 3G4. Fc domain-mediated immune effector functions such as antibody 
dependent cell-mediated cytotoxicity (ADCC), complement-dependent 
cytotoxicity and antibody-mediated phagocytosis appear to be responsible for the 
anti-tumor effect of 3G4. (17) 
The combination of 3G4 with cytotoxic chemotherapy has been shown to have an 
additive effect in multiple tumor models.  Cytotoxic chemotherapy including 
gemcitabine and docetaxel increases PS exposure on tumor vascular endothelium 
providing additional targets for binding of the 3G4 antibody.  Combination 
gemcitabine-plus- 3G4 therapy reduced tumor growth in a pancreatic cancer 
tumor model 5-fold compared to either gemcitabine or 3G4 alone. (20) Similar 
results were seen with a combination of docetaxel and 3G4 in a breast cancer 
tumor model. (25) We have recently demonstrated that sorafenib also increases 
PS exposure in the human HCC cell lines, C3A and Huh7. (unpublished results 
from Dr. Phillip Thorpe) (Figure 1)   


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The likely mechanism of vascular damage seen with 3G4 is the antibody binds to 
tumor vasculature expressing PS secondary to chemotherapy induction, mediating 
attachment of FcgR-positive monocytes that destroy the endothelial cells by an 
ADCC mechanism.  Recently, however, it has been suggested that binding of an 
anti-PS antibody to PS elicits the release of proinflammatory cytokines activating 
dendritic cells and conferring immune protection against tumor growth. (22)  
 
 
3.2.2 Chimeric 3G4 (Bavituximab) 
Chimeric 3G4 (bavituximab) is a genetically engineered IgG1 κ immunoglobulin 
containing the variable region sequences (Fab) of a murine PS-targeting 
monoclonal antibody (MAb) and human IgG1 κ constant region sequences (Fc). 
Bavituximab is produced by Chinese hamster ovary (CHO)-K1 cells in 
suspension culture in a nutrient medium. Bavituximab is purified by a 
combination of capture, cation, and anion-exchange chromatography. The 
purification process includes specific viral inactivation and removal procedures. 
Bavituximab is supplied as a sterile preservative-free liquid for intravenous (IV) 
administration. 
3.2.3 Nonclinical Studies with Chimeric 3G4 (Bavituximab) 
The nonclinical safety program to date comprises IV pharmacokinetic (PK) 
studies in rats and monkeys and tissue distribution studies in rats. Single and 
repeat-dose IV toxicity studies were performed in rats, rabbits, and cynomolgus 
monkeys with treatment duration up to 8 weeks. Special toxicity studies 


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evaluating the effects of bavituximab on coagulation, vascular disease, wound 
healing, and platelet aggregation were conducted in rats, rabbits, mice, and 
monkey and human citrated whole blood, respectively. Central nervous system 
(CNS) safety pharmacology and immunogenicity studies were integrated into the 
Good Laboratory Practice (GLP) repeat-dose studies performed in rats. 
Cardiovascular safety pharmacology, immunogenicity, and immunotoxicity 
studies were integrated into the GLP repeat-dose studies performed in monkeys. 
In single-dose studies, findings were limited to in vitro assay interference in 
phospholipid-based coagulation parameters (i.e., activated partial thromboplastin 
time [aPTT] and prothrombin time [PT]) in all species examined. Drug-induced in 
vitro coagulation interference peaked within 24 hours post-dose and generally 
resolved by 7 days post-dose. A coagulation study in rats (using a single 60 mg/kg 
dose) confirmed that while aPTT and PT were elevated 2.88- and 1.34-fold, 
respectively, at 24 hours post dose, bleeding time, thrombin time, fibrin 
degradation products, and fibrinogen were not significantly affected compared to 
the vehicle control animals. 
Two in vitro studies were conducted that demonstrate an interference effect of 
bavituximab (or 3G4) on phospholipid-based coagulation assays. Plasma 
harvested from normal rats and spiked with increasing concentrations of 
bavituximab suggests that the drug interferes, in a dose-dependent manner, with 
the analytical performance of aPTT determination. Four procoagulant 
T-lymphoblastoid cell lines were characterized for their cell-surface procoagulant 
activity. At high concentrations, 3G4 partially inhibited phospholipid-dependent 
coagulation. Partial inhibition was explained by the lack of 3G4 binding to other 
phospholipids (eg, phosphatidylethanolamine). (25) 
In GLP repeat-dose toxicology studies, bavituximab was generally well tolerated 
with effects in the rat limited to histological findings (minimal, chronic 
subendocardial inflammation) in the high-dose group (100 mg/kg/week for 8 
weeks) and transient increases in coagulation times (aPTT and PT) at 
doses  20 mg/kg/week. Effects in monkeys were limited to transient increases in 
coagulation times (aPTT and PT) and histological changes (i.e., minimal to mild 
cardiac and pulmonary thrombi, subendocardial fibrosis, and minimal to mild 
pulmonary arteriopathy) in the high-dose group (100 mg/kg/week for 8 weeks). 
Bavituximab did not have any biologically significant effects on monkey or 
human whole blood platelet aggregation at the range of concentrations tested (i.e., 
1-3130 μg/mL bavituximab). Repeat doses of bavituximab up to 100 mg/kg did 
not affect time to healing in a full thickness excisional dermal wound model in 
rats. 
 
  
3.2.4 Clinical Studies with Bavituximab 
Bavituximab is currently being investigated in patients with refractory advanced 
solid tumor malignancies and in patients with chronic hepatitis C virus infection 
(HCV) by Peregrine Pharmaceuticals. 


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Antiviral studies 
Three clinical studies to evaluate the antiviral activity of bavituximab have been 
conducted or are ongoing. In a phase 1 study, 30 patients with chronic HCV 
infection were treated with a single dose of bavituximab at 0.1, 0.3, 1, 3, or 6 
mg/kg. Patients receiving 6 mg/kg had a slight elevation in d-dimer, which 
returned to baseline as the antibody cleared from circulation. Transient reductions 
in viral load suggestive of anti-viral activity were observed at all dose levels. In a 
phase 1b study, 24 patients with chronic HCV were treated twice weekly with 
bavituximab at 0.3, 1, 3, or 6 mg/kg. Bavituximab exhibited predictable PK 
characteristics in both studies. All dose levels tested exhibited transient anti-viral 
activity, and 3 mg/kg appeared most active.  
Cancer studies 
Five studies with bavituximab in oncology indications have been conducted or are 
ongoing.  
A phase 1 IND study in patients with advanced solid tumor malignancies was 
conducted to evaluate the safety, PK, and maximum tolerated/effective dose of 
bavituximab given as a single agent weekly for 4 weeks. Twenty-six patients were 
enrolled at 0.1, 0.3, 1, or 3 mg/kg. Most adverse events (AEs) related to 
bavituximab were mild or moderate, and linear PK characteristics were observed. 
Pulmonary embolism, considered serious and related to study drug, was the only 
dose limiting toxicity observed in the study. This adverse event was grade 4 in 
nature and occurred in one patient 7 days after initiation of therapy. 
Another study in advanced solid tumor malignancies was conducted using 3 
mg/kg bavituximab weekly for 8 weeks in combination with chemotherapy 
(docetaxel, gemcitabine, or paclitaxel + carboplatin). Two patients in the 
docetaxel arm discontinued bavituximab treatment after developing severe 
infusion reactions; urticaria in both patients. In response to these observed 
infusion reactions, the protocol was amended to add instructions for 
premedication with a steroid and an antihistamine prior to each bavituximab 
infusion. One patient with stage IV ovarian carcinoma developed grade 4 
refractory hypotension 2 days after receiving the initial dose of docetaxel and 
bavituximab and expired 1 week after the initial serious adverse event (SAE); 
these events are considered probably study drug related. Twelve of the 14 patients 
enrolled were evaluable for tumor response using Response Evaluation Criteria in 
Solid Tumors (RECIST). Three patients achieved partial response (PR) (2 in the 
paclitaxel/carboplatin arm, 1 in the gemcitabine arm) and continued bavituximab 
maintenance on compassionate grounds, 3 patients demonstrated stable disease, 
and 6 patients had tumor progression. (26) 
Two non-IND phase 2 studies are ongoing in locally advanced or metastatic 
breast cancer, to investigate the safety and efficacy of bavituximab 3 mg/kg 
weekly in combination with carboplatin plus paclitaxel in 28-day cycles or 
docetaxel in 28-day cycles. Fifteen of 46 patients treated in PPHM 0702 
experienced AEs considered related to bavituximab, including fatigue and 
anemia, and 4 patients experienced drug-related severe adverse events (SAE); 


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among stage A patients (in a Simon 2-stage design) in the intent-to-treat (ITT) 
group, the ORR was 60% (9/15). Thirty-six of 46 patients treated in PPHM 0704 
experienced AEs considered related to bavituximab, including epistaxis, infusion-
related reaction, nasal dryness, and nail bed bleeding, and 4 patients experienced 
drug-related SAEs; the ORR for all enrolled patients was 61% (28/46). In PPHM 
0702 and 0704 there were 6 grade 3 or 4 AEs (6 of 92 patients, incidence of 
6.5%). The median number of bavituximab doses for a grade 3 or 4 adverse event 
was 15 (range, 8 to 20). (27, 28) 
Another non-IND phase 2 study is being conducted in untreated locally advanced 
or metastatic NSCLC to investigate the safety and efficacy of bavituximab 3 
mg/kg weekly in combination with carboplatin plus paclitaxel in 21-day cycles. 
Twenty of 49 patients experienced AEs considered related to bavituximab, 
including anemia and fatigue, and 8 patients experienced drug-related SAEs, 
which included fatal myocardial infarction (in 2 patients) and fatal hemoptysis 
and aspiration (in 1 patient). Among stage A patients (in a Simon 2-stage design) 
in the ITT group, the ORR was 52% (11/21). Grade 3 or 4 AEs were experienced 
by 28.5% of patients.  The most common grade 3 or 4 AEs were anemia (4 
patients), asthenia (4 patients) and neutropenia (4 patients). (29) 
3.3 
Study Rationale 
Combination therapy consisting of bavituximab and sorafenib is attractive for 
patients with advanced HCC for the following reasons: 
1. Based on the previously mentioned SHARP trial, sorafenib is the first 
drug in the modern era to receive FDA approval for treatment of 
advanced HCC.  Although sorafenib is now established as part of 
standard therapy, its overall benefit is modest, and advanced HCC 
remains uniformly fatal.  Due to the multiple escape mechanisms for 
angiogenesis inhibition in HCC, a logical next step would be to 
combine sorafenib with other biologic or chemotherapeutic agents. 
2. Externalized PS is a desirable marker for tumor targeting for several 
reasons: PS is specifically and abundantly expressed on tumor vascular 
endothelium; it is present on a high percentage of tumor endothelial 
cells in a variety of solid tumors; it is absent from non-tumor 
vasculature; and it is expressed on the luminal side of tumor vascular 
endothelium, which is readily accessible for targeting drugs.  
Combining bavituximab, an angiogenesis inhibitor, with sorafenib, an 
angiogenesis inhibitor with a different mechanism, may prevent 
signaling escape mechanisms seen with either drug if given 
individually. 
3. Data from preclinical studies have demonstrated that sorafenib therapy 
increases PS exposure on tumor vascular endothelium in a HCC tumor 
model.  The increase of PS exposure will amplify the target for 
bavituximab and should increase tumor vessel destruction producing 
increased treatment efficacy. 


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It is our hypothesis that combination therapy with bavituximab and sorafenib will 
provide greater clinical efficacy than either agent alone with minimal toxicity. 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
 
4.1 
Design 
This is a non-randomized, open-label, single-institution phase I/II therapeutic trial 
of bavituximab and sorafenib in patients with advanced HCC. This study will be 
activated at the UT Southwestern Medical Center, (comprised of The Harold C. 
Simmons Comprehensive Cancer Center, UT Southwestern Hospitals-St. Paul and 
Parkland Memorial Hospital System), VA-North Texas, and UT Austin-Seton. 
Advanced HCC is defined as disease that is not amenable to surgical resection or 
orthotopic liver transplantation or is metastatic in nature.   
The phase I component of the study will consist of a traditional 3+3 dose 
escalation rule as outlined in section 11.0.  
The dose levels of bavituximab (0.3,1.0,and 3.0 mg/kg weekly) were selected 
based on available data from preclinical and clinical studies that is predicted to 
achieve and sustain biologically active blood antibody levels or tumor binding in 
cancer patients.  
 
A bavituximab dose of 3 mg/kg gives a blood concentration in excess of that 
needed for maximal efficacy based on preclinical models while having little 
effect on coagulation and safety laboratory parameters and causing no 
significant depletion of the cofactor protein, β2GP1. 
 
In preclinical models, dosing above the biologically effective blood 
concentration of 2 µg/mL did not increase anti-tumor efficacy. 
 
Treatment with ≤ 3 mg/kg bavituximab appears to be well tolerated. 
 
β2-glycoprotein I levels are significantly depleted above 3 mg/kg 
bavituximab. 
4.2Intervention 
4.2.1Phase I component 
 
The following is a brief schematic of Phase I component study flow:  
 


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Patients will be eligible for enrollment on study if they have a diagnosis of HCC by at 
least one of the following criterion listed below: 
a. 
Histologically confirmed hepatocellular carcinoma 
b. 
Axial imaging consistent with liver cirrhosis and at least one solid liver 
lesion ≥2 cm with early enhancement and delayed enhancement washout 
regardless of alpha-fetoprotein (AFP) levels. 
c. 
AFP ≥ 400 ng/ml and evidence of at least one solid liver lesion ≥ 2 cm 
regardless of specific imaging characteristics. 
 
Patients also need to have advanced disease as defined previously in section 4.1. 
Attending surgical oncology, hepatologists and liver transplant physicians (either 
surgeons or hepatologists) with expertise in the management of HCC will assess 
suitability of surgical resection and liver transplantation at participating sites. 
All patients will initially be staged with a liver protocol MRI or CT of the abdomen. A 
chest CT will be done if there is a concern for intra-pulmonary metastases. 
Bavituximab will be administered on a weekly schedule until completion of the phase I 
component of the study or the development of any of the criteria for requiring removal 
from the study as outlined in Section 11 of the protocol. Bavituximab will be dosed 
according to the timeline of the phase I and II components of the study.  In the phase I 
component, bavituximab will be started at 0.3 mg/kg and will be escalated pending DLT 
to 1.0 mg/kg and 3.0 mg/kg.  These doses will be given intravenously over 90 minutes 
starting on day 1. Sorafenib will be initially dosed at 200 mg orally twice a day and 
escalated to the target dose of 400 mg orally twice a day at the discretion of the treating 
medical oncologist. Sorafenib will be started within 3 days of the initial bavituximab 
Patient with 
suspected advanced 
HCC
Patient with 
suspected advanced 
HCC
MRI or CT 
MRI or CT 
Therapy
Bavituximab
Sorafenib
Therapy
Bavituximab
Sorafenib
Long-term follow-up
(30 days)
Long-term follow-up
(30 days)


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19
dose. At the completion of the study treatment period of one cycle sorafenib will be 
continued at the discretion of the treating oncologist. 
 
4.2.2 
Phase II Component 
 
 
Patients will be eligible for enrollment on study if Histologically confirmed 
hepatocelluar carcinoma. 
Patients also need to have advanced disease as defined previously in section 4.1. 
Attending surgical oncology, hepatologists and liver transplant physicians 
(surgeons or hepatologists) with expertise in the management of HCC will assess 
suitability of surgical resection and liver transplantation at participating sites. 
All patients will initially be staged with a liver protocol CT or MRI of the 
abdomen. A chest CT will be done if there is a concern for intra-pulmonary 
metastases. 
Prior to the initiation of therapy serological markers (alpha-fetoprotein and viral 
hepatitis markers, including hepatitis C antibody and hepatitis B surface antigen), 
serum, image guided core biopsy of an intra-hepatic tumor (performed for clinical 
care.  If the biopsy is performed for clinical care, additional needle core 
specimens (up to 3) will be obtained in addition to the number needed for 
Patient with 
suspected advanced 
HCC
Patient with 
suspected advanced 
HCC
CT or MRI
CT or MRI
CT guided biopsy of 
liver, serum
CT guided biopsy of 
liver, serum
Therapy
Bavituximab
Sorafenib
Therapy
Bavituximab
Sorafenib
Long-term follow-up
Long-term follow-up
CT guided biopsy of 
liver, serum
CT guided biopsy of 
liver, serum


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histopathological analysis. This is of minimal additional risk as same needle tract 
will be used to acquire additional specimens. 
Bavituximab will be administered on a weekly schedule until intolerable toxicity, 
or the development of any of the criteria for requiring removal from the study as 
outlined in Section 14 of the protocol.  Sorafenib will be administered on a daily 
schedule until intolerable toxicity, or the development of any of the criteria for 
requiring removal from the study as outlined in Section 14 of the protocol. The 
dose of bavituximab for the phase II component will be the maximum tolerated 
dose determined in the phase I component.  In the phase I component, 
bavituximab will be started at 0.3 mg/kg and will be escalated pending DLT to 1.0 
mg/kg and 3.0 mg/kg.  These doses will be given intravenously over 90 minutes 
starting on day Sorafenib will be initially dosed at 200 mg orally twice a day and 
escalated to the target dose of 400 mg orally twice a day at the discretion of the 
treating medical oncologist. Sorafenib will be started within 3 days of the initial 
bavituximab dose. 
Between five and six weeks following the first dose of bavituximab, alpha-
fetoprotein(serum), a second image guided core biopsy of an intra-hepatic tumor 
will be performed.. This second image guided biopsy is optional and will be 
subject to informed consent with the enrolled patient. This biopsy will be for 
research purposes only and performed in the exact same way as the clinical care 
biopsy.  
Bavituximab and sorafenib will be administered until intolerable toxicity, or the 
development of any of the criteria for requiring removal from the study as 
outlined in Section 14 of the protocol.  Serum studies (including alfa-fetoprotein) 
and CT or MRI will be performed every 6 weeks +/- 5 days following the initial 
2-week studies until removal from study.  All patients will be followed long-term 
for the secondary endpoint, overall survival, to a point 12 months from accrual of 
the final patient. 
 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS 
 
5.1 Bavituximab 
IND Number: 109134 
Finished Product 
Presentation and Composition 
Bavituximab is supplied as a sterile, preservative-free solution with 10 mM 
acetate at pH 5.0 and diluted with 0.9% (w/v) saline (normal saline) to a final 
volume of 100 mL. 
Storage 
Bavituximab is stored at 2°C to 8°C. Once diluted, it should be stored at room 
temperature and used within 8 hours.  


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Availability and Accountability 
Peregrine Pharmaceuticals, Inc in Tustin, CA will provide bavituximab. The 
pharmacist or designee must keep an accurate accounting of the number of 
investigational units received from Peregrine, dispensed to patients, and returned 
to Peregrine during and at the completion of the study. A detailed inventory must 
be completed for the study medication. The study medication must be dispensed 
only by an appropriately qualified person to patients in the study. The medication 
is to be used in accordance with the protocol in patients who are under the direct 
supervision of an investigator.  All unused clinical study medications/treatments 
will be returned to Peregrine. 
Administration 
Bavituximab will be administered weekly. Prior to each bavituximab infusion, the 
patient must be pre-medicated with a steroid and an antihistamine to decrease the 
risk of an infusion reaction, 250 mg hydrocortisone IV and 50 mg 
diphenhydramine IV administered 30 minutes prior to infusion will be given.  
Infusion preparation and administration are to be performed as follows:  
1. Draw up the volume of a vial using a sterile syringe attached to an appropriate 
needle (a vented spike or other appropriate transfer device may be used). Fill 
treatment into a sterile glass bottle or plastic IV bag. 
2. Using aseptic techniques, repeat procedure until the calculated volume has 
been put in to the container. Bring the final volume to 100 mL using 0.9% 
Sodium Chloride Injection, USP.  
3. Administer through a low protein binding 0.2-micrometer in-line filter (placed 
as proximal to the patient as practical). 
4. Affix the infusion line and prime it with infusate before starting the infusion. 
Infuse the solution intravenously over 90 (± 10) minutes. No reduction in 
infusion time will be permitted. Flush the line with normal saline after 
infusion. 
5.2 Sorafenib Tosylate (NexavarTM) 
Please refer to the FDA-approved package insert for NexavarTM for product 
information, extensive preparation instructions and a comprehensive list of 
adverse events. 
Active Ingredient 
Chemical Name: 
4-(4-{3-[4-Chloro-3-
(trifluoromethyl)phenyl]ureido}phenoxy)N2-
methylpyridine-2-carboxamide 4-
methylbenzenesulfonate 
Trade Name: 
NexavarTM 
Empirical Formula: 
C21H16ClF3N4O3 x C7H8O3S 
Relative Molecular Weight: 637.0 


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Physical Properties: 
Insoluble in aqueous media 
 
Slightly soluble in ethanol 
 
Soluble in PEG 400 
Finished Product 
Presentation and Composition 
NexavarTM contains sorafenib tosylate (274 mg) equivalent to 200 mg of 
sorafenib and the following inactive ingredients: croscarmellose sodium, 
microcrystalline cellulose, hypromellose, sodium lauryl sulphate, magnesium 
stearate, polyethylene glycol, titanium dioxide and ferric oxide red.  
NexavarTM tablets are supplied as round, biconvex, red film-coated tablets, 
debossed with the “Bayer cross” on one side and “200” on the other side, each 
containing sorafenib tosylate equivalent to 200 mg of sorafenib. 
Storage 
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) (see USP 
controlled room temperature). Store in a dry place. 
Availability 
NexavarTM tablets are manufactured by Bayer Healthcare Systems and are 
commercially available. 
Administration 
NexavarTM tablets will be administered orally, as outlined in sections 4.2.1 and 
4.2.2. 
6.0  
CRITERIA FOR SUBJECT ELIGIBILITY 
 
6.1 Subject Inclusion Criteria 
 
1. Patients must have a diagnosis of hepatocellular carcinoma by at least one 
criterion listed below: 
a. Histologically confirmed hepatocellular carcinoma 
b. Axial imaging consistent with liver cirrhosis and at least one solid 
liver lesion ≥2 cm with early enhancement and delayed enhancement 
washout regardless of alpha-fetoprotein (AFP) levels. 
c. AFP ≥ 400 ng/ml and evidence of at least one solid liver lesion ≥ 2 cm 
regardless of specific imaging characteristics. 
2. Locally advanced or metastatic disease. 
a. Patients with locally advanced disease must have disease deemed to   
be unresectable or not eligible for hepatic transplantation surgical 
oncologist or transplant physician.  
b. Measurable disease, as defined as lesions that can accurately be 
measured in at least one dimension (longest diameter to be 


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measured) according to Response Evaluation Criteria in Solid 
Tumors (RECIST, version 1.1) at least 2 cm with conventional 
techniques or at least 1 cm with spiral computed tomography. 
3. Child-Pugh Score A or B7. 
4. Age ≥ 18 years. 
5. Eastern Cooperative Oncology Group (ECOG) Performance Score of 0-2. 
6. Absolute neutrophil count ≥ 1,200 cells/mm3. 
7. Platelet count ≥ 70,000 cells/mm3. 
8. Total bilirubin ≤ 3.0 mg/dl. 
9. Hemoglobin ≥ 8.5 g/dl. 
10. INR ≤ 1.8 (therapeutic anticoagulation allowed as long as medically 
indicated.) 
11. Creatinine ≤ 1.5 times upper limit of normal. 
12. Women of childbearing potential must have a negative pregnancy test. 
13. No clinically significant episode of gastrointestinal bleeding within the 
previous 30 days. 
14. Men and women of childbearing potential must be willing to consent to using 
effective contraception while on treatment and for at least 3 months thereafter. 
15. At least 4 weeks since prior locoregional therapy including surgical resection, 
radiotherapy, hepatic arterial embolization or chemoembolization, 
radiofrequency ablation, percutaneous injection or cryoablation (treatment of 
target lesion only, non-target lesions can be treated with locoregional therapy).  
Provided the target lesion increased in size by 25% or more or the target 
lesion was not treated with locoregional therapy. 
16. Greater than 4 weeks since prior interferon therapy. 
17. Greater than 4 weeks since prior and no concurrent use of rifampin or St 
John’s wort. 
18. Prior antiviral therapy is allowed. 
19. Life expectancy > 12 weeks. 
20. Ability to understand informed consent and signing of written informed 
consent prior to initiation of protocol therapy. 
21. Non-English speaking patients will be enrolled. 
6.2 Subject Exclusion Criteria 
1. History of bleeding diathesis or coagulopathy. 
2. Symptomatic or clinically active brain metastases. 
3. Major surgery within previous 4 weeks. 
4. Clinically significant non-gastrointestinal bleeding within previous 12 months. 
5. Concurrent hormone therapy (including hormone replacement therapy and 
anti-estrogen). 
6. History of any condition requiring anti-platelet therapy with the exception of 
general cardiovascular prophylaxis with aspirin. 
7. History of thromboembolic events (including both pulmonary embolisms and 
deep vein thrombosis but not including tumor thrombus) 
8. Active infection 
9. Patients who are pregnant or lactating. 


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10. Hypersensitivity to IV contrast not suitable for pre-medication. 
11. Patients with known hypersensitivity to any of the components of bavituximab 
or sorafenib. 
12. Any other medical condition, including mental illness or substance abuse 
deemed by the investigators to likely interfere with a patient’s ability to sign 
informed consent, cooperate and participate in the study or follow-up 
procedures.  
13. Patients with human immunodeficiency virus (HIV). 
14. Significant history of cardiac diseases, including any of the following: 
a.  LVEF < 40% by MUGA or myocardial scintigram. 
b.  NYHA class III-IV congestive heart failure. 
c.  Myocardial infarction within previous 6 months. 
d.  Cardiac arrhythmias requiring anti-arrhythmic therapy (other than beta     
blockers or digoxin) 
15. Evidence of poorly controlled hypertension (medically controlled hypertension 
is allowed provided blood pressure ≤150/90.) 
16. History of liver or renal transplantation. 
17. Prior adjuvant therapy with sorafenib or other Raf/MEK/RAS or VEGFR 
inhibitors. Prior adjuvant therapy is allowed provided it was completed > 6 
months ago and there is documented recurrence of hepatocellular carcinoma. 
 
7.0      RECRUITMENT PLAN 
The study will be open to all patients seen at the UT Southwestern Medical Center 
(including Parkland Memorial Hospital System, UT Southwestern-St. Paul 
Hospital and the Harold C. Simmons Cancer Center), VA-North Texas, and UT 
Austin-Seton who meet the eligibility criteria outlined in section 6.0. 
In addition, a description of the study and the enrollment criteria will placed on 
the UT Southwestern Medical Center website to maximize patient recruitment. 
Patients will be identified from surgical, hepatology, gastroenterology and 
medical oncology clinics for treatment of their disease.  After a discussion of the 
patient’s disease and a formulation of the initial treatment plan, the physician-
investigator will describe the study to the patient.  The protocol will be discussed 
in a private clinic room or office.  Details including the risks and obligations of 
the subjects will be explained.  For non-English speaking patients, an independent 
translator will be available to communicate the details of the protocol.  A research 
coordinator will be available either in the clinic or by phone to answer any 
additional questions.  
Upon completion of the informed consent form and confirmation of protocol 
eligibility, the Clinical Research Office (CRO) at the Harold C. Simmons Cancer 
Center will be notified of the new enrollment.  All patients will be entered into the 
Velos Clinical Trials Management System for ongoing monitoring. 
The investigators take due notice of the NIH policy concerning inclusion of 
women and minorities in clinical research populations.  There will be no 
limitation to access with regard to race or gender.  Patients will be required to 


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read, agree to and sign an IRB-approved informed consent form prior to 
registration on this trial.  The registration procedure will be conducted as 
described above.  Patients will not receive payment for their participation on this 
study.  
8.0       PRETREATMENT EVALUATION 
 
8.1 
Phase I component 
 
To be completed within 30 +/- 3 days of starting therapy; 
 
 CT abdomen or MRI abdomen with liver protocol 
 A 12 lead electrocardiogram 
 Bilateral venous duplex of lower extremities 
 Documentation of all measurable or non-measurable disease 
parameters including radiographic imaging procedures within four 
weeks of study entry, and measure of biochemical marker of 
disease (if applicable) within four weeks of study entry.  The 
RECIST criteria as defined by CTEP 
(http://ctep.info.nih.gov/policies) define measurable and non-
measurable disease. 
 Signed informed consent for study participation. 
To be completed within 14 +/- 3 days of starting therapy: 
 History and physical examination, including height, weight, 
calculated body surface area (BSA), vital signs (temperature, pulse 
rate, respiration rate, blood pressure), and performance status 
(ECOG).  See Appendix A for ECOG scale. 
 Serum pregnancy test for all women of childbearing potential 
within 14 days of starting therapy.  If the test result is positive, the 
patient will not be allowed to participate in the study. 
 Laboratory evaluation and coagulation parameters 
o CBC with differential and platelet count 
o Serum chemistries (Na, Cl, BUN, Creatinine, K, 
bicarbonate and glucose), albumin and calcium  
o Liver function tests (AST, ALT, alkaline phosphatase, total 
bilirubin),  
o Coagulation parameters (aPTT, PT and INR)  
o Urinalysis, record protein, glucose and blood 
 Recording of concomitant medications 
 
 
 


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8.2 Phase II component 
To be completed within 30 +/-5 days of starting therapy; 
 
 CT or MRI abdomen with liver protocol 
 A 12 lead electrocardiogram 
 Biopsy (US or CT guided) of malignancy with histologic 
confirmation  
 Bilateral venous duplex of lower extremities 
 Documentation of all measurable or non-measurable disease 
parameters including radiographic imaging procedures within four 
weeks of study entry, and measure of biochemical marker of 
disease (if applicable) within four weeks of study entry.  The 
RECIST criteria as defined by CTEP 
(http://ctep.info.nih.gov/policies) define measurable and non-
measurable disease. 
 Signed informed consent for study participation. 
To be completed within 14 +/- 5 days of starting therapy: 
 History and physical examination, including height, weight, 
calculated body surface area (BSA), vital signs (temperature, pulse 
rate, respiration rate, blood pressure), and performance status 
(ECOG).  See Appendix A for ECOG scale. 
 Serum pregnancy test for all women of childbearing potential 
within 14 days of starting therapy.  If the test result is positive, the 
patient will not be allowed to participate in the study. 
 Laboratory evaluation and coagulation parameters 
o CBC with differential and platelet count 
o Serum chemistries (Na, Cl, BUN, Creatinine, K, 
bicarbonate and glucose), albumin and calcium  
o Liver function tests (AST, ALT, alkaline phosphatase, total 
bilirubin),  
o Coagulation parameters (aPTT, PT and INR)  
o Urinalysis, record protein, glucose and blood 
o Alfa-fetoprotein 
o Viral hepatitis titers 
 Recording of concomitant medications 
 
9.0      TREATMENT/INTERVENTION PLAN 
9.1 
Therapy (Bavituximab and Sorafenib) 
All therapy must be delivered within the UT Southwestern Medical Center and 
affiliates, VA-North Texas, and UT Austin-Seton. 
Eligible patients with advanced HCC will receive the following: 


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Bavituximab: 
Phase I:  0.3 mg/kg, 1.0 mg/kg, or 3.0 mg/kg IV over 90 
minutes weekly until disease progression or completion of 
1 cycle of treatment.  The dose of bavituximab will be 
determined by the progression of the standard 3+3 dose 
escalation rule explained in section 11.0. 
Phase II: 0.3 mg/kg,1.0 mg/kg, or 3.0 mg/kg IV over 90 
minutes weekly until disease progression or DLT.  The 
dose of bavituximab will be determined as the MTD from 
the phase I component as described in section 11.0. 
Sorafenib: 
200 mg PO twice a day escalating to 400 mg PO twice a 
day at the discretion of the treating oncologist. 
A cycle constitutes 4 doses of bavituximab and 4 weeks of daily sorafenib. The 
treatment schema is shown below for one cycle of therapy. 
 
Patients will be seen the day of, or within one day preceding administration of and 
bavituximab.  An interim medical history, with particular reference to toxicities, 
including medication review and physical examination will be conducted at each 
therapy treatment visit. 


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A therapy treatment may be moved +/- 5 days for specific administration reasons, 
including clinic closure for holidays. Pre-treatment laboratory values will be 
captured during therapy treatment. 
9.2 
Therapy (Bavituximab and Sorafenib) Treatment Parameters 
Parameters for initiation of therapy (day 1) cycle #1 are as follows: 
 Absolute neutrophil count ≥ 1,200 cells/mm3 
 Platelet count ≥ 70,000/mm3 
 Hemoglobin ≥ 8.5 g/dl 
 Creatinine ≤ 1.5 times upper limit of normal 
 Total bilirubin ≤ 3.0 mg/dl 
Parameters for subsequent cycles of therapy (cycles 2-6+) on day of or day-1 pre-
therapy: 
 Absolute neutrophil count ≥ 1,000 cells/mm3 
 Platelet count ≥ 50,000/mm3 
 Total bilirubin ≤ 5.0 mg/dl 
All laboratory and coagulation evaluations as listed in the screening period should 
be performed prior to start of each cycle. 
If above parameters are not met for therapy, hold until recovered, maximum 4 
weeks then re-treat per section 9.4, Dose Delays and Modifications.  
9.3 
Supportive Care Guidelines for Therapy (Bavituximab and 
Sorafenib) 
 Recommended anti-emetics for therapy regimen 
o Bavituximab and sorafenib are minimal risk emetogenic regimens. 
The anti-emetic regimen is per institution guidelines and typically 
includes no additional anti-emetic therapy. 
 Recommended pre-medication regimen to reduce infusion reactions 
o The recommended pre-medication regimen includes the following 
prior to bavituximab infusion prior to infusion: 
 
 Hydrocortisone 250 mg IV on all days of IV therapy 
 Diphenhydramine 50 mg IV on all days of IV therapy 
The dose of hydrocortisone may be reduced or omitted where medically indicated 
(i.e. diabetes). 
Concurrent supportive care is not restricted, including the use of narcotics for pain 
control, anti-emetics or anti-diarrheals.  No concurrent chemotherapy, 
immunotherapy, radiation therapy or chemoembolization is permitted during 
therapy.  Use of epoetin alfa and white blood cell support is permitted at the 
discretion of the treating physician. 


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9.4 
Therapy (Bavituximab and Sorafenib) Dose Delay and Modification 
Treatment may be delayed no more than 4 weeks to allow recovery from acute 
toxicity, i.e. if treatment ends up being held for a total of >4 weeks due to toxicity, 
the patient should come off study.   
Dose reductions are to be made according to the system showing the greatest 
degree of toxicity.  Toxicities will be graded according to the National Cancer 
Institute (NCI) Common Toxicity Criteria (CTC) Version 4.0 
(http://ctep.cancer.gov/forms/CTCAEv4.pdf). 
Management of Toxicities Specific for Sorafenib 
 Dose modification for skin toxicity 
o Grade 1:  Continue sorafenib and consider symptomatic treatment 
with topical therapy 
o Grade 2: 
 First occurrence: Continue sorafenib and consider 
symptomatic treatment with topical therapy 
 Second or third occurrence: Hold treatment until resolves to 
grade 0 or 1: resume treatment with dose reduced by one 
dose level (400 mg daily or 400 mg every other day) 
 Fourth occurrence: discontinue drug 
o Grade 3: 
 First or second occurrence: Hold treatment until resolves to 
grade 0 or 1: resume treatment with dose reduced by one 
dose level (400 mg daily or 400 mg every other day) 
 Third occurrence: discontinue drug 
There will be no listed dose delay or modification specific for bavituximab other 
than those illustrated in section 14.0. 
10.0 
EVALUATION DURING TREATMENT/INTERVENTION 
 
Investigations/Tests Baseline At Each Dose 
of 
Bavituximab 
6 Weeks (+/-5 
days) After 
Initiation of 
Therapy 
Detailed history and 
physical 
examination 
(including height, 
weight, ECOG, 
vitals) 
 
X 
X (Day 1 of 
each cycle 
only)  
 
Written Informed 
Consent 
X 
 
X (for image 
guided biopsy 


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30
of tumor) 
(phase II only) 
EKG 
X 
 
 
Research Serum 
X 
(phase II 
only) 
 
X (and every 6 
weeks 
thereafter) 
(phase II only) 
Image-guided 
biopsy of tumor,  
 
X 
(phase II 
only) 
 
X (phase II 
only, between 5 
and 6 weeks) 
Hematology (CBC 
with differential) 
 
X 
X 
 
Liver function tests 
(including total 
bilirubin, AST, 
ALT) 
 
X 
X 
 
Coagulation tests 
(including PT, 
aPTT, INR) 
 
X 
X 
 
Urinalysis 
X 
 
 
Alpha-fetoprotein 
X  
X 
 
MRI abdomen with 
gadolinium or CT 
Abdomen  
X 
 
X (and every 6 
weeks 
thereafter) 
(phase II only) 
Bilateral lower 
extremity venous 
duplex 
 
X  
 
X (phase II 
only) 
Viral hepatitis titers 
(Hepatitis B and C) 
X 
(phase II 
only) 
 
 
 
Investigations/tests at study exit due to disease progression or toxicity or 
following completion of the phase I component 
 Bilateral venous duplex of lower extremities 


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31
 History and physical examination (this will continue every 6 weeks for 
determination of secondary endpoint of overall survival) 
 Laboratory tests: same as required at baseline 
 
10.1 
Correlative Studies (Phase II patients only) 
Pathology Correlative Studies 
 A major obstacle to molecularly targeted chemotherapeutic agents has been 
obtaining relevant tumor tissue to measure the agents’ biologic effects on target 
molecules or cellular pathways within the tumor.  The utilization of sequential 
tumor biopsies to obtain tissue following treatment is well established in breast 
and colorectal carcinoma. (30) However, sequential tumor biopsies of liver 
tumors are less established due to a fear of procedural complications.  The fear of 
bleeding events following liver biopsy of HCC appears unfounded and based on 
anecdotal evidence.  A large, multi-institutional trial where patients with 
advanced chronic hepatitis C underwent sequential liver biopsies demonstrated 16 
cases (0.6%) of bleeding following 2740 liver biopsies.  There were no deaths 
from peri-procedural bleeding and a platelet count under 60000 was identified as 
a risk factor. (31) Two large published series of core needle biopsy of HCC as a 
diagnostic measure report bleeding events in less than 1% of patients with no 
reported mortalities.  In both series capsular location of HCC was associated with 
increased incidence of bleeding event. (32,33) 
In this study all patients will potentially undergo up to two image-guided (either 
CT or ultrasound) core needle biopsy of a single site of HCC at baseline (for 
clinical care) and between five and six weeks after the initiation of bavituximab. 
In addition to the patients receiving treatment as part of this clinical trial, patients 
identified from the HCC clinics at UT Southwestern who are initiating sorafenib 
monotherapy will undergo biopsies at baseline and between five and six weeks 
after initiation. These biopsies are not mandatory to initiate or continue with 
therapy and are subject to a separate informed consent.  To increase patient safety 
the following conditions must be met prior to liver biopsy: 
 Platelet count ≥ 70,000 
 INR ≤ 1.8 
 Target lesion not subcapsular in nature as determined by the 
participating interventional radiology team 
 Sorafenib will be discontinued for a period of 24-48 hours prior to 
biopsy 
The patient will sign the informed consent for participation in research liver 
biopsy prior to the procedure. The liver biopsy will be performed by 
radiologists and the ancillary staff of Department of Radiology following the 
standard clinical protocol, which includes obtaining a separate informed 
consent for the procedure itself.  The core samples will be provided to the 
surgical oncology laboratory. If a core biopsy is performed as a part of the 


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32
patient’s clinical care, extra cores will be obtained for surgical oncology 
laboratory, in addition to the cores necessary for clinical care.  All cores will 
be obtained through the same needle to avoid the need of additional 
punctures and to minimize associated risks. 
We will plan to use this tissue to correlate patient outcome measures with markers of 
anti-angiogenesis therapy and immune response modulation on patients with matched 
samples.  Specifically, we will perform the following tissue based analysis at baseline 
and 5 and 6 following initiation of either monotherapy with sorafenib or combination 
therapy with bavituximab and sorafenib : 
 Histologic analysis of cell infiltrate of the tumor (specifically macrophage 
and T cell, both cytotoxic and regulatory) 
 Localization of PS exposure on tumor vascular endothelium 
 Markers of immune response including T cell activation assays 
 Analysis of angiogenic, hypoxia and RAS/MAPK pathway tissue 
biomarkers  
These tissue-based analyses will be correlated with the primary endpoint of time 
to progression. The collection of tissue in patients treated with sorafenib alone 
and with combination of sorafenib and bavituximab will allow us to further define 
the mechanism of action as it pertains to bavituximab. We believe the liver 
biopsies provide minimal risk to the patient and will allow us to validate whether 
the therapy regimen affects intended molecular targets to further elucidate 
mechanism of action. This will allow us in the future to develop a predictive 
profile to tailor this regimen in patients who will show the most benefit. 
Laboratory Correlative Studies 
The kinetics of alpha-fetoprotein and viral hepatitis titers (in those patients with 
baseline elevation) may serve as an early indicator of response to treatment in 
patients with advanced HCC.  These biomarkers have been associated with 
response to sorafenib therapy and may serve as a predictive biomarker to 
treatment outcome with the bavituximab and sorafenib regimen.  We plan to 
conduct an analysis of alfa-fetoprotein and viral hepatitis titer levels as biomarker 
surrogates of outcome.  Specifically, alfa-fetoprotein titers will be drawn at 
baseline, at 2 weeks after initiation of therapy and every 6 weeks thereafter while 
still enrolled in the study.  Quantitative changes in alfa-fetoprotein will be 
described for patients where matched samples are available and will be correlated 
with the primary clinical endpoint of time to progression. 
In addition, serum angiogenic and hypoxia biomarkers will be analyzed from 
serum and plasma samples collected from patients treated with bavituximab and 
sorafenib and sorafenib alone. Blood will be collected in two separate vacutainer 
tubes, a red top with no additive and a purple top with EDTA additive. 


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Quantitative changes in the above biomarkers will be described for patients where 
matched samples are available and will be correlated with the primary clinical 
endpoint of time to progression. 
The biopsy and serum samples for the above correlative studies will be shipped to 
Peregrine Pharmaceuticals for the completion of only the listed studies.  The 
samples will be de-identified and shipped with codes only known to the primary 
investigator.  All left over tissue or serum will be destroyed by Peregrine 
Pharmaceuticals. 
11.0 
DOSE-LIMITING TOXICITIES-PHASE I COMPONENT 
The phase I component of the study will consist of a traditional 3+3 dose 
escalation rule with the dose of sorafenib remaining constant and the dose of 
bavituximab escalating up to 3.0 mg/kg weekly to determine the maximum 
tolerated dose (MTD) that will be used during the phase II component. Sorafenib 
has been demonstrated in multiple phase I and II studies in advanced HCC to have 
minimal toxicity and to be safe, therefore doses will be constant. (13,14) Cohorts 
of three patients will be assigned to one dose level of bavituximab starting at 0.3 
mg/kg weekly.   Only the first cycle of therapy (4 doses of bavituximab and 4 
weeks of sorafenib constitutes a cycle) will be used to determine dose limiting 
toxicity (DLT). The patients will be followed for thirty days following the end of 
the first cycle for adverse events. These adverse events will be submitted to the 
Data Safety Monitoring Committee for evaluation.  During this thirty-day period 
and beyond patients will be administered sorafenib at the discretion of the treating 
oncologist. Patients will be enrolled into the next highest drug cohort only after 3 
or 6 patients have completed the first cycle of therapy. The number of observed 
toxicities is counted and the traditional escalation rule applied: 
 No toxicity: the next three patients will be assigned to next higher 
dose level (3.0 mg/kg of bavituximab is the highest dose assigned). 
 At least two toxicities: the MTD is exceeded and the phase I 
component of the trial will be stopped with the next lowest dose to 
be defined as the MTD that will be used in the phase II component. 
 One toxicity: the cohort will be expanded to 6 patients. 
o One DLT within the last six patients:  The next cohort of 
three patients will be assigned to the next highest dose level 
o At least two DLTs within the last six patients: the MTD is 
exceeded and the phase I component of the trial will be 
stopped with the next lowest dose to be defined as the dose 
that will be used in the phase II component. 
The Data and Safety Monitoring Committee and investigators as described below 
will regularly review all adverse events. The study will utilize the Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.0 for grading of all 
adverse events related to treatment. 


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The following will be considered a dose-limiting toxicity: 
 
 Grade 4 neutropenia and thrombocytopenia ≥ 7 days (absolute granulocyte 
count < 0.5 x 109/L) 
 platelet count < 25,000 
 ALT or AST levels ≥ grade 3 adverse event for 7 days 
 ≥ grade 3 adverse event for any non-hematologic toxicity (excluding 
alopecia and non-premedicated nausea/vomiting) attributable to drug 
therapy by the definition of definite or probable and not possibly.  In the 
SHARP trial patients in the placebo arm had over a 50% ≥ grade 3 adverse 
event rate due to the comordities seen in the patient population with 
advanced HCC.   
 
12.0 
TOXICITIES/SIDE EFFECTS 
12.1 
Sorafenib 
1. Cardiac ischemia and/or infarction:  The incidence of cardiac 
ischemia/infarction was 2.7% in NexavarTM patients compared with 1.3% 
in the placebo group and in patients treated with renal cell carcinoma. 
Temporary or permanent discontinuation of NexavarTM should be 
considered in patients who develop cardiac ischemia and/or infarction. 
2. Risk of hemorrhage: An increased risk of bleeding may occur following 
NexavarTM administration. In the SHARP trial, an excess of bleeding 
regardless of causality was not apparent and the rate of bleeding from 
esophageal varices was 2.4% in NexavarTM patients and 4% in placebo 
patients. 
3. Hypertension: Blood pressure should be monitored weekly during the first 
6 weeks of NexavarTM therapy and thereafter monitored and treated, if 
required, in accordance with standard medical practice. In the SHARP 
trial, hypertension was reported in approximately 9.4% of NexavarTM -
treated patients and 4.3% of patients in the placebo group. 
4. Dermatologic: Hand-foot skin reaction and rash represent the most 
common adverse reactions attributed to NexavarTM. Rash and hand-foot 
skin reaction are usually CTCAE Grade 1 and 2 and generally appear 
during the first six weeks of treatment with NexavarTM. Management of 
dermatologic toxicities may include topical therapies for symptomatic 
relief, temporary treatment interruption and/or dose modification of 
NexavarTM, or in severe or persistent cases, permanent discontinuation of 
NexavarTM.  
12.2 
Bavituximab 
1. Thromboembolic events: in the initial studies administering bavituximab   
for patients with chronic HCV infection there were no reports of 


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thromboembolic events including arterial thrombosis or venous 
thrombosis (deep vein thrombosis or pulmonary embolism).  In later 
studies combining bavituximab and chemotherapy in cancer patients there 
was a small increase in thromboembolic events.  These events were 
mainly deep vein thrombosis or pulmonary embolism.  There were no fatal 
events attritubutable to these adverse events and it is unclear whether the 
events were a direct result of combined chemotherapy or the inherent risk 
of thromboembolic events seen in cancer patients. 
2. Infusion reactions: Bavituximab is a chimeric antibody and some patients 
may experience side effects associated with monoclonal antibody therapy, 
including allergic/hypersensitivity reactions or cytokine release 
syndrome/acute infusion reactions. There is significant overlap between 
these reactions, with common manifestations including (but not limited 
to):  drug fever, flushing, rash, dyspnea, bronchospasm, or hypotension. In 
studies investigating bavituximab in combination with chemotherapy, pre-
medication with antihistamines and/or steroids was administered resulting 
in 20-30% Grade I or II adverse infusion reactions. These have been 
generally well tolerated, and have not required an alteration in 
bavituximab dosing. 
3. Prolonged coagulation times: Prolonged coagulation times (e.g., aPTT) 
have been observed in preclinical and clinical studies that are not 
associated with significant bleeding.  In clinical studies, prolongation of 
aPTT has been noted at the highest doses administered (3 and 6 mg/kg).  
This concentration- dependent, transient and reversible phenomenon is 
believed to be due to in vitro assay interference and does not pose a 
significant bleeding risk to patients. 
4. Gastrointestinal: Nausea, vomiting and anorexia occur infrequently and 
are self-limiting without additional treatment. 
 
Because of the potential for thrombogenicity with agents such as bavituximab, 
patients will be monitored for the development of thromboembolic events as 
follows:  
 
Regular assessment of blood coagulation parameters (PT, INR, aPTT). 
Regular screening for potential arterial or venous thromboses during 
physical examination 
 
Regular bilateral lower extremity venous doppler ultrasound 
Thrombotic/thromboembolic events including, but not limited to, superficial 
thrombophlebitis, deep vein thrombosis, pulmonary embolism, 
cerebrovascular accident, ischemic stroke, coronary thrombosis, myocardial 
infarction, myocardial ischemia (including isolated ECG findings), arterial 
embolism, arterial thrombosis, catheter-related thrombosis, or intra-abdominal 
thromboembolism should be captured as an adverse event. Tumor thrombus is 
not a thrombotic/thromboembolic event and will not be captured as an AE. 


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Note:  Elevated d-dimer alone does not constitute a thrombotic AE and should 
not be captured as such.   
13.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 
(Phase II Component) 
 
For the purposes of this study, patients will be evaluated for response at 2 weeks 
after the first cycle of bavituximab and every 6 weeks thereafter. RECIST criteria 
are included below. 
 
13.1 
Definitions 
Response and progression will be evaluated in this study using the new 
international criteria proposed by the Response Evaluation Criteria in Solid 
Tumors (RECIST) Committee [JNCI 92(3):205-216, 2000].  Changes in only the 
largest diameter (unidimensional measurement) of the tumor lesions are  
used in the RECIST criteria. Note:  Lesions are either measurable or non-
measurable using the criteria provided below. The term “evaluable” in reference 
to measurability will not be used because it does not provide additional meaning 
or accuracy.  
 
13.1.1 Measurable disease 
 
 
 
Measurable lesions are defined as those that can be accurately measured in at least 
one dimension (longest diameter to be recorded) as > 20 mm with conventional 
techniques (PET, CT, MRI, x-ray) or as > 10 mm with a high-resolution CT scan.  
All tumor measurements must be recorded in millimeters or decimal fractions of 
centimeters.  A “high-resolution” CT scan is one in which images are recorded at 
least every 5 mm.  
 
 
 
13.1.2 Non-Measurable disease 
 
All other lesions (or sites of disease), including small lesions (longest diameter < 
20 mm with conventional techniques or < 10 mm using spiral CT scan), are 
considered non-measurable disease.  Bone lesions, leptomeningeal disease, 
ascites, pleural / pericardial effusions, lymphangitis cutis/pulmonis, inflammatory 
breast disease, abdominal masses (not followed by CT or MRI), and cystic lesions 
are all non-measurable. 
 
13.1.3 Target lesions 
 
All measurable lesions up to a maximum of five lesions per organ and 10 lesions 
in total representative of all involved organs should be identified as target lesions 
and recorded and measured at baseline.  Target lesions should be selected on the 
basis of their size (lesions with the longest diameter) and their suitability for 
accurate repeated measurements (either by imaging techniques or clinically).  A 


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sum of the longest diameter (LD) for all target lesions will be calculated and 
reported as the baseline sum LD.  The baseline sum LD will be used as reference 
by which to characterize the objective tumor response.  
 
13.1.4 Non-target lesions 
All other lesions (or sites of disease) that are not target lesions as defined in 
section 13.1.3 will be identified as non-target lesions and should also be recorded 
at baseline.  Non-target lesions include measurable lesions that exceed the 
maximum numbers per organ or total of all involved organs as well as non-
measurable lesions.  Measurements of these lesions are required when feasible, 
since a patient may have progressive disease on the basis of larger non-target 
lesions. The presence or absence of each non-target lesion should be noted 
throughout follow-up. 
 
13.2 
Evaluation of target lesions 
 
Complete Response (CR):  Disappearance of all target lesions. The patient must 
be free of all symptoms of cancer.  
  
Partial Response (PR):  At least a 30% decrease in the sum of the longest 
diameter (LD) of target lesions taking as reference the baseline sum LD.  Positive 
washing, brushing or biopsy and/or residual tumor may still be evident on 
endoscopy and/or CT scan. No lesion may increase in size and no new lesion may 
appear.  
 
Progression (PD):  At least a 20% increase in the sum of LD of target lesions 
taking as reference the smallest sum LD recorded since the treatment started or 
the appearance of one or more new lesions.  
 
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD taking as references the smallest sum LD.  
 
13.3 
Evaluation of non-target lesions 
 
Complete Response (CR): Disappearance of all non-target lesions and 
normalization of tumor marker level.  
 
Non-Complete Response (non CR):  Persistence of one or more non-target lesions 
or/ and maintenance of tumor marker level above the normal limits. 
 
Progression (PD):  Appearance of one or more new lesions. Unequivocal 
progression of existing non-target lesions. (Although a clear progression of "non-
target" lesions only is exceptional, in such circumstances, the opinion of the 
treating physician should prevail, and the progression status should be confirmed 
at a later time by the reference radiologist (or study chair).  
 


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13.4 
Evaluation of best overall response 
 
The best overall response is the best response recorded from the start of the 
treatment until disease progression/recurrence (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started). The 
patient's best response assignment will depend on the achievement of both 
measurement and confirmation criteria.   
 
 
Target Lesions 
Non-target lesions 
New lesions 
Overall response 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
 
 
1.  Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
reported as "symptomatic deterioration". Every effort should be made to 
document the objective progression even after discontinuation of treatment.  
  
2.  In some circumstances, it may be difficult to distinguish residual disease from 
normal tissue. When the evaluation of complete response depends upon this 
determination, it is recommended that the residual lesion be investigated (fine 
needle aspirate/biopsy) before confirming the complete response status. 
 
13.5 
Guidelines for evaluation of measurable disease 
 
All measurements should be recorded in metric notation using a ruler or calipers. 
All baseline evaluations should be performed as close as possible to the treatment 
start and never more than 4 weeks before the beginning of the treatment. The 
same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. Imaging-
based evaluation is preferred to evaluation by clinical examination when both 
methods have been used to assess the antitumor effect of a treatment.  
 
• Clinical lesions will only be considered measurable when they are 
superficial (e.g. skin nodules, palpable lymph nodes). In the case of skin 
lesions, documentation by color photography including a ruler to estimate the 
size of the lesion is recommended. 


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39
 
• Lesions on chest X-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung. However, CT is preferable.  
 
• Conventional CT and MRI should be performed with cuts of 10 mm or less 
in slice thickness contiguously. Spiral CT should be performed using a 5 mm 
contiguous reconstruction algorithm. This applies to the chest, abdomen, and 
pelvis. Head & neck and extremities usually require specific protocols.  
 
• When the primary endpoint of the study is objective response evaluation, 
ultrasound (US) should not be used to measure tumor lesions that are 
clinically not easily accessible. It is a possible alternative to clinical 
measurements of superficial palpable nodes, subcutaneous lesions, and 
thyroid nodules. US might also be useful to confirm the complete 
disappearance of superficial lesions usually assessed by clinical examination.  
 
 
13.6 
Confirmatory measurement/duration of response 
 
Confirmation:  The main goal of confirmation of objective response is to avoid 
overestimating the response rate observed.  In cases where confirmation of 
response is not feasible, it should be made clear when reporting the outcome of 
such studies that the responses are not confirmed.  To be assigned a status of PR 
or CR changes in tumor measurements must be confirmed by repeat studies that 
should be performed 4 weeks after the criteria for response are first met. In the 
case of SD, follow-up measurements must have met the SD criteria at least once 
after study entry at a minimum interval of 8 weeks.  
 
Duration of overall response:  The duration of overall response is measured from 
the time measurement criteria are met for CR/PR (whichever is first recorded) 
until the first date that recurrent or progressive disease is objectively documented, 
taking as reference for progressive disease the smallest measurements recorded 
since the treatment started). 
 
The duration of overall complete response is measured from the time 
measurement criteria are first met for CR until the first date that recurrent disease 
is objectively documented.  
 
Duration of stable disease:  Stable disease is measured from the start of the 
treatment until the criteria for progression are met, taking as reference the 
smallest measurements recorded since the treatment started.  
 
14.0 
CRITERIA FOR REMOVAL FROM STUDY 
 
 
In the absence of serious toxicity or complications, all patients will receive at least 
one cycle of treatment.  In the absence of treatment delays due to adverse 
event(s), treatment may continue until one of the following criteria applies: 


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40
 
 Disease recurrence/progression, defined as emergence of an unequivocal 
new tumor (site of metastasis) > 1 cm in size, clinical progression in non-
measurable sites of disease, or unequivocal changes in size of the primary 
tumor.  
 Development of an intercurrent medical condition or need for 
concomitant treatment that precludes further participation in the trial. 
 Unacceptable toxicity or any adverse event that precludes further 
participation in the trial. 
 The investigator removes the patient from the trial in the best interests of 
the patient. 
 Patient death. 
 Study completion or discontinuation. 
 Patient withdraws consent to continued participation in the trial or is lost 
to follow-up. 
 
15.0 
BIOSTATISTICS 
 
The study is an open-label, non-randomized single-arm, single institution phase 
I/II therapeutic clinical trial.  The study population will be patients with advanced 
hepatocellular carcinoma. 
 
 
 
15.1 
Sample size calculation 
 
The phase I component of the study will consist of a traditional 3+3 dose 
escalation rule with 3 or 6 patients in each cohort, the process for dose escalation 
is outlined in section 4.1. 
 
The median TTP of patients with advanced HCC treated with sorafenib therapy is 
5.5 months.  Using this as a benchmark, we will enroll 38 patients, which will 
allow us to differentiate between a median TTP of 5.5 months and 8.3 months 
with 80% power and a two-sided significance level of 10% assuming a 24-month 
accrual and a 12-month follow-up period.  TTP will be calculated from initiation 
of therapy to disease progression  (intention to treat) as outlined in section 13.0.  
Removal from study as outlined in section 14 will be a censored event. 
 
15.2 
Secondary endpoints 
 
Secondary endpoints of efficacy are to evaluate overall survival, progression-free 
survival and response rates.  The overall survival and progression-free survival 
will be estimated using the Kaplan-Meier method, and Greenwood’s formula will 
be used to calculate the standard error of the corresponding Kaplan-Meier 
estimate and 95% confidence interval.  Survival curves will be estimated using 
Kaplan-Meier methodology.  Response rates will be calculated as described in 
section 13.4.  Accrual is expected to take 2 years with a minimum of 1year 
subsequent follow-up, overall follow-up will range from 1 to 3 years. 
 


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Other secondary objectives will include description of toxicity of the therapy 
regimen.  These data will be analyzed separately.  The safety analyses will be 
performed on all patients who receive any dose of therapy.  Adverse events will 
be described using the NCI CTCAE v 4.0 criteria 
(ctep.cancer.gov/forms.CTCAEv4.pdf).  Frequency and severity of adverse events 
according to the NCI CTCAE v# body system and severity criteria will be 
described.  In addition, frequency of Grade 3 or 4 adverse events will be described 
separately.  Causality will also be noted. Adverse events will be recorded for up to 
1 year following discontinuation from study.  
 
Laboratory assessments will also be described according to the NCI CTCAE v 4 
criteria, with separate descriptions for Grade 3 or 4 laboratory abnormalities.  
Clinically significant laboratory abnormalities will be described as well.  Serious 
adverse events will be summarized, including a causality assessment.   
 
The number of treatment cycles and doses administered will be summarized using 
descriptive statistics.  Treatment delays will summarized using counts and 
percentages.  
 
 
Patients’ disposition will be summarized in the following manner: 
 
 The number and percentage of patients selected, included, completed, 
withdrawn and lost to follow-up will be summarized using descriptive 
statistics. 
 Major protocol deviations will be summarized. 
 The reason for withdrawal (adverse events, lack of efficacy, major 
protocol deviation, non-medical reason, recovery or remission) will be 
summarized. 
 
For pathology-, laboratory- and imaging-correlative studies, Cox regression 
analysis will be conducted to investigate the association between TTP and 
parameters from correlative studies. 
 
16.0 
DATA MANAGEMENT  
 
 
16.1 
Data and Safety Monitoring 
 
 
The UTSW Simmons Cancer Center (SCC) Data Safety Monitoring Committee 
(DSMC) is responsible for monitoring data quality and patient safety for all 
UTSW SCC clinical trials.  As part of that responsibility, the DSMC reviews all 
local serious adverse events in real time as they are reported and reviews adverse 
events on a quarterly basis.  The quality assurance activity for the Clinical 
Research Office provides for periodic auditing of clinical research documents to 
ensure data integrity and regulatory compliance.  
  


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A detailed description of the Data and Safety Monitoring Plan is available in 
section X of the Clinical Research Office Operations Manual.  
 
The SCC DSMC meets quarterly and conducts annual comprehensive reviews of 
ongoing clinical trials, for which it serves as the DSMC of record. The QAC 
works as part of the DSMC to conduct regular audits based on the level of risk. 
Audit findings are reviewed at the next available DSMC meeting.  In this way, 
frequency of DSMC monitoring is dependent upon the level of risk.  Risk level is 
determined by the DSMC Chairman and a number of factors such as the patient 
population to be studied; adequacy of the data management system; and 
procedures to ensure the safety of study subjects based on the associated risks of 
the study.  Protocol-specific DSMC plans must be consistent with these 
principles. The following examples can be used to begin developing DSMC 
plans for individual protocols.  
 
 
High risk examples include Phase 1 studies; Phase II or III studies where 
the SCC is the DSMC; gene therapy or recombinant DNA studies; and studies in 
which the investigator holds the IND.  
 
 
Moderate risk examples include pilot studies and other Phase II or III 
studies where the SCC DSMC is not the DSMC of record and which involve a 
non-FDA approved drug. 
 
 
Low risk examples include Phase II or III studies involving FDA-
approved drugs where the SCC DSMC is not the DSMC of record, or trials, which 
involve non-therapeutic interventions. 
 
 
Exempt examples include non-interventional studies, which are exempt 
from audit requirements outlined above. 
 
17.0 
PROTECTION OF HUMAN SUBJECTS 
 
Participation in this trial is voluntary.  All patients will be required to sign a 
statement of informed consent, which must conform to IRB guidelines. 
 
 
Inclusion of Women and Minorities:  Patients of all races, both male and female, 
will be accepted into the protocol. 
 
Exclusion of Lactating or Pregnant Women:  Children have been excluded from 
this study.  Hepatocellular carcinoma is an adult cancer.  Thus, the relevance of 
this drug to the pediatric population has not been established.  Lactating and 
pregnant women are also excluded because of potential anti-proliferative effects 
of therapy that may be harmful to the developing fetus or nursing infant. 
 
Benefits:  It is possible that this treatment will result in shrinkage of 
hepatocellular carcinoma or in a stabilization of an otherwise progressing disease.  


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It is not know, of course, whether these or any other favorable events will occur.  
It is not known whether this treatment will affect overall survival of the patients. 
 
Costs:  The patient will be responsible for the costs of standard medical care, 
including, MRI scans (excluding the MRI scan at week 5 of treatment), all drug 
administration fees (excluding sessions where bavituximab is given), and all 
hospitalizations, even for complications of treatment.  Bavituximab will be 
supplied to patients without costs from Peregrine Pharmaceuticals.  Patients will 
not be responsible for the costs of tissue or serum procurement (including image 
guided biopsies) obtained for research purposes. 
 
Incentives:  No incentives will be offered to patients/subjects for participation in 
this study. 
 
Alternatives:  For patients with advanced hepatocellular carcinoma, alternative 
treatments may include other chemotherapy regimens or loco-regional therapies 
including transarterial chemoembolization and radiofrequency ablation.  At 
present, no specific treatment approach is considered standard of care for the 
disease.  Patients may be eligible for other investigational studies. 
 
Confidentiality:  Every effort will be made to maintain patient confidentiality.  
Research and hospital records are confidential.  Patient’s name or any personally 
identifying information will not be used in reports or publications resulting from 
this study.  The Food and Drug Administration or other authorized agencies (i.e., 
qualified monitors from UT Southwestern Medical Center, the NCI, etc.), may 
review patients records and pathology slides, as required. 
 
17.1 
Privacy 
 
It is the responsibility of the research staff to endure that protocol subjects receive 
the UT Southwestern Medical Center Notice of Privacy Practices.  
 
17.2 
Adverse Events 
 
Adverse Events will be reported as indicated by the appropriate following table 
(see below).    
 
Definition  
An adverse event is defined as any untoward or unfavorable medical occurrence 
in a human research study participant, including any abnormal sign (for example, 
abnormal physical exam or laboratory finding), symptom, clinical event, or 
disease, that occurs during the subject’s participation in the research, whether or 
not it is considered related to the subject’s participation in the research. 


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Adverse events encompass clinical, physical and psychological harms. Adverse 
events occur most commonly in the context of biomedical research, although on 
occasion, they can occur in the context of social and behavioral research. Adverse 
events may be expected or unexpected. 
Severity  
Adverse events will be graded by a numerical score according to the defined NCI 
Common Terminology Criteria for Adverse Events (NCI CTCAE) and version 
number specified in the protocol. Adverse events not specifically defined in the 
NCI CTCAE will be scored on the Adverse Event log according to the general 
guidelines provided by the NCI CTCAE and as outlined below.   
 
Grade 1: Mild  
 
Grade 2: Moderate 
 
Grade 3: Severe or medically significant but not immediately life 
threatening 
 
Grade 4: Life threatening consequences 
 
Grade 5: Death related to the adverse event 
 
Serious Adverse Events  
ICH Guideline E2A and the UTSW IRB define serious adverse events as those 
events, occurring at any dose, which meets any of the following criteria:  
 
Results in death   
 
Immediately life-threatening  
 
Results in inpatient hospitalization or prolongation of existing 
hospitalization  
 
Results in persistent or significant disability/incapacity  
 
Results in a congenital anomaly/birth defect  
 
Based upon appropriate medical judgment, may jeopardize the 
subject’s health and may require medical or surgical intervention to 
prevent one of the other outcomes listed in this definition. 
Note: A “Serious adverse event” is by definition an event that meets any of the 
above criteria. Serious adverse events may or may not be related to the research 
project. A serious adverse event determination does not require the event to be 
related to the research. That is, both events completely unrelated to the condition 
under study and events that are expected in the context of the condition under 
study may be serious adverse events, independent of relatedness to the study 
itself. As examples, a car accident requiring overnight hospitalization would be a 
serious adverse event for any research participant; likewise, in a study 
investigating end-stage cancer care, any hospitalization or death would be a 
serious adverse event, even if the event observed is a primary clinical endpoint of 
the study. 
 


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Unanticipated Problems: 
The term “unanticipated problem” is found, but not defined in the regulations for 
the Protection of Human Subjects at 45 CFR 46, and the FDA regulations at 21 
CFR 56. Guidance from the regulatory agencies considers unanticipated problems 
to include any incident, experience, or outcome that meets each of the following 
criteria: 
 
Unexpected (in terms of nature, severity or frequency); AND 
 
Definitely, probably, or possibly related to participation in the research; AND 
 
Serious or a possible unexpected problem in that the research places subjects 
or others at a greater risk of harm than was previously known or recognized. 
Note: Any serious adverse event would always suggest a greater risk of harm. 
 
Follow-up  
 
All adverse events will be followed up according to good medical practices.  
  
Reporting 
Local unanticipated problems require expedited reporting, are submitted to the 
UTSW IRB through the UTSW eIRB and to the SCC DSMC Coordinator.  
Hardcopies or electronic versions of the eIRB report; FDA Form #3500A forms, 
or other sponsor forms, if applicable; and/or any other supporting documentation 
available should be forwarded to the DSMC Coordinator.  The DSMC 
Coordinator forwards the information onto the DSMC Chairman who determines 
if immediate action is required.  Follow-up eIRB reports, and all subsequent SAE 
documentation that is available are also submitted to the DSMC Chair who 
determines if further action is required.    
  
All local serious adverse events which occur on research subjects on protocols for 
which the SCC is the DSMC of record require reporting to the DSMC regardless of 
whether IRB reporting is required. Hardcopies or electronic versions of the FDA 
Form #3500A forms, or other sponsor forms, if applicable; and/or any other 
supporting documentation available should be forwarded to the DSMC Coordinator. 
 
If the event occurs on a multi-institutional clinical trial coordinated by the Cancer Center, the 
DOT Manager or lead coordinator ensures that all participating sites are notified of the event 
and resulting action, according to FDA guidance for expedited reporting. DSMC Chairperson 
reviews all serious adverse events within upon receipt from the DSMC Coordinator. The 
DSMC Chairperson determines whether action is required and either takes action 
immediately, convenes a special DSMC session (physical or electronic), or defers the action 
until a regularly scheduled DSMC meeting.   
 
 


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Written reports to:UTSW SCC Data Safety Monitoring Committee Coordinator 
Email: SCCDSMC@utsouthwestern.edu 
Fax: 214-648-1906 or deliver to NB2.418 
UTSW Institutional Review Board (IRB) 
Submit via eIRB with a copy of the final sponsor report as attached supporting 
documentation 
 
 
1. SAEs  
Local serious adverse events (SAEs) for studies where SCC DSMC is the DSMC of 
record require reporting to the DSMC coordinator within 2 working days of PI 
awareness, or as described in the protocol.  
 
2. Unanticipated Problems  
Local unanticipated problems require reporting to the UTSW IRB within 2 working 
days of PI awareness of the event.  
Unanticipated problems, including those that occur as non-local events, require 
reporting to the UTSW IRB within 10 working days of PI awareness of the event.  
For further guidance for Investigators regarding safety reporting requirements for 
INDs and BA/BE studies, refer to FDA Draft Guidance document: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/G
uidances/UCM227351.pdf  
 
Fax reports to study sponsor at: 
 
IST Clinical Program Manager 
Peregrine Pharmaceuticals, Inc. 
Fax:  (714) 200-0104 
 
18.0 
INFORMED CONSENT PROCEDURES 
 
Before protocol-specified procedures are carried out, consenting professionals 
will explain full details of the protocol and study procedures as well as the risks 
involved to patients prior to their inclusion in the trial.  Patients will also be 
informed that they are free to withdraw from the study at any time.  All patients 
must sign an IRB-approved consent form indicating their consent to participate.  
This consent form will meet the requirements of the code of federal regulations, 
and the IRB of this center.  The consent form will included the following: 
 
1. The nature and objectives, potential toxicities and benefits of the intended 
study. 
2. The length of therapy and the likely follow-up required. 


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3. Alternatives to the proposed therapy.  This will included available 
standard and investigational therapies.  In addition, patients will be offered 
an option of supportive care. 
4. The name of the investigator (s) responsible for the protocol. 
5. The right of the patient to accept or refuse treatment and to withdraw from 
participation in the study. 
 
 
Each patient and consenting professional will sign the consent form in triplicate.  
One original signed consent form will become part of the patient’s medical 
record, another original signed consent form will be stored in the patient’s 
research file, and the third original signed consent form will be given to the 
patient. 
 
19.0  
SATELLITE SITE PATIENT ENROLLMENT PROCESS 
 
Once screening procedures are completed. The following documentation must be 
provided to GI Clinical Research Manager (CRM) for review and enrollment: 
 
– Signed signature page of informed consent; 
– Signed and dated by Sub-Investigator and coordinator: 
• 
I/E criteria checklist; 
• 
Child-Pugh score form; 
• 
RECIST tumor assessment worksheet; 
• 
Subject Eligibility Verification form; 
 
Once required materials are received and verified by the CRM. The enrollment 
verification form (EVF) will be signed and a study ID assigned to the patient. 
Once the signed EVF has been received by study staff the patient is ready to begin 
therapy.  
 
 
 
 
 
 
 
 
 
 
 


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20.0 
References 
1. 
Parkin DM, Bray F, Ferlay J, et al. Estimating the world cancer burden: Globocan 
2000. Int J Cancer 2001; 94(2):153-6. 
2. 
Altekruse SF, McGlynn KA, Reichman ME. Hepatocellular carcinoma incidence, 
mortality, and survival trends in the United States from 1975 to 2005. J Clin 
Oncol 2009; 27(9):1485-91. 
3. 
El-Serag HB, Mason AC. Rising incidence of hepatocellular carcinoma in the 
United States. N Engl J Med 1999; 340(10):745-50. 
4. 
El-Serag HB. Hepatocellular carcinoma: recent trends in the United States. 
Gastroenterology 2004; 127(5 Suppl 1):S27-34. 
5. 
Chen MS, Li JQ, Zheng Y, et al. A prospective randomized trial comparing 
percutaneous local ablative therapy and partial hepatectomy for small 
hepatocellular carcinoma. Ann Surg 2006; 243(3):321-8. 
6. 
Shiina S, Teratani T, Obi S, et al. A randomized controlled trial of radiofrequency 
ablation with ethanol injection for small hepatocellular carcinoma. 
Gastroenterology 2005; 129(1):122-30. 
7. 
Llovet JM, Real MI, Montana X, et al. Arterial embolisation or 
chemoembolisation versus symptomatic treatment in patients with unresectable 
hepatocellular carcinoma: a randomised controlled trial. Lancet 2002; 
359(9319):1734-9. 
8. 
Lo CM, Ngan H, Tso WK, et al. Randomized controlled trial of transarterial 
lipiodol chemoembolization for unresectable hepatocellular carcinoma. 
Hepatology 2002; 35(5):1164-71. 
9. 
Boige V, Taieb J, Hebbar M, et al. Irinotecan as first-line chemotherapy in 
patients with advanced hepatocellular carcinoma: a multicenter phase II study 
with dose adjustment according to baseline serum bilirubin level. Eur J Cancer 
2006; 42(4):456-9. 
10. 
Guan Z, Wang Y, Maoleekoonpairoj S, et al. Prospective randomised phase II 
study of gemcitabine at standard or fixed dose rate schedule in unresectable 
hepatocellular carcinoma. Br J Cancer 2003; 89(10):1865-9. 
11. 
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(21):3069-75. 
12. 
Yeo W, Mok TS, Zee B, et al.  A randomized phase III study of doxorubicin 
versus cisplatin/interferon alpha-2B/ doxorubicin/fluorouracil (PIAF) 
combination chemotherapy for unresectable hepatocellular carcinoma. J Natl 
Cancer Inst 2005;97(20):1532-8.  


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13. 
Wilhelm SM, Carter C, Tang L, et al. BAY 43-9006 exhibits broad spectrum oral 
antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine 
kinases involved in tumor progression and angiogenesis. Cancer Res 2004; 
64(19):7099-109. 
14. 
Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular 
carcinoma. N Engl J Med 2008; 359(4):378-90. 
15. 
Ran S, Downes A, Thorpe PE. Increased exposure of anionic phospholipids on 
the surface of tumor blood vessels. Cancer Res 2002; 62(21):6132-40. 
16. 
Toyokuni S, Okamoto K, Yodoi J, et al. Persistent oxidative stress in cancer. 
FEBS Lett 1995; 358(1):1-3. 
17. 
Ran S, Thorpe PE. Phosphatidylserine is a marker of tumor vasculature and a 
potential target for cancer imaging and therapy. Int J Radiat Oncol Biol Phys 
2002; 54(5):1479-84. 
18. 
Ran S, He J, Huang X, et al. Antitumor effects of a monoclonal antibody that 
binds anionic phospholipids on the surface of tumor blood vessels in mice. Clin 
Cancer Res 2005; 11(4):1551-62. 
19. 
Luster TA, He J, Huang X, et al. Plasma protein beta-2-glycoprotein 1 mediates 
interaction between the anti-tumor monoclonal antibody 3G4 and anionic 
phospholipids on endothelial cells. J Biol Chem 2006; 281(40):29863-71. 
20. 
Huang Y, Fayad R, Smock A, et al. Induction of mucosal and systemic immune 
responses against human carcinoembryonic antigen by an oral vaccine. Cancer 
Res 2005; 65(15):6990-9. 
21. 
Beck AW, Luster TA, Miller AF, et al. Combination of a monoclonal anti-
phosphatidylserine antibody with gemcitabine strongly inhibits the growth and 
metastasis of orthotopic pancreatic tumors in mice. Int J Cancer 2006; 
118(10):2639-43. 
22. 
He J, Luster TA, Thorpe PE. Radiation-enhanced vascular targeting of human 
lung cancers in mice with a monoclonal antibody that binds anionic 
phospholipids. Clin Cancer Res 2007; 13(17):5211-8. 
23. 
He J, Yin Y, Luster TA, et al. Antiphosphatidylserine antibody combined with 
irradiation damages tumor blood vessels and induces tumor immunity in a rat 
model of glioblastoma. Clin Cancer Res 2009; 15(22):6871-80. 
24. 
Huang Y, Bennet M, Thorpe PE. A monoclonal antibody that binds anionic 
phospholipids on tumor blood vessels enhances the antitumor effect of docetaxel 
on human breast tumor in mice. Cancer Res 2005; 65:4408-4416. 
25.  
Pickering W, Gray E, Goodall AH, et al. Characterization of the cell surface 
procoagulant activity of T-lymphoblastoid cell lines. J Thrombosis Haemos 
2004;2:459-467. 


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26. 
Digamurti R, Bapsy PP, Shan JS. A phase 1B safety and pharmacokinetic study of 
bavituximab plus chemotherapy in patients with refractory advanced solid tumor 
malignancies. J Clin Onc 2008;26: abst 3038. 
27. 
Tabagari D, Nemsadze G, Jincharadze M, et al. Phase II study of bavituximab 
plus doectaxel in patients with locally advanced or metastatic breast cancer. J Clin 
Onc 2009:27;abst 3005. 
28. 
Jain M, Raizada N, Kuttan R, et al. Phase II study of bavituximab plus paclitaxel 
and carboplatin in locally advanced or metastatic breast cancer; interim results. J 
Clin Onc 2010:28:abst 1062. 
29. 
Digumurti R. Suresh AV, Bhattacharyya GS, et al. Phase II study of bavituximab 
pluse paclitaxel and carboplatin in locally advanced or metastatic non-small cell 
lung cancer: interim results. J Clin Onc 2010; 28: abst 7589. 
30. 
Dowlati A, Haaga J, Remick SC, et al. Sequential tumor biopsies in early phase 
clinical trial of anticancer agents for pharmacodynamic evaluation. Cancer Res 
2001;7(10);2971-6. 
31. 
Seeff LB, Everson GT, Morgan TR, et al. Complication rate of percutaneous liver 
biopsies among persons with advanced chronic liver disease in the HALT-C trial. 
Am J Gastro doi:10.1016lj.cgh.2010.03.025. 
32. 
Giorgio A, Tarantino L, de Stefano, et al. Complications after interventional 
sonography of focal liver lesions: a 22-year single-center experience. J Ultrasound 
Med 2003;22:193-205. 
33. 
Caturelli E, Solmi L, Anti M, et al. Ultrasound guided fine needle biopsy of early 
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2004;53:1356-62. 
 
 
 
 
 
 
 
 
 
 
 
 


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21.0 
Appendices 
Appendix A ECOG Performance Status 
 
 
Grade 
ECOG 
0 
Fully active, able to carry on all pre-disease performance without 
restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to 
carry out work of a light or sedentary nature, i.e., 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 be or chair more than 
50% of waking hours. 
4  
Completely disabled.  Cannot carry on any self-care. Totally confined 
to bed or chair. 
5 
Dead 
 
 
 
 
 
 
 
 
 
 
 


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Appendix B Child-Pugh Score 
 
 
Measure 
1 point 
2 points 
3 points 
Total bilirubin 
(mg/dl) 
<2.0 
2.0-3.0 
>3.0 
Serum albumin (g/l) 
>3.5 
2.8-3.5 
<3.5 
INR  
<1.7 
1.7-2.2 
>2.2 
Ascites 
None 
Mild (based on 
clinical findings) 
Severe (based on 
clinical findings) 
Hepatic 
Encephalopathy 
None 
Controlled 
Medically 
Refractory 
 
5-6 points  
Child-Pugh A 
7-9 points  
Child-Pugh B 
10-15 points Child-Pugh C 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix C NYHA Classification 
 
Class 
Patient Symptoms 
I 
No limitation of physical activity. Ordinary 
physical activity does not cause undue 
fatigue, palpitation, or dyspnea (shortness 
of breath). 
II 
Slight limitation of physical activity. 
Comfortable at rest, but ordinary physical 
activity results in fatigue, palpitation, or 
dyspnea. 
III 
Marked limitation of physical activity. 
Comfortable at rest, but less than ordinary 
activity causes fatigue, palpitation, or 
dyspnea. 
IV 
Unable to carry out any physical activity 
without discomfort. Symptoms of cardiac 
insufficiency at rest. If any physical 
activity is undertaken, discomfort is 
increased 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix D Sample Consent Form 
The University of Texas Southwestern Medical Center at Dallas 
Parkland Health & Hospital System 
Children’s Medical Center 
Texas Scottish Rite Hospital for Children 
Presbyterian Hospital of Dallas 
VA-North Texas 
 
CONSENT TO PARTICIPATE IN RESEARCH 
Consent 1 of 2 
Title of Research: 
A Phase I/II Study of Bavituximab and Sorafenib in 
Patients with Advanced Hepatocellular Carcinoma 
Funding Agency/Sponsor: 
UT Southwestern Medical Center; Peregrine 
Pharmaceuticals 
Study Doctors: 
Adam C. Yopp, John C. Mansour, C. Glen Balch, Yull 
Arriaga, Sirrisha Karri, Muhammad Shaalan Beg, , 
William M. Lee, Juan Arenas, Meelie Debroy, , 
Jonathan Dowell, Takeshi Yokoo, and Hao Zhu 
Research Personnel: 
Tyson Dudley, Alisha Hill, Erika Lopez,  
You may call these study doctors or research personnel during regular office hours 
at 214.648.5870. At other times, you may call them at 214.645.8424. 
Instructions: 
Please read this consent form carefully and take your time making a decision about 
whether to participate.  As the researchers discuss this consent form with you, 
please ask him/her to explain any words or information that you do not clearly 
understand.  The purpose of the study, risks, inconveniences, discomforts, and other 
important information about the study are listed below.  If you decide to participate, 
you will be given a copy of this form to keep. 
Why is this study being done? 
This study is being done to find out whether an investigational (non-FDA approved) 
drug combination including bavituximab and sorafenib can treat hepatocellular 
carcinoma better or more safely than standard medication. The word 
“investigational” means the combination of bavituximab and sorafenib is still being 


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tested in research studies and is not approved by the U.S. Food and Drug 
Administration (FDA) for combination treatment of hepatocellular carcinoma.  
Sorafenib has been approved by the FDA and is not considered an investigational 
drug. 
Why is this considered research?  
This is a research study because the combination of bavituximab and sorafenib has 
not been previously used in combination as study drugs for hepatocellular 
carcinoma. 
The following definitions may help you understand this study:  
 Standard medical care means the regular care you would receive from your 
personal doctor if you choose not to participate in this research. 
 Researchers means the study doctor and research personnel at the 
University of Texas Southwestern Medical Center at Dallas and its affiliated 
hospitals. 
Why am I being asked to take part in this research study? 
You are being asked to take part in this study because you have hepatocellular 
carcinoma.   
Do I have to take part in this research study?” 
No.  You have the right to choose whether you want to take part in this research 
study.  If you decide to participate and later change your mind, you are free to stop 
participation at any time. 
If you decide not to take part in this research study it will not change your legal 
rights or the quality of health care that you receive at this center. 
How many people will take part in this study? 
About 56 people will take part in this study at UT Southwestern, Parkland Health 
and Hospital System VA-North Texas or UT Austin-Seton. 
What is involved in the study? 
If you volunteer to take part in this research study, you will be asked to sign this 
consent form and will have the following tests and procedures.  Some of the 
procedures may be part of your standard medical care, but others are being done 
solely for the purpose of this study. 
Screening Procedures 
To help decide if you qualify to be in this study, the researchers may ask you 
questions about your health, including medications you take and any surgical 
procedures you have had. 


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You may also have to fill out certain forms or have the following exams, tests or 
procedures: 
 Demographic information 
 Medical history and physical exam 
 Vital signs 
 Blood tests 
 Radiology (x-ray) tests 
 Biopsy of liver tumor 
 Urinalysis 
 EKG 
 
Treatment 
If you decide to participate in this study you will take the following: 
 1-2 tablets of sorafenib (200-400mg daily, twice a day) and 
 Bavituximab is given intravenously once a week, the approximate time to 
complete each infusion is 90 minutes 
o The study uses increasing doses of bavituximab and your dose of 
bavituximab may be different from other patients in the study. 
 
Participation and Evaluation during the Research 
Participation in this study will involve several procedures.  Many of these 
procedures are part of the normal process of treating tumors such as yours.  
However, some of these procedures can be uncomfortable, inconvenient or painful.  
In addition to the procedures associated with the administration of bavituximab and 
sorafenib as detailed above, you will be asked to participate in other procedures as 
part of your involvement in this study. 
1. Blood tests:  Blood will be drawn from your vein prior to enrollment in the 
study and every week prior to the administration of bavituximab up until the 
time you are no longer receiving bavituximab. No more than 45 ml (3 
tablespoons) of blood will be collected at any one time. 
2. Urinalysis: A urine sample will be collected prior to enrollment and every 
week prior to the administration of bavituximab up until the time you are no 
longer receiving bavituximab. 
3. CT or MRI Scan: This imaging test will be performed prior to enrollment in 
the study and every 6 weeks up until the time you are no longer receiving 
bavituximab. 
4. Biopsy of liver tumor:  If a biopsy of your liver tumor is deemed necessary for 
your clinical care, we would like to collect additional specimens for research 
in addition to the amount needed for clinical care. A second biopsy may be 
collected at the 5-6 week visit or after five to six doses of bavituximab.  This 
second biopsy is the optional component of the study.  A separate consent 
form will be completed by the study participant prior to performing this 


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procedure.  
5. Bilateral lower extremity venous duplex:  This routine test will be performed 
prior to enrollment and at 6 weeks after the first dose of bavituximab. 
 
There will be no scheduled additional doctors’ office visits for the study.  Study visits 
will be included during the routinely scheduled follow-up, which is routine for these 
types of treatment.  
The first biopsy will be collected prior to enrollment in the study. If a biopsy of your 
liver tumor is deemed necessary for your clinical care, we would like to collect a 
small amount of specimen for research in addition to the amount needed for clinical 
care. The second biopsy of the liver tumor (completed 6 weeks after the first dose of 
bavituximab) is designed for research, not for medical purposes.  They are not 
useful for finding problems or diseases.  Even though the researchers are not 
looking at your second tumor biopsy to find or treat a medical problem, you will be 
told if they notice something unusual.  You and your regular doctor can decide 
together whether to follow up with more tests or treatment.  Because the second 
tumor biopsy done in this study is not for medical purposes, the research results 
will not be sent to you or to your regular doctor.  
Procedures for storing of extra or left over samples 
 
The tissue obtained from the biopsies of the liver tumor will go to the 
surgical oncology laboratory at UT Southwestern Medical Center.  The samples will 
be labeled with your name and Social Security Number to properly identify the 
samples. Only Dr. Adam C. Yopp will have access to the samples.  
 
The biopsy and serum samples will be shipped to Peregrine Pharmaceuticals 
to complete research studies testing how the drugs you are taking in the study work. 
The samples will not have any personal information on them and shipped with 
codes only known to Dr. Adam C. Yopp.  All left over tissue or serum will be 
destroyed by Peregrine Pharmaceuticals.How long can I expect to be in this 
study? 
We will ask you to be in this study for the rest of your life.  You will receive the study 
drugs, bavituximab and sorafenib, until your hepatocellular carcinoma shows 
growth based on radiologic (X-ray) tests.  After the initial treatment period, your 
participation in this study will be primarily limited to the follow-up, which is routine 
for patients with your type of tumor. 
You can choose to stop participating for any reason at any time.  However, if you 
decide to stop participating in the study, we encourage you to tell the researchers.  
You may be asked if you are willing to complete some study termination tests. 
 
 


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What are the risks of the study? 
Study Procedure/Intervention 
Because of your participation in this study, you are at risk for the following side 
effects. You should discuss these with the researchers and your regular health care 
provider. The risks of this study are primarily related to the combination 
chemotherapy and the biopsy of your liver tumor. 
Bavituximab will be given to you as part of this study. Bavituximab is an 
investigational drug.  Because it is an antibody made of human and mouse proteins, 
some people may experience an allergic reaction to bavituximab.  Possible side 
effects may include rash, hives, itching, shortness of breath, fever, flushing, chills, 
headache, nausea, vomiting, weakness, diarrhea, low blood pressure, difficulty 
breathing, or anaphylaxis (a severe form of allergic reaction).  To lower the risk of 
developing allergic reactions your study doctor will give you medication(s) before 
each infusion. 
Bavituximab is still being studied in humans and little is known about the possible 
side effects of bavituximab.  Over 243 people have received bavituximab in research 
studies to date.   
Frequent (Greater than 20% of patients): 
 Nausea 
 Fatigue 
 Headache 
 Abdominal pain 
  Vomiting 
 
Occasional (<20% of patients): 
 Constipation 
 High blood pressure 
 Cough 
 Anemia (decreased number of red blood cells) 
 Anxiety 
 Dry skin 
 Dizziness 
  Mild nose bleed 
 Nasal dryness 
 Back pain  
 Joint pain 
 Inflammation of the mouth 
 Nail bed bleeding,  
 Chest pain 
 Irregular heartbeat 


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 Blurred vision 
 Mild disorientation. 
 
Rare but serious (< 2% of patients): 
 Hypotension (low blood pressure)  
 Ischemic heart disease and heart attack 
 Blood clots involving arteries, veins, and in the lungs; 
 Muscle weakness, 
 Neuropathy (abnormal nerve function),  
 Severe diarrhea  
 Severe chest pain requiring hospitalization,  
 Fever with low white blood cell count.   
 
Many of these effects occurred in people with advanced cancer who were also 
receiving chemotherapy. 
Animal studies also suggest that bavituximab may cause small clots in arteries found 
in the heart and lungs and/or thickening in arteries found in the heart and lungs.  
Clots may become life-threatening emergencies, especially if they break free in the 
veins or arteries and move to the heart, lungs, or brain, resulting in a heart attack, 
pulmonary embolism, or stroke.  However, clots and thickened arteries were only 
seen in animals given a high enough bavituximab dose to significantly alter their 
clotting tests.  The risk of both clotting and bleeding complications is unknown for 
the doses of study drug being tested in this study.  As noted above, blood clots 
involving arteries, veins, and lungs have occurred uncommonly in people receiving 
bavituximab for cancer.  
 It is possible that in the event of a clotting event, management of appropriate levels 
of anti-clotting drugs may not work as well when given in combination with 
bavituximab.  Your blood pressure and your blood’s ability to form a normal clot will 
be closely monitored at each study visit.  Additionally, if you experience any side 
effects between study visits (for example abdominal pain, bleeding, 
limpness/lameness, swelling, cold-induced symptoms such as Raynaud’s 
phenomenon [such as discoloration of fingers and toes in response to cold]), 
headache, migraine (including change in severity or pattern of existing migraines), 
bone pain, joint pain, and visual disturbance, you should notify the study doctor 
right away. 
Although uncommon, temporary disorientation, blurred vision, hypertension, and 
irregular heartbeat were reported in studies of bavituximab in people with chronic 
hepatitis C infection.  Events usually resolve on their own without treatment and 
additional tests did not reveal any heart damage or blood clots. 
Sorafenib will be given to you as part of this study.  Sorafenib may cause some, all, or 
none of the side effects listed below.  Sorafenib will be given in a standard fashion 
for people with tumors like yours.  


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60
Frequent (Greater than 20% of patients): 
 Fatigue 
 Rash of hands and feet 
 Diarrhea 
 Elevated liver enzyme blood levels 
 Nausea 
 
Occasional (<20% of patients): 
 Elevated blood pressure 
 Loss of hair 
 Headache 
 Dry cough 
 Pain in joints 
 Difficulty breathing 
 Erectile dysfunction 
 Dry skin 
 Loss of feeling in hands and feet 
 Itchy skin 
 Constipation 
 Drop in white blood count 
 Decreased appetite 
 Dry mouth 
 Weight loss 
 Not feeling hungry 
 
Rare but serious (< 2% of patients): 
 Heart attack 
 Organ failure, death 
 Kidney dysfunction 
 Vomiting blood 
 
Loss of Confidentiality 
Any time information is collected; there is a potential risk for loss of confidentiality.  
Every effort will be made to keep your information confidential; however, this 
cannot be guaranteed.  
Risks to Sperm, Embryo, Fetus or Breast-fed Infant 
Males: Being in this research may damage your sperm, which could cause harm to a 
child that you may father while on this study. If you take part in this study and are 
sexually active, you must agree to use a medically-acceptable form of birth control. 
Medically-acceptable forms of birth control include: 


 Current: Version 18 dated 07/05/2016 
61
(1) surgical sterilization (vasectomy), or 
(2) a condom used with a spermicide (a substance that kills sperm). 
Females: If you are part of this study while pregnant or breast-feeding an infant, it 
is possible that you may expose the unborn child or infant to risks.  For that reason, 
pregnant and breast-feeding females cannot participate in the study.  If you can 
become pregnant, a blood pregnancy test will be done (using 1 teaspoon of blood 
drawn from a vein by needle-stick), and it must be negative before you participate in 
this study. If you take part in this study and you are sexually active, you and any 
person that you have sex with must use medically-acceptable birth control 
(contraceptives) during the study.  Medically-acceptable birth control 
(contraceptives) includes: 
(1) surgical sterilization (such as hysterectomy or “tubes tied”), 
(2) approved hormonal contraceptives ( such as birth control pills, patch or 
ring; Depo-Provera, Depo-Lupron, Implanon), 
(3) barrier methods (such as condom or diaphragm) used with a spermicide 
(a substance that kills sperm), or  
(4) an intrauterine device (IUD). 
If you do become pregnant during this study, you must tell the researchers 
immediately. 
Risks of Radiation-Diagnostic Test 
The radiation dose that you will get from diagnostic tests is medically indicated for 
your condition and it is the same that you would get if you were not involved in this 
research study. 
Risks of Blood Drawing 
Risks associated with drawing blood from your arm include minimal discomfort 
and/or bruising.  Infection, excess bleeding, clotting, and/or fainting also are 
possible, although unlikely. 
You will have 45ml (3 tablespoons) of blood collected because you are in this 
research study. 
Other Risks 
There may possibly be other side effects that are unknown at this time. If you are 
concerned about other, unknown side effects, please discuss this with the 
researchers. 
 


 Current: Version 18 dated 07/05/2016 
62
How will risks be minimized or prevented?   
Study risks will be minimized or prevented by several measures at the beginning of 
the study and throughout your participation in the study.  Patients will be screened 
prior to enrollment to assure that each patient meets the safety requirements of the 
study.  All treatments will be modified within the study parameters to match your 
treatment needs. These modifications will include the area being treated with 
chemotherapy.  Throughout your participation in the study you will be evaluated by 
personnel trained to recognize, minimize, and treat side effects of your treatment.  
You will be withdrawn from the study if you experience an adverse event which 
causes unacceptable risk as determined by the investigators. You will continue to 
receive standard medical care if you are no longer participating in the study. 
 What will my responsibilities be during the study?   
While you are part of this study, the researchers will follow you closely to determine 
whether there are problems that need medical care.  It is your responsibility to do 
the following: 
 Ask questions about anything you do not understand. 
 Keep your appointments. 
 Follow the researchers’ instructions. 
 Let the researchers know if your telephone number or address changes. 
 Store study materials and sorafenib tablets in a secure place at home away 
from anyone who is unable to read and understand labels, especially 
children. 
 Tell the researchers before you take any new medication, even if it is 
prescribed by another doctor for a different medical problem or something 
purchased over the counter. 
 Tell your regular doctor about your participation in this study. 
 Carry information about sorafenib and bavituximab in your purse or wallet. 
 Report to the researchers any injury or illnesses while you are on study even 
if you do not think it is related.  
 
If I agree to take part in this research study, will I be told of any new risks that 
may be found during the course of the study? 
Yes.  You will be told if any new information becomes available during the study that 
could cause you to change your mind about continuing to participate or that is 
important to your health or safety. 
What should I do if I think I am having problems? 
If you have unusual symptoms, pain, or any other problems while you are in the 
study, you should report them to the researchers right away.  Telephone numbers 
where they can be reached are listed on the first page of this consent form. 


 Current: Version 18 dated 07/05/2016 
63
If you have a sudden, serious problem, like difficulty breathing or severe pain, go to 
the nearest hospital emergency room, or call 911 (or the correct emergency 
telephone number in your area).  Tell emergency personnel about any medications 
you are taking, including any medications you are taking for this study.   
What are the possible benefits of this study? 
If you agree to take part in this study, there may be direct benefits to you.  The 
researchers cannot guarantee that you will benefit from participation in this 
research.  The type of chemotherapy drugs used in this study may be superior to 
standard treatment. 
We hope the information learned from this study will benefit others with 
hepatocellular carcinoma in the future.  Information gained from this research could 
lead to better treatment.   
What options are available if I decide not to take part in this research study? 
You do not have to participate in this research to receive care for your medical 
problem. Instead of being in this study, you have the following options: 
 Evaluation by a medical oncologist for chemotherapy 
 
Please talk to the researchers or your personal doctor about these options.  
Will I be paid if I take part in this research study? 
No.  You will not be paid to take part in this research study. There are no funds 
available to pay for parking expenses, transportation to and from the research 
center, lost time away from work and other activities, lost wages, or child care 
expenses. 
Will my insurance provider or I be charged for the costs of any part of this 
research study? 
No. Neither you, nor your insurance provider, will be charged for anything done 
only for this research study (i.e., the Screening Procedures, Experimental 
Procedures, or Monitoring/Follow-up Procedures described above).   
However, the standard medical care for your condition (care you would have 
received whether or not you were in this study) is your responsibility (or the 
responsibility of your insurance provider or governmental program).  You will be 
charged, in the standard manner, for any procedures performed for your standard 
medical care. 
What will happen if I am harmed as a result of taking part in this study? 
It is important that you report any illness or injury to the research team listed at the 
top of this form immediately. 


 Current: Version 18 dated 07/05/2016 
64
Compensation for an injury resulting from your participation in this research is not 
available from the University of Texas Southwestern Medical Center at Dallas, 
Parkland Health & Hospital System, VA-North Texas, or UT Austin-Seton. 
You retain your legal rights during your participation in this research 
Can I stop taking part in this research study? 
Yes.  If you decide to participate and later change your mind, you are free to stop 
taking part in the research study at any time. 
If you decide to stop taking part in this research study, it will not affect your 
relationship with the UT Southwestern staff or doctors.  Whether you participate or 
not will have no effect on your legal rights or the quality of your health care. 
If you are a medical student, fellow, faculty, or staff at the Medical Center, your 
status will not be affected in any way. 
Your doctor is a research investigator in this study.  S/he is interested in both your 
medical care and the conduct of this research study.  At any time, you may discuss 
your care with another doctor who is not part of this research study.  You do not 
have to take part in any research study offered by your doctor. 
If I agree to take part in this research study, can I be removed from the study 
without my consent? 
Yes.  The researchers may decide to take you off this study if: 
 Your medical problem remains unchanged or becomes worse. 
 The researchers believe that participation in the research is no longer safe 
for you. 
 The researchers believe that other treatment may be more helpful. 
 The sponsor or the FDA stops the research for the safety of the participants. 
 The sponsor cancels the research. 
 You are unable to keep appointments or to follow the researcher’s 
instructions. 
 
Will my information be kept confidential? 
Information about you that is collected for this research study will remain 
confidential unless you give your permission to share it with others, or if we are 
required by law to release it.  You should know that certain organizations that may 
look at and/or copy your medical records for research, quality assurance, and data 
analysis include: 
• 
Representatives of government agencies, like the U.S. Food and Drug 
Administration (FDA), involved in keeping research safe for people; and 
• 
The UT Southwestern Institutional Review Board.  


 Current: Version 18 dated 07/05/2016 
65
 
In addition to this consent form, you will be asked to sign an "Authorization for Use 
and Disclosure of Protected Health Information."  This authorization will give more 
details about how your information will be used for this research study, and who 
may see and/or get copies of your information. 
Whom do I call if I have questions or problems? 
For questions about the study, contact Adam C. Yopp, MD at 214.648.5870 during 
regular business hours and at 214.645.8424 after hours and on weekends and 
holidays.   
For questions about your rights as a research participant, contact the UT 
Southwestern Institutional Review Board (IRB) Office at 214-648-3060. 
Is there anything I should know before I decide? 
Dr. Adam Yopp is a paid speaker for Onyx Pharmaceuticals and Bayer Healthcare, 
and Dr. Takeshi Yokoo is a paid consultant for Bayer Healthcare who manufactures 
the study drug Nexavar ®(Sorafenib).  You should feel free to ask questions about 
this. 


 Current: Version 18 dated 07/05/2016 
66
SIGNATURES: 
 
YOU WILL BE GIVEN A COPY OF THIS CONSENT FORM TO KEEP. 
Your signature below certifies the following: 
• You have read (or been read) the information provided above. 
• You have received answers to all of your questions and have been told who to call if 
you have any more questions. 
• You have freely decided to participate in this research. 
• You understand that you are not giving up any of your legal rights. 
 
_________________________________________________ 
Participant’s Name (printed) 
 
 
__________________________________________________ 
Participant’s Signature 
 
_______________ 
Date 
__________________________________________________ 
Legally Authorized Representative’s Name (printed) 
 
 
__________________________________________________ 
Legally Authorized Representative’s Signature 
 
________________ 
Date 
__________________________________________________ 
Name of person obtaining consent (printed) 
 
 
__________________________________________________ 
Signature of person obtaining consent 
 
________________ 
Date 
 
 
 


 Current: Version 18 dated 07/05/2016 
67
INTERPRETER STATEMENT: 
I have interpreted this consent form into a language understandable to the 
participant and the participant has agreed to participate as indicated by their 
signature on the associated short form. 
 
_________________________________________ 
Name of Interpreter (printed) 
 
 
_________________________________________ 
Signature of Interpreter 
 
___________________ 
Date 
 
 
 


 Current: Version 18 dated 07/05/2016 
68
The University of Texas Southwestern Medical Center at Dallas 
Parkland Health & Hospital System 
Children’s Medical Center 
Texas Scottish Rite Hospital for Children 
Presbyterian Hospital of Dallas 
CONSENT TO PARTICIPATE IN RESEARCH 
Consent 2 of 2 (Biopsy) - Optional 
 
Title of Research: 
A Phase I/II Study of Bavituximab and Sorafenib in 
Patients with Advanced Hepatocellular Carcinoma 
Funding Agency/Sponsor: 
UT Southwestern Medical Center 
Study Doctors: 
Adam C. Yopp, John C. Mansour, C. Glen Balch, Yull 
Arriaga, Sirrisha Karri, Muhammad Shaalan Beg, 
William M. Lee, Juan Arenas, Meelie Debroy, 
Jonathan Dowell, Takeshi Yokoo, and Hao Zhu 
Research Personnel: 
Tyson Dudley, Alisha Hill, Erika Lopez,  
You may call these study doctors or research personnel during regular office hours 
at 214.648.5870. At other times, you may call them at 214.645.8424. 
Instructions: 
Please read this consent form carefully and take your time making a decision about 
whether to participate.  As the researchers discuss this consent form with you, 
please ask him/her to explain any words or information that you do not clearly 
understand.  The purpose of the study, risks, inconveniences, discomforts, and other 
important information about the study are listed below.  If you decide to participate, 
you will be given a copy of this form to keep. 
Why is this study being done? 
This study is being done to find out whether an investigational (non-FDA approved) 
drug combination including bavituximab and sorafenib can treat hepatocellular 
carcinoma better or more safely than standard medication. The word 
“investigational” means the combination of bavituximab and sorafenib is still being 
tested in research studies and is not approved by the U.S. Food and Drug 
Administration (FDA) for combination treatment of hepatocellular carcinoma.  
Sorafenib has been approved by the FDA and is not considered an investigational 
drug. 


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69
Why is this considered research?  
This is a research study because the combination of bavituximab and sorafenib has 
not been previously used in combination as study drugs for hepatocellular 
carcinoma. 
The following definitions may help you understand this study:  
 Standard medical care means the regular care you would receive from your 
personal doctor if you choose not to participate in this research. 
 Researchers means the study doctor and research personnel at the 
University of Texas Southwestern Medical Center at Dallas and its affiliated 
hospitals. 
Why am I being asked to take part in this research study? 
You are being asked to take part in this study because you have hepatocellular 
carcinoma and you are participating in treatment portion of this study 
Do I have to take part in this research study?” 
No.  You have the right to choose whether you want to take part in this research 
study.  If you decide to participate and later change your mind, you are free to stop 
participation at any time. 
If you decide not to take part in this research study it will not change your legal 
rights or the quality of health care that you receive at this center. 
How many people will take part in this study? 
About 56 people will take part in this study at UT Southwestern or Parkland Health 
and Hospital System. 
What is involved in the study? 
Participation in this study will involve several procedures.  Many of these 
procedures are part of the normal process of treating tumors such as yours.  
However, some of these procedures can be uncomfortable, inconvenient or painful.  
In addition to the procedures associated with the administration of bavituximab and 
sorafenib as detailed above, you will be asked to participate in other procedures as 
part of your involvement in this study. 
Biopsy of liver tumor:  A second biopsy will be collected at the 
5-6 week visit or after five to six doses of bavituximab  
This second biopsy of the liver tumor is designed for research and not for medical 
purposes.  In other words, they are not useful for finding problems or diseases.  
Even though the researchers are not looking at your second tumor biopsy to find or 
treat a medical problem, you will be told if they notice something unusual.  You and 
your regular doctor can decide together whether to follow up with more tests or 


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treatment.  Because the second tumor biopsy done in this study is not for medical 
purposes, the research results will not be sent to you or to your regular doctor.  
Procedures for storing of extra or left over samples 
The biopsy and serum samples will be shipped to Peregrine Pharmaceuticals to 
complete research studies testing how the drugs you are taking in the study work. 
The samples will not have any personal information on them and shipped with 
codes only known to Dr. Adam C. Yopp.  All left over tissue or serum will be 
destroyed by Peregrine Pharmaceuticals. 
The researchers will record and use your Social Security Number (SSN) in order 
to properly label the sample.  You do not have to give this information to the 
researchers; it will not affect study participation.  This information will remain 
confidential unless you give your permission to share it with others or if we are 
required by law to release it. 
How long can I expect to be in this study? 
We will ask you to be in this study for the rest of your life.  After the initial treatment 
period, your participation in this study will be primarily limited to the follow-up, 
which is routine for patients with your type of tumor 
You can choose to stop participating for any reason at any time.  However, if you 
decide to stop participating in the study, we encourage you to tell the researchers.  
You may be asked if you are willing to complete some study termination tests. 
What are the risks of the study? 
Study Procedure/Intervention 
Because of your participation in this study, you are at risk for the following side 
effects. You should discuss these with the researchers and your regular health care 
provider. The risks of this study are primarily related to the combination 
chemotherapy and the biopsy of your liver tumor. 
Biopsy of liver tumor 
Prior to receiving bavituximab and sorafenib and five weeks after the study drugs 
have been given one of the tumors in your liver will be biopsied as part of this study.  
Biopsy of the liver tumor may cause some, all, or none of the side effects listed 
below. The biopsies will be performed in the standard way it performed for patients 
with tumors like yours.  Your radiologist will discuss the risks of the biopsy with you 
in detail and will ask you to sign a separate consent form. If a liver biopsy is to be 
performed for clinical care anyway, additional specimens will be taken for research 
purpose in the same biopsy session.  No additional puncture will be necessary for 
additional specimen, and this is unlikely to significantly increase the overall 
procedure risk.  


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71
Occasional (2-20% of patients): 
 Pain at site of biopsy 
 
Rare but serious (< 2% of patients): 
 Bleeding from liver 
 Leakage of bile from liver 
 Difficulty in breathing  
 Death 
 
Loss of Confidentiality 
Any time information is collected; there is a potential risk for loss of confidentiality.  
Every effort will be made to keep your information confidential; however, this 
cannot be guaranteed.  
Risks to Sperm, Embryo, Fetus or Breast-fed Infant 
Males: Being in this research may damage your sperm, which could cause harm to a 
child that you may father while on this study. If you take part in this study and are 
sexually active, you must agree to use a medically-acceptable form of birth control. 
Medically-acceptable forms of birth control include: 
(1) surgical sterilization (vasectomy), or 
(2) a condom used with a spermicide (a substance that kills sperm). 
Females: If you are part of this study while pregnant or breast-feeding an infant, it 
is possible that you may expose the unborn child or infant to risks.  For that reason, 
pregnant and breast-feeding females cannot participate in the study.  If you can 
become pregnant, a blood pregnancy test will be done (using 1 teaspoon of blood 
drawn from a vein by needle-stick), and it must be negative before you participate in 
this study. If you take part in this study and you are sexually active, you and any 
person that you have sex with must use medically-acceptable birth control 
(contraceptives) during the study.  Medically-acceptable birth control 
(contraceptives) includes: 
(1) surgical sterilization (such as hysterectomy or “tubes tied”), 
(2) approved hormonal contraceptives ( such as birth control pills, patch or 
ring; Depo-Provera, Depo-Lupron, Implanon), 
(3) barrier methods (such as condom or diaphragm) used with a spermicide 
(a substance that kills sperm), or  
(4) an intrauterine device (IUD). 


 Current: Version 18 dated 07/05/2016 
72
If you do become pregnant during this study, you must tell the researchers 
immediately. 
Other Risks 
There may possibly be other side effects that are unknown at this time. If you are 
concerned about other, unknown side effects, please discuss this with the 
researchers. 
How will risks be minimized or prevented?   
Study risks will be minimized or prevented by several measures at the beginning of 
the study and throughout your participation in the study.  Patients will be screened 
prior to enrollment to assure that each patient meets the safety requirements of the 
study.  All treatments will be modified within the study parameters to match your 
treatment needs. These modifications will include the area being treated with 
chemotherapy.  Throughout your participation in the study you will be evaluated by 
personnel trained to recognize, minimize, and treat side effects of your treatment.  
You will be withdrawn from the study if you experience an adverse event which 
causes unacceptable risk as determined by the investigators. You will continue to 
receive standard medical care if you are no longer participating in the study. 
What will my responsibilities be during the study?   
While you are part of this study, the researchers will follow you closely to determine 
whether there are problems that need medical care.  It is your responsibility to do 
the following: 
 Ask questions about anything you do not understand. 
 Keep your appointments. 
 Follow the researchers’ instructions. 
 Let the researchers know if your telephone number or address changes. 
 Store study materials and sorafenib tablets in a secure place at home away 
from anyone who is unable to read and understand labels, especially 
children. 
 Tell the researchers before you take any new medication, even if it is 
prescribed by another doctor for a different medical problem or something 
purchased over the counter. 
 Tell your regular doctor about your participation in this study. 
 Carry information about sorafenib and bavituximab in your purse or wallet. 
 Report to the researchers any injury or illnesses while you are on study even 
if you do not think it is related.  
 
 
 


 Current: Version 18 dated 07/05/2016 
73
If I agree to take part in this research study, will I be told of any new risks that 
may be found during the course of the study? 
Yes.  You will be told if any new information becomes available during the study that 
could cause you to change your mind about continuing to participate or that is 
important to your health or safety. 
What should I do if I think I am having problems? 
If you have unusual symptoms, pain, or any other problems while you are in the 
study, you should report them to the researchers right away.  Telephone numbers 
where they can be reached are listed on the first page of this consent form. 
If you have a sudden, serious problem, like difficulty breathing or severe pain, go to 
the nearest hospital emergency room, or call 911 (or the correct emergency 
telephone number in your area).  Tell emergency personnel about any medications 
you are taking, including any medications you are taking for this study.   
What are the possible benefits of this study? 
If you agree to take part in this study, there may be direct benefits to you.  The 
researchers cannot guarantee that you will benefit from participation in this 
research.  The type of chemotherapy drugs used in this study may be superior to 
standard treatment. 
We hope the information learned from this study will benefit others with 
hepatocellular carcinoma in the future.  Information gained from this research could 
lead to better treatment.   
What options are available if I decide not to take part in this research study? 
You do not have to participate in this research to receive care for your medical 
problem. Instead of being in this study, you have the following options: 
 Evaluation by a medical oncologist for chemotherapy 
 
Please talk to the researchers or your personal doctor about these options.  
Will I be paid if I take part in this research study? 
No.  You will not be paid to take part in this research study. There are no funds 
available to pay for parking expenses, transportation to and from the research 
center, lost time away from work and other activities, lost wages, or child care 
expenses. 
 
 


 Current: Version 18 dated 07/05/2016 
74
Will my insurance provider or I be charged for the costs of any part of this 
research study? 
No. Neither you, nor your insurance provider, will be charged for anything done 
only for this research study (i.e., the Screening Procedures, Experimental 
Procedures, or Monitoring/Follow-up Procedures described above).   
However, the standard medical care for your condition (care you would have 
received whether or not you were in this study) is your responsibility (or the 
responsibility of your insurance provider or governmental program).  You will be 
charged, in the standard manner, for any procedures performed for your standard 
medical care. 
What will happen if I am harmed as a result of taking part in this study? 
It is important that you report any illness or injury to the research team listed at the 
top of this form immediately. 
Compensation for an injury resulting from your participation in this research is not 
available from the University of Texas Southwestern Medical Center at Dallas or, 
Parkland Health & Hospital System. 
You retain your legal rights during your participation in this research 
Can I stop taking part in this research study? 
Yes.  If you decide to participate and later change your mind, you are free to stop 
taking part in the research study at any time. 
If you decide to stop taking part in this research study, it will not affect your 
relationship with the UT Southwestern staff or doctors.  Whether you participate or 
not will have no effect on your legal rights or the quality of your health care. 
If you are a medical student, fellow, faculty, or staff at the Medical Center, your 
status will not be affected in any way. 
Your doctor is a research investigator in this study.  S/he is interested in both your 
medical care and the conduct of this research study.  At any time, you may discuss 
your care with another doctor who is not part of this research study.  You do not 
have to take part in any research study offered by your doctor. 
If I agree to take part in this research study, can I be removed from the study 
without my consent? 
Yes.  The researchers may decide to take you off this study if: 
 Your medical problem remains unchanged or becomes worse. 
 The researchers believe that participation in the research is no longer safe 
for you. 


 Current: Version 18 dated 07/05/2016 
75
 The researchers believe that other treatment may be more helpful. 
 The sponsor or the FDA stops the research for the safety of the participants. 
 The sponsor cancels the research. 
 You are unable to keep appointments or to follow the researcher’s 
instructions. 
 
Will my information be kept confidential? 
Information about you that is collected for this research study will remain 
confidential unless you give your permission to share it with others, or if we are 
required by law to release it.  You should know that certain organizations that may 
look at and/or copy your medical records for research, quality assurance, and data 
analysis include: 
• 
Representatives of government agencies, like the U.S. Food and Drug 
Administration (FDA), involved in keeping research safe for people; and 
• 
The UT Southwestern Institutional Review Board.  
In addition to this consent form, you will be asked to sign an "Authorization for Use 
and Disclosure of Protected Health Information."  This authorization will give more 
details about how your information will be used for this research study, and who 
may see and/or get copies of your information. 
Whom do I call if I have questions or problems? 
For questions about the study, contact Adam C. Yopp, MD at 214.648.5870 during 
regular business hours and at 214.645.8424 after hours and on weekends and 
holidays.   
Is there anything I should know before I decide? 
Dr. Adam Yopp is a paid speaker for Onyx Pharmaceuticals and Bayer Healthcare, 
and Dr. Takeshi Yokoo is a paid consultant for Bayer Healthcare who manufactures 
the study drug Nexavar ®(Sorafenib).  You should feel free to ask questions about 
this. 
 
For questions about your rights as a research participant, contact the UT 
Southwestern Institutional Review Board (IRB) Office at 214-648-3060. 
 


 Current: Version 18 dated 07/05/2016 
76
SIGNATURES: 
YOU WILL BE GIVEN A COPY OF THIS CONSENT FORM TO KEEP. 
Your signature below certifies the following: 
• You have read (or been read) the information provided above. 
• You have received answers to all of your questions and have been told who to call if 
you have any more questions. 
• You have freely decided to participate in this research. 
• You understand that you are not giving up any of your legal rights. 
__________________________________________________ 
Participant’s Name (printed) 
 
 
__________________________________________________ 
Participant’s Signature 
 
_______________ 
Date 
__________________________________________________ 
Legally Authorized Representative’s Name (printed) 
 
 
__________________________________________________ 
Legally Authorized Representative’s Signature 
 
________________ 
Date 
__________________________________________________ 
Name of person obtaining consent (printed) 
 
 
__________________________________________________ 
Signature of person obtaining consent 
 
________________ 
Date 
 
 
 


 Current: Version 18 dated 07/05/2016 
77
INTERPRETER STATEMENT: 
I have interpreted this consent form into a language understandable to the 
participant and the participant has agreed to participate as indicated by their 
signature on the associated short form. 
 
_________________________________________ 
Name of Interpreter (printed) 
 
 
_________________________________________ 
Signature of Interpreter 
 
___________________ 
Date