Clinical trial NCT01306058
Conditions: Hepatoma Liver Neoplasms Adenoma, Liver Cell Carcinoma, Hepatocellular Liver Neoplasms, Experimental
Keywords: Hepatocellular Carcinoma TRC105 Sorafenib Liver Cancer Monoclonal Antibody
Sponsor: National Cancer Institute (NCI)
Start date: 2011-02-11; Completion date: 2017-06-09
Enrollment: 27 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Background:

Sorafenib is a drug that has been approved to treat kidney and liver cancer (hepatocellular carcinoma, or HCC) and has been shown to prolong survival in patients with HCC. It works by slowing the spread of cancer cells, but it does not fully prevent the cancer from growing again. Researchers are interested in combining sorafenib with the experimental drug TRC105, which has been designed to block the growth of blood vessels that lead to tumor growth, in order to determine whether this drug combination stops tumor growth and reduces tumor size better than sorafenib alone.

Objectives:

To determine the safety and effectiveness of the combination of sorafenib and TRC105 as a treatment for hepatocellular cancer that has not responded to other treatments.

Eligibility:

Individuals at least 18 years of age who have been diagnosed with hepatocellular cancer that has not responded to other treatments, and who are not considered to be candidates for liver transplantation. Patients cannot be receiving anticoagulant therapy with the exception of low dose aspirin. No history of bleeding problems or peptic ulcer disease.

Design:

Participants will be screened with a full medical history and physical examination, blood and urine tests, and tumor imaging studies. Participants will have a tumor biopsy or provide previously collected tumor tissue for study. An examination of the esophagus to look for problems with blood vessels will be completed in patients with a history of cirrhosis.

Participants will receive sorafenib tablets twice every day, in the morning and at night, with a full glass of water.

Participants will receive TRC 105 infusions once every two weeks on days 1 and 15 of a 28 day cycle.

At each visit during the first cycle, participants will have a physical examination and blood tests. Participants will continue to have blood tests and a urine test every cycle to monitor the effects of treatment, including tests of kidney function. Participants will have imaging studies after every two cycles to evaluate the results of treatment, and may also provide tumor samples for study.

Treatment will continue as long as the tumor does not grow and side effects remain tolerable.

Detailed description:
Background:

* Worldwide, hepatocellular carcinoma (HCC) is the fifth most common malignancy with a median survival of 6-9 months. The Study of Heart and Renal Protection (SHARP) study established sorafenib as a standard consideration in this disease and set the bar for future studies of systemic therapy.
* TRC105 is a chimeric anti-angiogenic monoclonal antibody that binds cluster of differentiation 105 (CD105), a transmembrane receptor selectively expressed by proliferating endothelial cells. TRC105 binds to CD105-expressing endothelial cells and mediates growth inhibition, apoptosis and antibody-dependent cell-mediated cytotoxicity (ADCC).

Objectives:

Primary:

* Phase I: To establish the maximum tolerated dose (MTD) of TRC105 when given with standard-dose sorafenib for HCC.
* Phase II:To determine the estimate response rate according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria for the combination of TRC105 with sorafenib in HCC.

Eligibility:

* Histologically or cytologically confirmed diagnosis of HCC.
* Childs-Pugh A or B (7 points) cirrhosis is allowed.
* Patients must have disease that is not amenable to potentially curative resection, radiofrequency ablation, or liver transplantation.
* In phase I, prior systemic therapy is allowed.
* In phase II, prior systemic therapy for HCC (including sorafenib) is allowed.
* No history of bleeding varices in previous 1 year (unless subsequent liver transplant).
* No anti-coagulation (except low-dose aspirin).

Design:

* TRC105 will be administered intravenously every two weeks, on days 1 and 15 of each 28 day cycle. Sorafenib will be self-administered twice daily by mouth.
* Phase 1: The first part of this study was a standard 3+3 dose escalation phase I study with the primary objective of establishing MTD for TRC105 when given in combination with standard-dose sorafenib. Sorafenib is taken orally at a dose of 400 mg twice daily. TRC105 is administered as an intravenous infusion every two weeks. Patients will be restaged including imaging studies to assess for response and progression every 8 weeks. The TRC105 dose was escalated in cohorts of 3 to 6 patients up to a maximum of 15 mg/kg every two weeks. Intra-patient dose escalation was not allowed.
* Phase II: TRC105 will be administered as an intravenous infusion every two weeks at the recommended phase II dose, 15 mg/kg of TRC105 ever two weeks in combination with standard dose sorafenib, defined in phase I. The sample size and interim stopping rule will be determined using a Simon optimal two-stage design. The first stage will initially enroll 6 evaluable patients, and if 0 of the 6 have a clinical response, then no further patients will be accrued. If 1 or more of the first 6 patients has a clinical response, then accrual would continue until a total of 23 patients have been enrolled. As it may take several weeks to determine if a patient has experienced a response, a temporary pause in the accrual may be necessary to ensure that enrollment to the second stage is warranted. If there are 1 to 2 clinical responses in 23 patients, this would be an uninterestingly low response rate. If there were 3 or more complete responses in 23 patients (13.0%), this would be sufficiently interesting to warrant further study in later trials. Under the null hypothesis (5% response rate), the probability of early termination is 73.5%.

Cohort: -0; Sorafenib (mg by mouth (PO) twice daily): 400 bid; TRC105 (mg/kg intravenous (IV) weekly): 1

Cohort: 1; Sorafenib (mg PO twice daily): 400 bid; TRC105 (mg/kg IV weekly): 3

Cohort: 2; Sorafenib (mg PO twice daily): 400 bid; TRC105 (mg/kg IV weekly): 6

Cohort: 3; Sorafenib (mg PO twice daily): 400 bid; TRC105 (mg/kg IV weekly): 10

Cohort: 4; Sorafenib (mg PO twice daily): 400 bid; TRC105 (mg/kg IV weekly): 15

Arms: arm 1: CA (cancer); 15 mg/kg TRC105 intravenous (IV) every 2 weeks and 400 mg sorafenib by mouth (PO) twice per day
Interventions: intervention 1: TRC 105 intervention 2: Sorafenib
Intervention descriptions: intervention 1: 15 mg/kg intravenous (IV) every 2 weeks intervention 2: 400 mg twice a day (bid) continuously in a 28 days cycle

Protocol documents:
Prot_SAP_ICF_000.pdf: 
Amendment
Protocol Number:
11C0102-N
Principal Investigator: Tim Greten 
NCI 
TGIB 
301.451.4723 
tim.greten@nih.gov
(NIH Employee Name, Institute/Branch, Telephone and e-mail)
Reference Number:
359988
Protocol Title:
A Phase I/II Study of TRC105 in Combination with Sorafenib in Hepatocellular Carcinoma (HCC)
SIGNATURES
Principal Investigator (*): 
Tim Greten - applied signature on 06/30/2016 1:10 PM EDT
Accountable Investigator:
PI is the Accountable Investigator
Branch Chief/CC Department Head (**):
Raffit Hassan - applied signature on 06/30/2016 2:46 PM EDT
Medical Advisory Investigator (if applicable):
N/A
Lead Associate Investigator signature:
N/A
Referral Contact signatures:
N/A
Associate Investigators signatures:
Donna Mabry - applied signature on 07/01/2016 9:49 AM EDT
For Institute/Center Scientific Review Committee:
N/A
Other IC Clinical Director signatures:
N/A
APPROVALS
IRB Chair:
Michael Hamilton - applied signature on 07/07/2016 5:58 PM EDT
Clinical Director:
N/A
CONCURRENCE
OPS Protocol Specialist:
Signature
Print Name
Date
* Signature signifies that investigators on this protocol have been informed that the collection and use of personally identifiable information at
the NIH are maintained in a system of record governed under provisions of the Privacy Act of 1974. The information provided is mandatory for 
employees of the NIH to perform their assigned duties as related to the administration and reporting of intramural research protocols and 
used solely for those purposes.  Questions may be addressed to the Protrak System Owner. 
** I have reviewed this research project and considered the NIH Policy for Inclusion of Women and Minorities in Clinical Research. Taking into 
account the overall impact that the project could have on the research field involved, I feel the current plans adequately includes both sex/
gender, minorities, children, and special populations, as appropriate. The current enrollment is in line with the planned enrollment report for 
inclusion of individuals on the basis of their sex/gender, race, and ethnicity and is appropriate and of scientific and technical merit. 
IRB Meeting Date:
Expedited
DEC Clearance Date:
06/22/2016
Protocol Version Date:06/10/2016
%POOB.BCSZ	TFFCFMPX
Royal Reed 
 
 
 
AM N  
 
    07/12/16


1 
Abbreviated Title:  Sorafenib and TRC105 in HCC 
NCI Protocol #: 11-C-0102 
Version Date:  June 10, 2016 
Amendment: N 
Title: A Phase I/II study of TRC105 in combination with Sorafenib in Hepatocellular Carcinoma (HCC) 
Principal Investigator:    
 
Tim Greten, MD 
Thoracic and GI Oncology Branch 
National Cancer Institute 
Building 10, Rm 12N226 
9000 Rockville Pike 
Bethesda, MD 20892 
301-451-4723 
FAX: 301-480-8780 
gretentf@mail.nih.gov 
Lead Associate Investigator: 
 
Austin Duffy, MD, TGIB, CCR, NCI 
Associate Investigators:    
William D. Figg, PharmD, GMB, CCR, NCI 
Jane Trepel, DTB, CCR, NCI 
Douglas K. Price, PhD, GMB, CCR, NCI 
Peter Choyke, MD, CCR, MIP, NIH 
Xin Wang, PhD, LHC, CCR, NCI 
Brad Wood MD, OADRIS, DDR, CC, NIH 
Liang Cao PhD, GB, CCR, NCI 
Suzanne Fioravanti, RN, OCD, CCR, NCI 
Melissa Walker, RN, OCD, CCR, NCI 
 
Donna Mabry, NP, TGIB, CCR, NCI 
Statistician:                                
Seth Steinberg, PhD 
Biostatistics and Data Management Section  
National Cancer Institute 
 
 
9609 Medical Center Drive 2W334 
                    
Rockville, MD 20892-9716 
       
Phone: 240-276-5563 
Fax: 240-276-7885 
steinbes@mail.nih.gov  
Referral Contact/ 
Donna Mabry, NP, TGIB, CCR, NCI 
Study Coordinator:  
 
      Suzanne Fioravanti, RN, OCD, CCR, NCI 
 
Building 10, Room 12N226 
 
9000 Rockville Pike 
 
Bethesda, MD 20892-1906 
 
Phone: 301-594-6544 
 
Fax: 301-402-7901 
 
Email: fioravas@mail.nih.gov 
 
Investigational Agents:     
Drug Name: 
TRC105 


2 
Abbreviated Title:  Sorafenib and TRC105 in HCC 
NCI Protocol #: 11-C-0102 
Version Date:  June 10, 2016 
Amendment: N 
IND Number: 
 110744 
Sponsor: 
Center for Cancer Research, NCI 
Manufacturer 
Tracon Pharmaceuticals, Inc. 
Commercial Agent: Sorafenib 


3 
Abbreviated Title:  Sorafenib and TRC105 in HCC 
NCI Protocol #: 11-C-0102 
Version Date:  June 10, 2016 
Amendment: N 
PRÉCIS 
Background:  
• Worldwide, hepatocellular carcinoma (HCC) is the fifth most common malignancy with a 
median survival of 6-9 months. The SHARP study established sorafenib as a standard 
consideration in this disease and set the bar for future studies of systemic therapy.  
• TRC105 is a chimeric anti-angiogenic monoclonal antibody that binds CD105, a 
transmembrane receptor selectively expressed by proliferating endothelial cells. TRC105 
binds to CD105-expressing endothelial cells and mediates growth inhibition, apoptosis 
and antibody-dependent cell-mediated cytotoxicity (ADCC). 
Objectives: 
Primary: 
• Phase I: To establish the maximum tolerated dose (MTD) of TRC105 when given with 
standard-dose sorafenib for HCC. 
• Phase II: To determine the estimate response rate according to RECIST criteria for the 
combination of TRC105 with sorafenib in HCC. 
Eligibility: 
•  Histologically or cytologically confirmed diagnosis of HCC.   
• Childs-Pugh A or B (7 points) cirrhosis is allowed.  
• Patients must have disease that is not amenable to potentially curative resection, 
radiofrequency ablation, or liver transplantation. 
• In phase I, prior systemic therapy is allowed.   
• In phase II, prior systemic therapy for HCC (including sorafenib) is allowed. 
• No history of bleeding varices in previous 1 year (unless subsequent liver transplant). 
• No anti-coagulation (except low-dose aspirin). 
Design: 
• TRC105 will be administered intravenously every two weeks, on days 1 and 15 of each 
28 day cycle.  Sorafenib will be self-administered twice daily by mouth.  
• Phase 1: The first part of this study was a standard 3+3 dose escalation phase I study 
with the primary objective of establishing MTD for TRC105 when given in combination 
with standard-dose sorafenib. Sorafenib is taken orally at a dose of 400 mg twice daily. 
TRC105 is administered as an intravenous infusion every two weeks.  Patients will be re-
staged including imaging studies to assess for response and progression every 8 weeks.  
The TRC105 dose was escalated in cohorts of 3 to 6 patients up to a maximum of 15 
mg/kg every two weeks (see table below).  Intra-patient dose escalation was not allowed. 
• Phase II: TRC105 will be administered as an intravenous infusion every two weeks at 
the recommended phase II dose, 15 mg/kg of TRC105 ever two weeks in combination 
with standard dose sorafenib, defined in phase I. The sample size and interim stopping 
rule will be determined using a Simon optimal two-stage design.  


4 
Abbreviated Title:  Sorafenib and TRC105 in HCC 
NCI Protocol #: 11-C-0102 
Version Date:  June 10, 2016 
Amendment: N 
The first stage will initially enroll 6 evaluable patients, and if 0 of the 6 have a clinical 
response, then no further patients will be accrued. If 1 or more of the first 6 patients has a 
clinical response, then accrual would continue until a total of 23 patients have been 
enrolled. As it may take several weeks to determine if a patient has experienced a 
response, a temporary pause in the accrual may be necessary to ensure that enrollment to 
the second stage is warranted. If there are 1 to 2 clinical responses in 23 patients, this 
would be an uninterestingly low response rate. If there were 3 or more complete 
responses in 23 patients (13.0%), this would be sufficiently interesting to warrant further 
study in later trials. Under the null hypothesis (5% response rate), the probability of early 
termination is 73.5%. 
Cohort 
Sorafenib 
(mg PO twice daily) 
TRC105 
(mg/kg IV every two 
weeks) 
0 
400 bid 
1 
1 
400 bid 
3 
2 
400 bid 
6 
3 
400 bid 
10 
4 
400 bid 
15 
 


5 
Abbreviated Title:  Sorafenib and TRC105 in HCC 
NCI Protocol #: 11-C-0102 
Version Date:  June 10, 2016 
Amendment: N 
TABLE OF CONTENTS 
Précis ..........................................................................................................................................3 
Table of Contents ........................................................................................................................5 
1 
INTRODUCTION ...............................................................................................................7 
1.1 
Study Objectives ...........................................................................................................7 
1.2 
Background and Rationale: ...........................................................................................7 
2 
ELIGIBILITY ASSESSMENT AND ENROLLMENT ..................................................... 26 
2.1 
Eligibility Criteria ....................................................................................................... 26 
2.2 
Screening Evaluation .................................................................................................. 29 
2.3 
Registration Procedures............................................................................................... 30 
3 
STUDY IMPLEMENTATION .......................................................................................... 30 
3.1 
Study Design............................................................................................................... 30 
3.2 
Phase I (Dose Escalation Complete as of Amendment L) ............................................ 30 
3.3 
Phase II ....................................................................................................................... 33 
3.4 
Dosing Delays and Dose Modifications ....................................................................... 35 
3.5 
Correlative Studies for Research/Pharmacokinetic Studies .......................................... 41 
3.6 
Imaging Studies .......................................................................................................... 51 
3.7 
Summary of Correlative Tests ..................................................................................... 54 
3.8 
SAMPLE STORAGE, TRACKING, AND DISPOSITION ......................................... 55 
3.9 
On-Study and Follow Up Evaluations ......................................................................... 56 
3.10 
Criteria for Removal from Protocol Therapy and Off Study Criteria ........................ 56 
3.11 
Early stopping rules for safety/accrual ..................................................................... 56 
4 
SUPPORTIVE CARE ....................................................................................................... 57 
5 
DATA COLLECTION AND EVALUATION ................................................................... 57 
5.1 
Data Collection ........................................................................................................... 57 
5.2 
Response Criteria ........................................................................................................ 58 
5.3 
Toxicity Criteria .......................................................................................................... 66 
5.4 
Sample Storage, Tracking and Disposition .................................................................. 66 
6 
STATISTICAL Considerations ......................................................................................... 66 
6.1 
Phase I Portion ............................................................................................................ 66 
6.2 
Phase II Portion ........................................................................................................... 67 


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Abbreviated Title:  Sorafenib and TRC105 in HCC 
NCI Protocol #: 11-C-0102 
Version Date:  June 10, 2016 
Amendment: N 
6.3 
Accrual and Study Duration ........................................................................................ 68 
7 
HUMAN SUBJECTS PROTECTIONS ............................................................................. 68 
7.1 
Rationale For Subject Selection ................................................................................... 68 
7.2 
Participation of Children ............................................................................................. 68 
7.3 
Evaluation of Benefits and Risks/Discomforts ............................................................. 68 
7.4 
Risks/Benefits Analysis............................................................................................... 68 
7.5 
Consent Process and Documentation ........................................................................... 69 
8 
SAFETY REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING PLAN
 
70 
8.1 
Definitions .................................................................................................................. 70 
8.2 
NCI-IRB Reporting ..................................................................................................... 72 
8.3 
IND Sponsor Reporting Criteria .................................................................................. 73 
8.4 
FDA Reporting Criteria ............................................................................................... 73 
8.5 
Recording of Adverse Events ...................................................................................... 75 
8.6 
Data and Safety Monitoring Plan................................................................................. 76 
9 
PHARMACEUTICAL INFORMATION .......................................................................... 76 
9.1 
TRC105 (NSC #754227) ............................................................................................. 76 
9.2 
Sorafenib (Nexavar ®; BAY 43-9006; NSC 724772) .................................................. 81 
10 REFERENCES .................................................................................................................. 87 
11 APPENDICES .................................................................................................................. 91 
11.1 
APPENDIX 1:  Performance Status Criteria ............................................................ 91 
11.2 
Appendix 2:  Child-Pugh classification system ........................................................ 92 
11.3 
APPENDIX 3:  Correlative Study Specimen Processing Procedures ........................ 93 
11.4 
Appendix 4: STUDY CALENDAR ......................................................................... 96 
11.5 
Appendix 5: Correlative Study Specimen and Data Storage Procedures ................... 98 
 
 


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Abbreviated Title:  Sorafenib and TRC105 in HCC 
NCI Protocol #: 11-C-0102 
Version Date:  June 10, 2016 
Amendment: N 
1 
INTRODUCTION 
1.1 
STUDY OBJECTIVES 
1.1.1 Primary Objective(s): 
1.1.1.1 Phase I: To establish the MTD for TRC105 when given with sorafenib in HCC. 
1.1.1.2 Phase II: To determine the estimateresponse rate according to RECIST criteria for the 
combination of TRC105 with sorafenib in HCC. 
1.1.2 Secondary Objective(s): 
1.1.2.1 To evaluate the safety of the combination of TRC105 and sorafenib in HCC. 
1.1.2.2 To evaluate the immunogenicity of TRC105 as measured by human antichimeric 
antibody (HACA) and human antimouse antibody formation.  
1.1.2.3 To evaluate overall response rate (ORR) as determined by both standard and EASL-
modified RECIST criteria. 
1.1.2.4 To determine progression-free survival (PFS) and overall survival (OS) for TRC105 and 
sorafenib in HCC. 
1.1.2.5 To perform correlative studies assessing 1) potential biomarkers of response to 
angiogenic therapy, 2) changes in frequency and function of immune cells upon 
treatment and 3) molecular characterization of tumors. 
1.2 
BACKGROUND AND RATIONALE: 
1.2.1 Hepatocellular Carcinoma (HCC): Current standard of care. 
Worldwide, hepatocellular carcinoma (HCC) is the fifth most common malignancy with a 
median survival of 6-9 months1, 2.  There is a marked geographic heterogeneity with regard to the 
etiology of this disease and this complicates the design and interpretation of clinical trials.  In 
addition, for the majority of patients with HCC, the presence of underlying cirrhosis is an 
additional non-cancer factor that is prognosis-determining and must be taken into account.  The 
approach to treating HCC has traditionally comprised of locoregional strategies: surgery (partial 
resection or transplantation) or interventional radiologic procedures, such as chemoembolization 
or ablative techniques.  These approaches still have primacy and the surgical and ablative 
techniques remain the only real possibility of cure.  However, the publication of the landmark 
SHARP study established sorafenib as a standard consideration in this disease and set the bar for 
future studies of systemic therapy3. 
1.2.1.1 Cytotoxic chemotherapy. 
A clearcut survival benefit for chemotherapy compared to best supportive care has never been 
satisfactorily established in HCC.  Doxorubicin became the most widely studied 
chemotherapeutic agent based on older flawed studies that suggested good single-agent activity. 
A more reliable indicator of its efficacy was demonstrated in a phase III study comparing 


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Abbreviated Title:  Sorafenib and TRC105 in HCC 
NCI Protocol #: 11-C-0102 
Version Date:  June 10, 2016 
Amendment: N 
doxorubicin to nolatrexed, a thymidylate synthetase inhibitor4.  Median overall survival was 
better for the doxorubicin arm (32.3 v 22.3 weeks; P = .0068) with a response rate of 4% (v 1.4% 
in the nolatrexed which was considered inactive).  Doxorubicin was then used to form the 
backbone of the so-called PIAF regimen, in combination with cisplatin, interferon and 
fluorouracil.  This regimen appeared to be active based on a single-arm phase II study 
demonstrating a partial response rate of 26% and a median survival of 8.9 months5.  What was 
particularly striking in that study was that of the 9 patients who were able to undergo resection 
after achieving a response, no viable tumor cells were found in 4 of the resected specimens.  A 
phase III study was performed to compare the PIAF regimen with the de facto standard, single-
agent doxorubicin6.  Although there was a trend towards improved response rate (20.9% v 
10.5%) and median survival (8.7 v 6.8 months) in the PIAF group, these were not statistically 
significant (P=.83).  In addition the PIAF regimen had a significant increase in serious toxicity. 
One interpretation of the role of the PIAF regimen is for its very select use in patients of good 
performance status and hepatic function in whom cytoreduction is being attempted prior to 
potential resection7.  There has been a paucity of phase III studies evaluating other chemotherapy 
combinations.  Single-arm phase II studies have evaluated gemcitabine-based combinations, 
standard in pancreatico-biliary cancers, suggesting modest activity only.  For example a small 
phase II study (N=34) of gemcitabine in combination with oxaliplatin revealed a response rate of 
18% and a median survival of 11.5 months (95% CI: 8.5-14.3 months)8.  There is a consensus in 
the field that chemotherapy combinations by themselves are unlikely to result in significant 
progress. 
1.2.1.2 The SHARP and Asian-Pacific studies 
The first systemic medical therapy to demonstrate a prolongation of survival in hepatocellular 
carcinoma was sorafenib - an oral multi-kinase inhibitor of vascular endothelial growth factor 
(VEGF) receptor, the platelet-derived growth factor (PDGF) receptor, and Raf3.  A landmark 
phase III randomized, placebo-controlled study demonstrated – after closure of the study at the 
second pre-specified interim analysis – a median overall survival benefit in favor of the sorafenib 
arm (10.7 months v 7.9 months; HR 0.69; 95% CI, 0.55 to 0.87; P<0.001) and has resulted in the 
adoption of sorafenib monotherapy as the standard of care for patients with HCC who are not 
eligible for, or have had disease progression after, surgical or locoregional therapies.  Of note, in 
this study was the inclusion of ‘symptomatic progression’ (measured by a questionnaire) as a co-
primary endpoint.  Also of note was the fact that 95-98% of patients had Child-Pugh class A 
cirrhosis.  A second major study confirming the role of sorafenib – albeit with ostensibly less 
impressive results – was a study conducted in Asia in predominantly Hepatitis B patients9.  In 
that study overall survival was 6.5 months versus 4.2 months in favor of the sorafenib arm 
(P=0.014). 
1.2.1.3 Augmenting sorafenib by combining with chemotherapy. 
Abou-alfa, et al. conducted a randomized placebo-controlled phase II study (N=96) evaluating 
sorafenib in combination with the prior (de facto) standard, doxorubicin10.  Median OS was 13.7 
months versus 6.5 months in favor of the sorafenib-containing arm, thus providing further 
evidence in favor of sorafenib, although unable to define what additional benefit, if any, was due 
to the contribution of doxorubicin.  Shen and colleagues performed a phase II study combining 
metronomic UFT/tegafur chemotherapy with sorafenib in a predominantly BCLC stage C 


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Abbreviated Title:  Sorafenib and TRC105 in HCC 
NCI Protocol #: 11-C-0102 
Version Date:  June 10, 2016 
Amendment: N 
(advanced stage) population demonstrating a 6% partial response rate, median progression-free 
survival of 3.7 months (95% C.I., 1.9- 5.5) and overall survival of 7.4 months (95% C.I., 3.4- 
11.4)11.  Similarly Petrini and colleagues performed a study of continuous infusional 5-FU at 200 
mg/m2/day for 14 days of a 21 day cycle demonstrating a median TTP of 7.6 months (CI 
95%=5.3–9.9) and median overall survival of 12.2 months (CI 95%=4.45–19.8)12.  Other 
chemotherapy combinations of sorafenib currently being evaluated consist of capecitabine with 
oxaliplatin (XELOX) and gemcitabine with cisplatin (clinicaltrials.gov). 
1.2.1.4 Augmenting the anti-angiogenic effects of sorafenib. 
The difficulty in combining anti-angiogenic agents was demonstrated in a phase I study of 
sorafenib and bevacizumab in which overlapping toxicity resulted in an inability to dose-
escalate, albeit with some evidence of clinical benefit13.  As a result of this and a possible plateau 
effect with anti-VEGF therapy14, interest has focused on overcoming the escape mechanisms 
employed by tumors rather than merely trying to saturate with anti-VEGF stategies.  For 
example, fibroblast growth factor (FGF) levels have been shown to increase after anti-VEGF 
therapy and to modulate resistance to VEGF inhibition15.  Brivanib is a dual inhibitor of VEGF 
and FGF receptors which is currently being compared to sorafenib in a phase III study16.  An 
earlier phase II study demonstrated single-agent activity for brivanib in both sorafenib-naïve and 
pretreated patients with HCC17.  Perhaps the most important escape mechanism employed by 
tumors in response to antiangiogenic therapy is hypoxia inducible factor (HIF)-1α, which plays a 
central role in tumor progression, acting as a master regulator of how cancer cells adapt to 
hypoxic conditions.  HIF-1α therefore represents an attractive target in oncology, particularly in 
concert with anti-angiogenic strategies18.  In preclinical models, anti-VEGF therapy with 
bevacizumab has been shown to cause an increase in intratumor-hypoxia – without the induction 
of apoptosis – and to result in a significant increase of HIF-1α-dependent gene expression19. 
Numerous strategies of targeting HIF-1α, including antisense oligonucleotides and use of 
topoisomerase-1 poisons (which appear to inhibit the translation of HIF-1α) are currently in the 
clinic20. 
1.2.2 CD105  
CD105 (endoglin) is a 180 kDa homodimeric transmembrane receptor overexpressed by 
proliferating endothelial cells21.  It appears that CD105 is specific to endothelial cells that are 
proliferating, as anti-CD105 monoclonal antibody reacts with activated endothelial cells in 
tumors but weakly or not at all in the endothelium of normal, stable vasculature21.  The CD105 
pathway is essential for angiogenesis during fetal development and cell-surface expression of 
this molecule is required for the formation of new blood vessels22.  This is evidenced by CD105 
null mice that die in utero as a result of impaired angiogenesis in the yolk sac22. 
CD105 acts as an accessory protein that interacts with the signaling receptor complex of the 
TGF- ß superfamily, thus modulating the effects of TGF- ß23.  CD105 expression protects 
endothelial cells from the growth-inhibitory effects of TGF-β signaling24.  When engaged by the 
TGF- ß/TGF-ßRII complex, CD105 preferentially activates Alk-1 which in turn phosphorylates 
Smad proteins 1, 5 and 8.  This ultimately leads to stimulatory effects on endothelial cell 
proliferation, migration and transcription of pro-angiogenic genes. CD105 expression is induced 
by hypoxia through HIF-1α and protects hypoxic endothelial cells from apoptosis25. 


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Abbreviated Title:  Sorafenib and TRC105 in HCC 
NCI Protocol #: 11-C-0102 
Version Date:  June 10, 2016 
Amendment: N 
Additionally, CD105 regulates components of the extracellular matrix to facilitate endothelial 
cell migration and promote formation of neo-vessels26. 
Anti-VEGF therapy up-regulates CD105 expression, indicating that a therapeutic strategy which 
targets CD105 may complement VEGF-inhibition27.  
Mutations in CD105 or its downstream signaling mediator leads to haplotype insufficiency 
causing a well-described syndrome known as hereditary hemorrhagic telangiectasia type 1 
(HHT-1 or Osler-Weber-Rendu Syndrome).  HHT-1 is a rare autosomal dominant genetic 
disorder characterized by vascular dysplasias, frequent episodes of epistaxis, mucocutaneous 
telangiectasias and arteriovenous malformations of the lung, brain, liver and gastrointestinal 
tract.  The genotype is manifested in utero, but the phenotype does not become apparent for 
many years following birth.  Affected patients most commonly present with epistaxis in the 
second decade of life.  The phenotype of this disorder is limited to vascular effects, indicating the 
specific role of CD105 in the vasculature.  Most patients affected with HHT-1 experience 
epistaxis by the age of 10 to 20 years, while telangiectasias of the skin and mucosa first appear 
by the age of 20 to 40 years.  Visceral arteriovenous malformations are less common sequelae 
but may result in significant morbidity, including pulmonary shunting and intracranial 
hemorrhage.  
1.2.2.1 CD105 in HCC 
The specificity of CD105 expression in HCC tumor tissue was studied by Yang, et al. who 
analyzed CD105 expression levels in para-carcinomatous and tumor tissue in 113 HCC resected 
specimens.  In addition, in 14 of these cases areas of distinct normal liver tissue were also 
resected.  It was found that CD105 was expressed in 100% of the HCC levels but 0% of either 
the normal or para-carcinomatous tissue21.  This was in contrast with the pan-endothelial anti-
CD34 staining which - in addition to being present in 100% of tumor tissue – was also present in 
94% and 87% of para-carcinomatous and normal liver tissue respectively.  
Preclinical data in support of the concept: 
CD105 and HCC: Studies performed in different laboratories using various antibodies to CD105 
(endoglin) have revealed expression and upregulation in a wide range of tumor endothelia, but 
seldom found in the endothelia of normal tissues, suggesting that CD105 is highly related to 
tumor angiogenesis28.  CD105 expression is an important prognostic factor in solid tumor 
patients including HCC21.  In two mouse models of hepatoma - formed from Hepal-6 and H22 
cell lines - tumor growth suppression, inhibition of angiogenesis, increased survival and tumor 


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apoptosis were observed on treatment with anti-CD105 antibody (Figure 1)28. 
 
Figure 1: Anti-murine CD105 antibody therapy delayed tumor growth (top panel) and extended mouse 
survival (bottom panel) in 2 xenograft models of HCC.  In additional correlative studies, the therapy reduced 
tumor microvessel density and increased tumor apoptosis. 
CD105 and VEGF: CD105 expression has been shown to be increased in certain tumors 
following inhibition of the VEGF pathway.  CD105 expression increased more than two-fold in 
human pancreatic cancers grown in mice treated with an antibody that binds VEGF27(Figure 2). 
Treatment of human bladder cancers grown in mice with an antibody that blocks activation of 
the VEGF receptor increased CD105 expression within the core tumor vasculature29. 
 


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Figure 2: Effect of anti-VEGF antibody treatment on angiogenic gene expression: A microarray 
analysis of angiogenic genes.  Genes altered more than 2-fold by anti-VEGF treatment are 
presented.  Relative expression levels indicate positive or negative fold differences in anti-VEGF 
antibody-treated group compared with control antibody-treated group. 
1.2.3 TRC105  
All data cited in this section (unless otherwise noted) has been obtained from Tracon 
Pharmaceuticals, Inc and is found in the Tracon Pharma Investigator’s Brochure, Project 
TRC105 Oncology, version 2.0: May 11, 2009. Edition 2.0.  
TRC105 is a human/murine chimeric anti-CD105 IgG1 kappa monoclonal antibody consisting of 
human Cκ and Cγ1 constant regions with murine Vκ and VH regions.  TRC105 is composed of 
two light chains of 213 amino acids and two heavy chains of 448 amino acids and has an 
approximate molecular weight of 148 kDa.  This monoclonal antibody binds with high avidity to 
human CD105 (endoglin), thus inhibiting angiogenesis and tumor growth. 
1.2.3.1   Nonclinical Pharmacology, Efficacy and Toxicology  
Pharmacology studies include in vitro and in vivo studies performed with the murine parent 
antibody (SN6j) and TRC105.  These antibodies share identical variable regions.  SN6j, the 
murine parent monoclonal antibody of TRC105, was generated by immunizing mice with an 
isolated CD105 preparation from human leukemia cells. 
Pharmacology studies were conducted in murine and human models.  Collectively, the studies 
demonstrate that TRC105 (or SN6j) binds with higher avidity to human than murine endothelial 
cells, and reacts more strongly with proliferating than quiescent endothelial cells.  Studies also 
indicate that these anti-CD105 antibodies are able to mediate TGF-β dependent growth 
inhibition, induce apoptosis of human umbilical vein endothelial cells (HUVECs), mediate 
antibody dependent cell-mediated cytotoxicity (ADCC) of HUVECs, saturate CD105 binding at 
concentrations ≥ 250 ng/mL, and inhibit the growth of human tumor xenografts. 
TRC105 binds to purified human CD105 with high avidity by surface Plasmon resonance assay 
(5 - 35 pM).  As expected, binding studies indicate that both SN6j and TRC105 bind with nearly 
identical avidity to human endothelial cells that express CD105 as determined by Scatchard 
analysis. 
In Vitro Pharmacology of SN6j  
Using Scatchard plot analyses performed by incubating fixed combinations of radiolabeled and 
native antibody with KM-3 cells, the avidity of SN6j was calculated by regression analysis to be 
2.85 x 109 liter/mole (or 3.51 x 10-10 mole/liter). 
TGF-β Dependent Growth Inhibition of HUVECs 
SN6j was studied for its ability to inhibit the growth of HUVECs in vitro in the presence of TGF- 
β.  HUVEC cells were cultured at 37 °C overnight prior to the addition of SN6j and TGF-β. Cells 
were then exposed to antibody or TGF-β for 72 hours, during which time the media containing 
antibody and/or growth factors was replaced every 24 hours.  Cell growth was then quantified by 
assaying tritiated thymidine incorporation for 20 hours.  The concentration of SN6j needed to 
inhibit HUVEC growth by 50% was 90 μg/mL in the absence of TGF-β.  However, the 


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concentration of SN6j needed to inhibit HUVEC growth by 50% was much lower when cells 
were incubated with antibody in the presence of TGF-β.  These data indicate that anti-endoglin 
antibody potently inhibits HUVEC growth in the presence of TGF-β.  At physiologic 
concentrations of TGF-β (>100 pg/mL), the amount of SN6j needed to inhibit HUVEC cell 
growth was <10 μg/mL. 
Induction of Apoptosis of Proliferating HUVECs 
SN6j was studied for its ability to induce apoptosis of proliferating HUVECs in vitro.  HUVEC 
cells were seeded and then incubated at 37 °C with SN6j (50 or 100 μg/mL) or 100 μg of MOPC, 
an IgG1-kappa isotype-matched control antibody.  Following incubation, cells were washed and 
then lysed.  The cytoplasmic and nuclear fractions were separated by centrifugation and 
nucleosomes contained in the cytoplasmic fraction were then detected via their histone 
components. Apoptosis was determined by assaying the fragmented nucleosome content of 
cytoplasmic fractions using a commercial ELISA (Roche Diagnostics).  The degree of apoptosis 
induced by SN6j on proliferating HUVECs from multiple donors was 9.1% at 50 μg/mL and 
25.6% at 100 μg/mL concentrations, relative to the value induced by camptothecin.  Apoptosis of 
SN6j (100 μg/mL) treated HUVECs was 4.58 times as large as that of MOPC control IgG (100 
μg/mL) treated HUVECs, while apoptosis of SN6j (50 μg/mL) treated HUVECs was 2.28 times 
as large as that of MOPC control IgG (100 μg/mL) treated HUVECs. 
In a separate experiment using HUVECs from a single donor, the degree of apoptosis induced by 
SN6j was 31.5% at 50 μg/mL and 43.7% at 100 μg/mL concentrations, relative to the value 
induced by camptothecin.  Apoptosis of SN6j (100 μg/mL) treated HUVECs was 2.53 times as 
large as that of MOPC control IgG (100 μg/mL) treated HUVECs, while apoptosis of SN6j (50 
μg/mL) treated HUVECs was 2.10 times as large as that of MOPC control IgG (100 μg/mL) 
treated HUVECs.  Overall, SN6j induced significant levels of apoptosis (although lower than 
those induced by camptothecin) on HUVECs at concentrations of ≥ 50 μg/mL. 
In Vitro Pharmacology of TRC105 
The constant regions of SN6j were humanized to yield TRC105 for full-scale development and 
evaluation in clinical studies.  TRC105 (c-SN6j) is a chimeric IgG1 kappa antibody made by 
grafting the constant regions of human IgG1 heavy chain and kappa light chain onto the murine 
variable regions of monoclonal antibody SN6j that binds human CD105.  Using Scatchard plot 
analyses performed by incubating fixed combinations of radiolabeled and native antibody with 
KM-3 cells, the avidity of TRC105 (c-SN6j) was calculated by regression analysis to be 2.98 x 
109 liter/mole (or 3.36 x 10-10 mole/liter). 
TRC105 Avidity to Human CD105 
A study of binding of TRC105 with human CD105 using a surface plasmon resonance assay 
indicated that avidity and affinity of TRC105 for human CD105 were approximately 5 x 10-12 
and 35 x 10-12 mole/liter, respectively. 
TRC105 Binding Potency to Human CD105 
An ELISA assay was performed using plates coated with human CD105.  TRC105 was found to 
half-saturate human CD105 at concentrations of approximately 34-50 ng/mL and to fully saturate 
human CD105 at concentrations of ≥ 250 ng/mL.  TRC105 concentrations of ≥ 250 ng/mL are 


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expected to saturate CD105 expressed on human endothelial cells and fully engage effector 
functions. 
TRC105 Avidity to HUVECs In Vitro 
A binding assay was performed to determine the avidity of TRC105 to cultured HUVECs. 
TRC105 was found to half saturate non-confluent (or proliferating) HUVECs at 2.3 ng/mL and 
to half saturate confluent (or non-proliferating) HUVECs at 22 ng/mL.  Saturation was achieved 
at approximately 250 ng/mL in both cases.  
TRC105 Induction of ADCC of Proliferating HUVECs In Vitro 
TRC105 was investigated for its ability to mediate antibody-dependent cell-mediated 
cytotoxicity (ADCC) in vitro.  In the presence of effector cells from three different donors, 
concentrations of ≥ 1 μg/mL of TRC105 lysed significant proportions of proliferating HUVECs, 
indicating that TRC105 exhibits ADCC activity in vitro.  Lower concentrations of TRC105 were 
evaluated for ADCC using HUVEC cells and peripheral blood mononuclear cells that were 
activated with interleukin-2 (see graph below).  TRC105 concentrations of < 1 ng/mL lysed 
significant proportions of proliferating HUVECs in the presence of interleukin-2 activated NK 
cells at an effector to target ratio of 10:1.  TRC105 did not engage complement-mediated 
cytotoxicity (CDC) on proliferating HUVECs in vitro. 
 
 
In vitro analysis has shown that anti-CD105 antibodies are internalized following binding to 
CD105.  SN6j and isotype-matched control IgG were individually labeled with FITC and then 
incubated with SVEC4-10 murine endothelial cells for four hours at room temperature.  SN6j 
reacted with viable SVEC4-10 murine endothelial cells and was internalized into the cells as 
shown by strong FITC-SN6j staining within the intracellular portion of cells.  In contrast, only 
weak background staining was seen with the cells treated with FITC-labeled isotype-matched 


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control IgG.  Internalization of bound TRC105 is expected to limit the ability of the antibody to 
engage effector functions at low CD105 surface densities, such as those on quiescent 
endothelium. 
1.2.3.2 In Vivo Nonclinical Toxicology Studies of TRC105 
TRC105 Toxicology 
TRC105 was administered by intravenous infusion over 30 minutes weekly for 5 doses to 
cynomolgus monkeys, at doses of 3 mg/kg, 10 mg/kg and 30 mg/kg.  Three monkeys of each 
gender were treated at the two lower doses and six animals of each gender were treated at the 
high dose (30 mg/kg).  Animals tolerated TRC105 at all doses tested.  There was no clinical, 
clinical pathologic or histopathologic evidence of toxicity.  The no observed event level (NOEL) 
was determined to be 30 mg/kg given by 30 minute intravenous infusion weekly for five doses. 
A GLP repeat-dose toxicology study was undertaken in cynomolgus monkeys to determine the 
onset, reversibility, persistence, or delayed occurrence of toxic effects after five weekly doses of 
TRC105, followed by a four-week recovery period.  Single-dose pharmacokinetic 
characterization of TRC105 was performed after Day 1 and multiple-dose pharmacokinetic 
characterization of TRC105 was performed after Day 29.  In addition, the immunogenicity of 
TRC105 was determined.  Doses were administered by a 30 minute infusion on days 1, 8, 15, 22 
and 29 into 36 adult monkeys.  There were three males and three females per dose at 3 and 10 
mg/kg/dose and six males and six females at control (vehicle) and 30 mg/kg/dose.  All animals 
were dosed on days 1, 8, 15, 22 and 29 via a 30 minute intravenous infusion.  Three animals per 
sex per group in Groups 1 through 4 were euthanized on Day 30, and three animals per sex per 
group in Groups 1 and 4 were euthanized on Day 57.  Toxicity was assessed by monitoring 
mortality, clinical condition, body weight, food consumption, ophthalmic examination results, 
electrocardiography (including heart rate), blood pressure, body temperature, respiratory rate, 
clinical pathology (hematology, coagulation, serum chemistry, urinalysis and fecal occult blood). 
All received a comprehensive necropsy; selected organs were weighed and tissues were 
evaluated microscopically. Survival, clinical condition, body weight, food consumption, 
ophthalmology examinations, physiologic parameters (electrocardiograms, blood pressure, body 
temperature, heart rate and respiratory rate), hematology and coagulation, clinical chemistry, 
urinalysis, fecal occult blood evaluations, organ weights, and macroscopic and microscopic 
findings were unaffected by TRC105 administration.  Accordingly, the no observed effect level 
(NOEL) for intravenous TRC105 under the conditions of this study was 30 mg/kg.  Tissue 
binding assays were conducted on selected tissues from the control and high-dose groups. 
Animals dosed with TRC105 demonstrated binding to endothelial cells consistent with 
internalization of bound antibody.  While this staining pattern is consistent with CD105 
distribution, internalized antibody may also reflect binding to Fc receptors known to be 
expressed by endothelial cells.  Roswell Park Cancer Institute sponsored a non-GLP study in 
which cynomolgus monkeys were dosed twice weekly for three weeks with 1.0 mg/kg, 3.0 
mg/kg or 10.0 mg/kg of TRC105 (c- SN6j).  In summary, TRC105 was well-tolerated by 
nonhuman primates when dosed up to 30 mg/kg weekly for five doses as a 30 minute 
intravenous infusion in a GLP study or up to 10 mg/kg twice weekly for six doses as an 
intravenous bolus.  The highest dose tested, 30 mg/kg weekly for five doses, produced no 
indications of a drug-related effect in a GLP study and is the NOEL. 


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1.2.3.3 TRC105 Nonclinical Pharmacokinetics and Immunogenicity 
Toxicokinetics and immunogenicity were studied following the administration of TRC105 by 
intravenous infusion over 30 minutes weekly for five doses to cynomolgus monkeys, at doses of 
3 mg/kg, 10 mg/kg and 30 mg/kg.  The mean central distribution volume was 0.029, 0.040 and 
0.038 L/kg in animals given 3 mg/kg, 10 mg/kg and 30 mg/kg of TRC105, respectively, by 
intravenous infusion over 30 minutes.  The mean steady-state volume of distribution was 0.075, 
0.087 and 0.076 L/kg in animals given 3 mg/kg, 10 mg/kg and 30 mg/kg of TRC105, 
respectively.  As expected, the central volume of distribution for TRC105 was similar to the 
serum volume in monkeys.  Both the central and steady-state distribution volumes were 
consistent with distribution volumes of other chimeric antibodies (e.g., rituximab and 
cetuximab).  The mean terminal half-life of TRC105 was 133, 149 and 153 hours among the 
anti-TRC105 antibody negative animals in the 3, 10, and 30 mg/kg dose groups, respectively. 
Steady-state was attained by 5 weeks in each dose group.  The mean serum TRC105 Cmax was 
83, 135 and 104 µg/mL in the 3 mg/kg dose group on Study Days 1, 22 and 29, respectively.  In 
the 10 mg/kg dose group the mean Cmax values were 212, 346 and 306 µg/mL, and were 834, 
1113 and 957 µg/mL in the 30 mg/kg dose group on Study Days 1, 22, and 29, respectively.  A 
single monkey dosed with 30 mg/kg of TRC105 tested positive for the formation of MACA 
(monkey anti-chimeric antibodies; i.e., antibodies reactive with the human portion of TRC105) 
on Study Days 36, 43, and 50, but not Study Day 57.  All animals that tested negative for 
MAMA (monkey anti-murine antibodies; i.e., antibodies reactive with the murine portion of 
TRC105) before dose administration on Study Day 1 also tested negative when subsequent 
samples were obtained throughout the remainder of the study.  Several other animals tested 
positive for MAMA prior to the first dose administration on Study Day 1 and also tested positive 
(at lower titers) at frequent times throughout the 57 day study period. 
1.2.3.4 TRC105 Nonclinical Efficacy  
TRC105 was studied in vivo for its ability to inhibit angiogenesis using a murine model of 
choroidal neovascularization (CNV).  C57B/L6 mice were given an intravitreal injection of 
TRC105 in one eye and PBS in the contralateral eye.  TRC105 demonstrated dose-dependent 
inhibition of CNV in C57B/L6 mice.  The highest dose administered (5 μg in1 μL) inhibited 
CNV by over 50% versus control. 
1.2.3.5 TRC105 Clinical Pharmacology, Toxicity and Efficacy  
Clinical Studies of TRC105  
Several studies with TRC105 are underway or have been completed.  An open-label, phase 1, 
multicenter study of TRC105 (Study 105ST101) enrolled fifty patients, who were treated until 
disease progression with TRC105 at 0.01-15 mg/kg/q2wk or 10-15 mg/kg/wk.  Studies of 
TRC105 in prostate, bladder, and ovarian cancer and a phase 1b study of TRC105 in 
combination with bevacizumab have also been completed.  Ongoing studies besides this phase 
1b study of TRC105 in combination with sorafenib in liver cancer include: a phase 1b/2 study of 
TRC105 in combination with axitinib in renal cell carcinoma, a phase 1b/2 study of TRC105 in 
combination with pazopanib, a phase 1b study of TRC105 in combination with bevacizumab in 
glioblastoma multiforme, and a single-patient study of TRC105 in combination with 
bevacizumab in choriocarcinoma. 


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TRC105 Clinical Pharmacokinetics 
In Study 105ST101, TRC105 pharmacokinetics were assessed on patients enrolled at doses up to 
15 mg/kg weekly.  Circulating TRC105 was not measurable above the lower limit of quantitation 
of the assay (78 ng/mL) in patients receiving doses below 0.3 mg/kg.  TRC105 was measurable 
above the target concentration based on preclinical data (200 ng/mL) for 4 hours at 0.3 mg/kg, 1 
day at 1 mg/kg, 5 days at 3 mg/kg, 7 days at 10 mg/kg TRC105 dosed every two weeks.  Serum 
concentrations expected to saturate CD105 binding sites (≥ 200 ng/mL) were achieved 
continuously at 15 mg/kg q2wk and 10 mg/kg weekly, and TRC105 accumulated at 15 mg/kg 
weekly (Figure 1). 
Figure 1: Single-Dose and Multiple-Dose Pharmacokinetic Data from Study 105ST101 
 
 
TRC105 Clinical Immunogenicity 
In Study 105ST101, serum samples for evaluation of TRC105 immunogenicity, including 
HAMA and HACA, were collected pre-dose on day 1 of each 28 day cycle, at the end of study, 
and then at 4 and 12 weeks after the end of study visit. 
HAMA and HACA data are available from the phase 1 monotherapy TRC105 trial.  Neither 
HAMA nor HACA were detected in patients treated with CHO-produced TRC105, which will be 
used for all future clinical trials, including this study.TRC105 Clinical Safety 
A total of 50 patients were treated on a phase 1 Study 105ST101 with escalating doses of 
TRC105 at 0.01, 0.03, 0.1, 0.3, 1, 3, 10 and 15 mg/kg every two weeks and then 10 and 15 
mg/kg weekly.  Dose escalation proceeded stepwise until the top dose was reached.  The 
maximum tolerated dose was exceeded at 15 mg/kg weekly and the recommended phase 2 dose 
of TRC105 was therefore determined to be 10 mg/kg weekly.  Three of 4 patients at 15 mg/kg 
weekly developed grade 3 hypoproliferative anemia (without leucopenia or thrombocytopenia) in 


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cycle 2, and one of the three progressed to grade 4 in cycle 3.  Anemia was associated with 
accumulation of TRC105 and characterized by a low reticulocyte production index.  Additional 
laboratory and clinical evaluations excluded common causes of anemia including blood loss, 
hemolysis, plasma volume expansion, inadequate erythropoietin, iron deficiency, and vitamin B-
12 or folate deficiency.  The anemia is believed to result from TRC105-mediated suppression of  
proerythroblasts, the only cells in the bone marrow known to express substantial levels of 
CD105.  Anemia was reversible and manageable with dose reduction and standard supportive 
measures including erythropoietin and blood transfusion.   
Infusion reactions, anemia, fatigue, epistaxis and headache were the most frequently observed 
adverse events considered related to TRC105.  The majority of treatment-related adverse events 
were grade 1 or 2. 
Infusion reactions, among the most common adverse events, were usually with the initial 
TRC105 dose and included one or more of the following signs or symptoms: rigors, 
bronchospasm, urticaria, hypertension, hypotension, tachycardia or bradycardia.  Infusion 
reactions were initially reported at 1 mg/kg every 2 weeks for patients receiving TRC105 
produced in NS0 cells without premedication.  TRC105 produced in CHO cells was known to 
more potently engage ADCC in vitro than TRC105 produced in NS0 cells.  Because of this, the 
initial dose level for patients receiving CHO-produced TRC105 was de-escalated to 0.3 mg/kg.  
Despite dose de-escalation, the first two patients at 0.3 mg/kg treated with CHO-produced 
TRC105 experienced grade 2 and grade 3 infusion reactions with the first dose in the absence of 
premedication.  The protocol was therefore amended to require a glucocorticoids -based 
premedication regimen and extend the initial infusion duration from 1 to 4 hours.   
The amendment mandating premedication and extended initial infusion duration successfully 
reduced the frequency and severity of infusion reactions and allowed dose escalation to continue. 
One additional patient who received CHO-produced TRC105 at 1 mg/kg developed a grade 3 
infusion reaction with the third dose given over 2 hours.  This patient had experienced a grade 2 
infusion reaction when the dose was administered over 4 hours.  In all three patients with grade 3 
infusion reactions, TRC105 was not detectable in serum at the time of dosing, which allowed de 
novo binding of TRC105 to CD105 expressing endothelium within the vasculature.  Grade 3 
infusion reactions were not observed in patients dosed at 10 or 15 mg/kg who maintained 
TRC105 serum levels known to saturate CD105 binding sites for the full dosing interval.  At 
dose levels where continuous TRC105 serum levels were achieved, glucocorticoids were safely 
discontinued and the infusion duration reduced to 1 hour. 
Three patients developed grade 1 cutaneous telangiectasia on the trunk early in the course of 
therapy, all at dose levels of 10 or 15 mg/kg weekly that resulted in continuous serum levels of 
TRC105 known to saturate CD105 sites on human endothelium.  Grade 1 or 2 hemorrhage was 
reported, including intermittent postcoital vaginal bleeding (that also occurred prior to TRC105 
treatment), epistaxis, and superficial gingival bleeding.    
Grade 1 or 2 headaches were observed, mainly in patients treated at doses of TRC105 above 3 
mg/kg.  Headaches began the day following infusion and were generally manageable with 
acetaminophen.  However, grade 2 headache in one patient at 15 mg/kg weekly prompted 
discontinuation prior to completion of the dose-limiting toxicity evaluation period.  Fatigue was 


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one of the more common adverse events attributable to TRC105 and was more prevalent at doses 
above 3 mg/kg.   
One patient developed dose-limiting toxicity of grade 4 hemorrhage presenting as melena from a 
gastric ulcer within 5 days of the initial TRC105 infusion at 0.1 mg/kg.  He discontinued 
TRC105 treatment, was transfused 2 units of packed red blood cells and the bleeding resolved 
with nonsurgical management by the time of upper endoscopy.  Serious bleeding was not 
observed following protocol amendment to exclude patients with a history of peptic ulcer disease 
(unless healing was documented) and patients on ulcerogenic medications including non-
steroidal anti-inflammatory drugs.  
Classic toxicities associated with VEGF inhibition, including hypertension, proteinuria and 
thrombosis were not prominent.  One patient with recurrent anal cancer treated at 0.1 mg/kg 
developed proteinuria considered possibly related to TRC105, but proteinuria was also noted 
prior to TRC105 dosing.  Transient hypertension (156/112) without QT changes occurred in a 
single patient one day following infusion of 15 mg/kg, and was controlled by a single dose of 
oral antihypertensive medication. There were no arterial or venous thromboembolic events, nor 
gastrointestinal or other perforations in these patients.TRC105 Clinical Efficacy 
In study 105ST101 stable disease ≥ 2 months was observed in 21 of 45 patients (47%) and stable 
disease ≥ 4 months in 6 of 44 patients (14%).  Decreases in CEA, PSA, or CA-125 were noted in 
7 of 21 patients (33%) and a global decrease in key angiogenic biomarkers was observed with 
treatment.  One patient with castrate-refractory prostate cancer remains on TRC105 treatment 
after 6 years at a TRC105 dose of 0.01 mg/kg every 2 weeks.  He has an ongoing complete PSA 
response, with resolution of bone pain and bone scan normalization. One patient with metastatic 
carcinosarcoma, manifested decreased tumor burden on computerized tomographic scanning and 
maintained stable disease for 20 months on therapy. The latter is especially notable when one 
considers that this patient had received three prior treatments -- carboplatin + paclitaxel for 4 
months, anastrozole for 8 months, and ifosfamide for 2 months -- and had manifested tumor 
progression on each.  In effect, TRC105 provided the most favorable clinical outcome and did so 
as a fourth-line therapy. 
1.2.3.6   TRC105 Physical, Chemical, and Pharmaceutical Properties and Formulations 
Physical, Chemical and Pharmaceutical Properties 
TRC105 is a chimeric anti-CD105 IgG1 antibody consisting of human Cκ and Cγ1 constant 
regions with murine Vκ and VH regions.  TRC105 is composed of two light chains of 213 amino 
acids and two heavy chains of 448 amino acids and has an approximate molecular weight of 148 
kDa. 
Formulation 
TRC105 is a sterile, clear colorless to slightly yellow opalescent solution for intravenous 
infusion.  The solution may contain small amounts of visible particulates.  TRC105 will be 
filtered through a 0.2 μm low protein binding filter at the clinical site prior to administration.  
Each single-use vial contains a 7 mg/ml or 25 mg/ml solution may be provided in one or more of 
the following presentations:   
(a) Phosphate Buffered Saline Formulation (7 mg TRC105/mL) 


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210 mg TRC105/30 mL single-use vial 
or 
 
(b) 20 mM L-Histidine/L-Histidine Monohydrochloride, 240 mM Trehalose, 0.01% Polysorbate 
20 Formulation (25 mg TRC105/mL) 
 
100 mg TRC105/4 mL single-use vial 
400 mg TRC105/16 mL single-use vial 
 
TRC105 is formulated as a preservative-free solution containing sodium chloride, monobasic 
sodium phosphate monohydrate, anhydrous dibasic sodium phosphate, and Sterile Water for 
Injection.  Hydrochloric acid and/or sodium hydroxide may be added to adjust the pH. TRC105 
is formulated to be isotonic with a pH of 6.2 – 8.2. 
Storage Conditions 
TRC105 should be stored refrigerated 2 °C to 8 °C (36 °F to 46 °F).  Preparations of TRC105 in 
infusion containers are stable for up to 8 hours at room temperature. 
Manufacturing Process 
The TRC105 production cell line for initial phase I clinical testing was a NS0 cell line.  The 
manufacturing process used bioreactors with media containing bovine sera from the US or New 
Zealand. A high producing CHO cell line was subsequently developed for phase I and later stage 
clinical development using media that is free of animal-derived components.  The manufacturing 
process uses conventional purification and filtration steps and concludes with the formulation of 
TRC105 in phosphate buffered saline.  The purity of TRC105 is greater than 95%.  Only CHO 
derived material will be used in this study. 
1.2.4 Sorafenib 
Sorafenib (Nexavar®) is FDA-approved for the use of advanced HCC and renal carcinoma.  A 
brief summary of the preclinical data including in vitro and in vivo activity, clinical 
pharmacology and toxicology is outlined below.  A complete list of CAEPRs for sorafenib is 
also provided.  
1.2.4.1 In Vitro Activity 
The ability of sorafenib to inhibit a number of kinases was evaluated (Investigator’s Brochure, 
2003).  The in vitro biochemical and cellular profile of sorafenib is summarized below: 
 
Biochemical Assay 
IC50 (µM) 
c-raf b 
0.002/0.006 
b-raf  wild-type 
0.025 


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b-raf V599E mutant 
0.038 
VEGFR-2 (human) 
0.090 
VEGFR-2 (murine) 
0.006 
VEGFR-3 (murine) 
0.010 
PDGFR-β (murine) 
0.028 
Flt-3 
0.058 
c-KIT 
0.068 
FGFR-1 
0.580 
p38α 
0.038 
Cellular Mechanismc 
IC50 (µM) 
MDA-MB-231 MEK phosphorylation (Human 
Breast) 
0.04 
BxPC-3 MEK phosphorylation (Human Pancreatic) 
1.00 
LOX ERK phosphorylation (Human Melanoma) 
0.80 
b-raf ER MEK activation (Human Chimera, 3T3 
cells) 
2.30 
VEGFR-2 phosphorylation (Human, 3T3 cells) 
0.03 
VEGFR-3 phosphorylation (Mouse, 293 cells) 
0.10 
PDGFR-β phosphorylation (Human, AoSMC)d 
0.02 
Cellular Proliferation 
IC50 (µM) 
MDA-MB-231 (10% FCS)e 
2.60 
MDA-MB-231 (0.1% FCS) 
0.10 
VEGF-HUVEC (2.0% FCS)f 
3.00 
PDGFR-β AoSMCd (0.1%  BSA)g 
0.23 
a Recombinant enzyme assay 
b Raf kinase activated with Lck (truncated/full length c-raf) 
c Mechanistic cellular assays all performed in 0.1% BSA 
d Human aortic smooth muscle cells 
e Fetal calf serum 
f  Human umbilical vein endothelial cells 
g Bovine serum albumin 
 
In vitro kinase assays demonstrated that sorafenib is a potent inhibitor of wild type and mutant 
(V599E) B-Raf and c-Raf Kinase isoforms (Investigator’s Brochure).  In addition, sorafenib did 
not inhibit human EGFR or Her2 kinases at 10 µM.  Nor were PKC-α, PKC-β, PKC-γ, and PKA 
(rat, rabbit and bovine sources) kinase activity inhibited in vitro.  Sorafenib demonstrated an IC50 
of 780 nM against p59 (bovine) Fyn kinase (Src family of protein tyrosine kinases).  In non-
kinase targets sorafenib had moderate potency against the adenosine A3, dopamine D1, and 
muscarinic M3 receptors with IC50 of 1.6 µM, 2.0 µM, and 3.1 µM, respectively.  Sorafenib did 
not inhibit MEK-1, ERK-1, EGFR, HER2/neu, c-met, PKA, PKB, Cdk-1/cyclin B, pim-1, GSK 


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3-b, CK-2, PKC-α (r), PKC-β (r), PKC-γ at concentrations as high as 10 µM.  In summary, 
sorafenib showed ≥100-fold more selectivity for raf kinase relative to other target proteins. 
Sorafenib also inhibited in vitro several receptor tyrosine kinases (RTKs) that are involved in 
tumor progression, human VEGFR-2, murine VEGFR-2, murine VEGFR-3, murine PDGFR-β, 
Flt-3, c-KIT, and p38α (MAPK family).  In cellular assays, sorafenib was found to be a potent 
inhibitor of human and murine VEGFR-2, murine VEGFR-3, and murine PDGFR-β receptor 
phosphorylation (Investigator’s Brochure, 2003). 
VEGF and PDGF receptors are involved in the mechanism of tumor angiogenesis30, 31.  PDGF 
receptors may also play a role in patients with chronic myeloproliferative cancers32.  Flt-3 is 
important in acute myelogenous leukemia 33 and c-Kit plays a critical role in gastrointestinal 
stromal tumors34. 
1.2.4.2 In Vivo Activity 
Sorafenib has demonstrated in vivo anti-tumor efficacy as a single agent against a broad range of 
human tumor xenografts as summarized in the following table.  The models evaluated include 
HCT-116 and DLD-1 colon tumor xenografts, MX-1 mammary tumor xenograft, NCI-H460 and 
A549 NSCLC xenografts, MiaPaCa-2 pancreatic tumor xenografts, and SK-OV-3 ovarian tumor 
xenografts.  In this table, compound efficacy is expressed as percent tumor growth inhibition 
(TGI) and is calculated as ((1-(T/C)) *100, where T and C represent the mean tumor size in the 
Treated and Control groups respectively at the first measurement after the end of treatment.  In 
the NCI-H460 (K-ras mutant) and A549 NSCLC tumor xenografts model, BAY 43-9600, at 
doses of 10mg/k, 30mg/k and 60mg/kg, induced a tumor growth inhibition of 27, 60 and 68%, 
respectively. 
Sorafenib Demonstrates Broad Spectrum Anti-Tumor Efficacy in 
Preclinical Xenograft Models 
Tumor Type 
Model 
Dose (mg/kg/dose 
free base equiv.)1 
Percent TGI 
((1-(T/C))100) 
Colon 
HCT-116 
10 
30 
100 
45 
64 
68 
Colon 
DLD-1 
15 
30 
60 
31 
66 
75 
NSCLC 
NCI-H460 
10 
30 
27 
56 
NSCLC 
A549 
30 
60 
60 
68 
Mammary 
MX-1 
30 
60 
51 
67 
Pancreatic 
Mia-PaCa-2 
10 
30 
45 
66 


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100 
73 
Ovarian 
SK-OV-3 
10 
30 
100 
58 
64 
81 
 
The majority of the initial anti-tumor efficacy evaluations in vivo were conducted in the HCT116 
colon tumor model since the tumorigenicity of this cell line was previously shown to be 
dependent on K-ras activation.  Additional studies indicated that prolonged anti-tumor efficacy 
could be attained by extending the duration of treatment and that, in this tumor model, sorafenib 
was able to arrest tumor growth even if therapy was initiated against a substantially greater 
tumor burden. 
Sorafenib also showed significant oral activity against two additional human tumor xenograft 
models that contain K-ras mutations: MiaPaCa-2 pancreatic carcinoma and H460 non-small cell 
lung carcinoma.  The anti-tumor efficacy of sorafenib was also evaluated against the human 
SKOV-3 ovarian tumor cell line that contains a wild-type Ras but over-expresses both the EGF 
and Her2 growth factor receptors.  These receptors also signal through the Ras/Raf/Mek 
pathway. 
In human tumor xenografts, MDA-MB-231 (breast) and Colo-205 (colon), there was a dramatic 
reduction of tumor neo-vascularization (Investigator’s Brochure).  Recent data also indicated that 
inhibition of c-raf may promote cell death in endothelial cells as a downstream event of VEGFR-
2 stimulation35. 
Taken together, data suggests that sorafenib may be of therapeutic value not only in human 
tumors containing ras gene mutations, but also in tumors over-expressing growth factor receptors 
in the Ras/Raf/Mek pathway, and by inhibiting tumor angiogenesis or neo-vascularization 
through inhibition of VEGFR-2, VEGFR-3, and/or PDGFR-β. 
The ability of sorafenib (or its tosylate salt, BAY 54-9085) to be combined with paclitaxel, 
irinotecan, gemcitabine, or cisplatin was evaluated in preclinical in vivo models.  In these studies, 
the focus was to evaluate if the co-administration of sorafenib would adversely affect the 
tolerance or anti-tumor efficacy of the ‘standard of care’ agent.  The general health of mice was 
monitored and mortality was recorded daily.  Tumor dimensions and body weights were 
recorded twice a week starting with the first day of treatment.  Treatments producing greater than 
20% lethality and/or 20% net body weight loss were considered ‘toxic’.  The results of these 
combinability analyses are summarized below: 
Combinability of Concurrent Treatment with Sorafenib and Clinically Established Agents 
Combination Agent 
Tumor Model 
Combinability 
Y/N 
Paclitaxel 
NCI-H460 NSCLC 
MX-1 Mammary 
Yes 
Yes 
Irinotecan 
DLD-1 Colon 
Yes 


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Gemcitabine 
MiaPaCa-2 Pancreatic 
Yes 
Cisplatin 
NCI-H23 NSCLC 
Yes 
Sorafenib can be safely combined with a variety of standard cytotoxic cancer chemotherapy 
agents, including paclitaxel, irinotecan, gemcitabine and cisplatin with no significant increase in 
the toxicity associated with those agents and without diminishing their anti-tumor efficacy in 
preclinical models. 
1.2.4.3 Preclinical Pharmacology 
Sorafenib’s absorption in mice and dogs is 92% and 69%, respectively.  The bioavailability in 
mice and rats was 79% and in dogs was 61%.  Plasma clearance in mice, rats and dogs was low 
(CL<0.21 l/h/kg) and the Vss was also low (~0.7 – 0.9 l/kg).  Excretion of the compound is 
primarily via the biliary/fecal route in rats and dogs.  Protein binding was high; the mean free 
fraction was 2.5% in mice, 1.6% in dogs, 1.4% in rats, and 1.2% in humans.  Sorafenib showed a 
market potency to inhibit several CYP isoforms involved in drug metabolism and clinically 
relevant drug-drug interactions with substrates of different isoforms appear to be possible.   In 
vitro model of enzyme induction using human hepatocyte showed no significant induction of 
CYP 1A, 2C9, 2C19 and 3A enzymes, but CYP 3A4 is the enzyme responsible for the 
metabolism of sorafenib in vitro in man. 
1.2.4.4 Clinical Pharmacology 
Evaluation of data across four different studies has indicated that in consistence with its half-life, 
plasma sorafenib accumulates upon multiple dosing.  There is no further increase in sorafenib 
Cmax and/or AUC values beyond 7 days of multiple dosing.  There is a less than proportional 
increase in sorafenib Cmax and AUC values with increasing doses from 100 mg bid to 800 mg 
bid.  Data from four ascending dose studies show that sorafenib exhibits high inter-patient 
pharmacokinetic variability that is not explained by age, race, gender, or body weight.  Sorafenib 
generally accounts for approximately 64-86% of the circulating analytes after at least 7 days of 
multiple dosing.  Approximately 19% of the dose is excreted in urine and 76% in feces.  BAY 
68-3472 is the major metabolite in plasma.  The relationship between dose and anti-tumor 
activity cannot be accurately estimated based on the available data.  The dose of 400 mg bid 
exhibits a similar safety profile in hepatoma patients with either Child’s Pugh A or Child’s Pugh 
B hepatic function status even though preliminary data shows numerical differences in PK. 
1.2.4.5 Preclinical Toxicology 
Single-dose oral toxicity/tolerance studies were conducted in the rat, mouse and dog.  Repeated-
dose toxicity was covered by studies with daily oral treatment of up to 6 months in rats, 3 months 
in mice, and up to 12 months in dogs.  Subacute studies in rats and dogs included a 4-week 
reversibility segment for the high dose level.  The preclinical toxicity profile of sorafenib short-
term high-dose treatment was well-tolerated clinically by rats, mice and dogs.  Exposure-
dependent mortality (mean time to death ≥ 3 weeks) occurred without preceding specific signs of 
morbidity in rats.  Dose-limiting toxicity in dogs was gastrointestinal (emesis, bloody diarrhea) 
at 30 mg/kg bid or 60 mg/kg bid.  Aside from effects on the GI tract (bloody diarrhea) and 
marked effects on the skin (hair loss, inflammation) once daily dosing of up to 60 mg/kg for 3 
months was clinically well tolerated by dogs.  In rats, repeated-dose toxicity studies were all 


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conducted with once daily oral administration.  Mortality was induced at a dose of 5 mg/kg/d 
sorafenib in a 3-month study.  In a chronic 6-month study, no mortality was induced at the 
highest dose tested of 2.5 mg/kg sorafenib; this dose is considered the MTD.  Histopathology 
revealed degeneration/regeneration processes in multiple organ systems including liver, kidneys, 
lymphoreticular/hematopoietic system, GI tract, pancreas, adrenals, reproductive organs, skin, 
teeth, and bone.  No main target organ of toxicity could be identified.  Some morphological 
lesions were not reversible within 4 weeks (e.g., bile duct proliferation, liver fibrosis, adrenal 
necrosis, effects on lymphoreticular system) following a 4-week course of treatment.  The 
morphological no-effect-level after 3 months of treatment was below 10mg/kg/d and 1 mg/kg/d 
for dogs and rats, respectively.  Some changes, notably in the liver (bile duct proliferation) and 
skin (degeneration of hair follicles), were observed at this dose level.  Changes in hematology 
and clinical chemistry were poor predictive indicators for specific organ lesions. Serum levels of 
hepatic transaminases were markedly, but not consistently, elevated.  At the repeated MTD in 
rats (2.5 mg/kg/d) and dogs (30 mg/kg/d), AUC 0-24 was about 35 mg/h/l at steady stat, 
indicating no substantial difference in toxicity in the two species when compared at systemic 
exposure.  Based on genotoxicity assays, SORAFENIB does not demonstrate a significant risk of 
genotoxicity to patients.  Results from the general (repeated dose) toxicity studies indicate that 
BAY43-9006 has the potential to adversely impair reproduction performance, as well as 
embryonic and fetal development. Various effects, including retardation, were observed in male 
and female reproductive organs of rats. 
1.2.4.6 Clinical Toxicology 
Preliminary anti-tumor activity has been reported in a variety of tumor types with tumor 
shrinkage seen in colorectal carcinoma, melanoma, thyroid, sarcoma, pancreatic cancer, and 
renal cell cancer.  Sorafenib is well tolerated at 400 mg bid.  Dose limiting toxicities occurring 
more frequently at higher doses include hand-foot syndrome, diarrhea, fatigue, hypertension, 
pain, and rash.  ≥Grade 3 and 4 drug-related adverse events were uncommon.  Significant events 
reported included grade 3 or 4 amylase and lipase elevation (not associated with symptoms of 
pancreatitis), and hand foot syndrome.  In addition, mild to moderate drug-related adverse events 
reported included flu-like symptoms, fever arthralgia, hypertension, weight loss, anorexia, 
abdominal pain, vomiting, elevated liver function tests, pruritus and alopecia. 
1.2.5 Rationale for combining TRC105 with Sorafenib  
By targeting a unique and important angiogenic pathway, TRC105 has the potential to 
complement existing antiangiogenic therapies.  One of the reasons postulated for the limited 
efficacy of anti-angiogenic agents is that they cause intra-tumoral hypoxia.  Intra-tumoral 
hypoxia causes the induction and up-regulation of hypoxia-inducible factors (HIF) such as HIF-
1α which can result in evasive mechanisms of resistance18.  CD105, the target for TRC105, is 
expressed at significantly higher levels following VEGF inhibition in animal models of human 
cancer.  The increase in CD105 expression is likely an attempt to compensate for or escape from 
VEGF inhibition.  This escape mechanism could be inhibited with a combination approach 
targeting both pathways simultaneously.  


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Our basic concept is based on two hypotheses: 1) angiogenesis plays a particularly crucial role in 
the pathogenesis of HCC and 2) interrupting the angiogenic pathway at different levels in 
combination will be more effective than targeting one level. 
1.2.6 Summary of Phase I 
As of July 2014, 15 patients were enrolled onto the phase 1 portion of this study which combined 
TRC105 – a monoclonal antibody that binds CD105, a transmembrane receptor overexpressed 
by proliferating endothelial cells – with standard of care sorafenib. The dose of sorafenib was 
fixed across all dose levels of the study and was as per standard of care (400mg BID). TRC-105 
was administered every two weeks at doses of 3, 6, 10 and 15mg/kg. All patients had HCC with 
either non-cirrhotic livers or cirrhosis (the majority) with compensated liver dysfunction (Childs 
Pugh A/B7) and an ECOG of 0/1. A recommended phase II dose was established of TRC-105 
15mg/kg in combination with sorafenib 400mg bid. Overall the treatment was well tolerated and 
the study proceeded as per protocol to testing of the maximum planned dose level, DL4 
(15mg/kg). One DLT was encountered at 10mg/kg – transaminase elevation – which necessitated 
expansion of that cohort. One grade 5 cardiac event was also experienced. The subject had 
severe three vessel disease, which is the most likely cause of his death.  However, the 
contribution of protocol treatment could not be excluded.  The most common side-effects we 
encountered were hand-foot skin reactions as a result of sorafenib. With regard to efficacy two 
patients - treated at 10 and 15mg/kg dose level - developed a PR by RECIST and the majority of 
patients had tumor reduction.  Median time on study was 4 months and one patient remained on 
treatment after 22 months. 
2 
ELIGIBILITY ASSESSMENT AND ENROLLMENT  
2.1 
ELIGIBILITY CRITERIA 
2.1.1 Inclusion Criteria 
2.1.1.1 Patients must have histopathological confirmation of hepatocellular carcinoma (HCC) by 
the Laboratory of Pathology of the NCI prior to entering this study.   
Or 


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2.1.1.2 histopathological confirmation of carcinoma in the setting of clinical and radiological 
characteristics which, together with the pathology, are highly suggestive of a diagnosis 
of HCC. 
2.1.1.3 Patients must have disease that is not amenable to potentially curative resection or 
ablative techniques.  In addition, disease must not be amenable to or have progressed on 
transhepatic arterial chemoembolization (TACE).  Patients must not be considered 
potential candidates for liver transplantation.  This determination will be made after 
hepatobiliary surgical input at the NCI multidisciplinary conference. 
2.1.1.4 If liver cirrhosis is present, patient must have a Child-Pugh A or B (7 points) 
classification (See Section 11.2). 
2.1.1.5 Patients with cirrhosis must have had esophagogastric endoscopy within the previous 6 
months prior to study entry for the assessment of varices.  If the patient has not had this 
done they must be willing to undergo this procedure prior to study entry. 
2.1.1.6 Age >18 years  
2.1.1.7 Life expectancy of greater than 3 months. 
2.1.1.8 ECOG performance status 0-2 (see Section 11.1) 
2.1.1.9 Patients must have normal organ and marrow function as defined below: 
2.1.1.9.1 Absolute neutrophil count >1,500/mcL  
2.1.1.9.2 Platelets >60,000/mcL without transfusion support within the past 30 days 
2.1.1.9.3 Total bilirubin 
 ≤ 3 mg/dl. 
2.1.1.9.4 AST/ALT ≤  10 × upper limit of normal 
2.1.1.9.5 Creatinine ≤ 1.5 x upper normal limits OR creatinine clearance > 40 
mL/min/1.73 m2 for patients with creatinine levels above institutional normal, 
as calculated by the Cockcroft Gault formula. 
2.1.1.10 Patients must have recovered from any acute toxicity related to prior therapy, including 
surgery.  Toxicity should be < grade 1 or returned to baseline. 
2.1.1.11 Patients must not have other invasive malignancies within the past 5 years (with the 
exception of non-melanoma skin cancers or non-invasive bladder cancer).  
2.1.1.12 Patient must be able to understand and willing to sign a written informed consent 
document. 
2.1.2 Additional Inclusion Criteria for PHASE I Portion 
2.1.2.1 Patients may have measurable or evaluable disease only.  
2.1.2.2 Prior therapy: prior systemic therapy with sorafenib is allowed.   
2.1.3 Additional Inclusion Criteria for PHASE II Portion  


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2.1.3.1 All patients will be required to have measurable disease.   
2.1.3.2 Prior therapy: prior systemic therapy with sorafenib is allowed.  
2.1.4 Exclusion Criteria 
2.1.4.1 Patients who have had chemotherapy (other than sorafenib treatment), large field 
radiotherapy, or major surgery must wait 4 weeks prior to entering the study. 
2.1.4.2 Patients may not be receiving any agents not approved by the FDA within the past 4 
weeks. 
2.1.4.3 Patients with known brain metastases will be excluded from this clinical trial because of 
their poor prognosis and because they often develop progressive neurologic dysfunction 
that would confound the evaluation of neurologic and other adverse events. 
2.1.4.4 Proteinuria, as demonstrated by a 24-hour protein of ≥ 2000 mg.  Urine protein will be 
screened by urine protein-creatinine ratio (UPC).  For UPC ratio > 1.0, a 24-hour urine 
protein will need to be obtained and the level should be < 2000 mg for patient 
enrollment. 
2.1.4.5 Uncontrolled intercurrent illness including, but not limited to, hypertension (systolic BP 
> 140, diastolic BP > 90), ongoing or active systemic infection, symptomatic congestive 
heart failure, unstable angina pectoris, cardiac arrhythmia or psychiatric illness/social 
situations that would limit compliance with study requirements.  
2.1.4.6  No anti-coagulation therapy is allowed with the exception of low-dose aspirin. 
2.1.4.7 No bleeding diathesis. 
2.1.4.8 Patients with a history of bleeding varices in previous 1 year are excluded (unless patient 
has subsequently had a liver transplant). Those with gastric varices or varices that are 
deemed as high risk by the endoscopist should be placed on appropriate medical therapy 
as advised by the gastroenterologist.  
2.1.4.9 History of peptic ulcer disease or hemorrhagic gastritis within 6 months of TRC105 
administration, unless patient has received adequate treatment for peptic ulcer disease or 
hemorrhagic gastritis and has evidence of complete resolution documented by EGD. 
Mild gastritis is allowed. 
2.1.4.10 QTc > 500 msec  
2.1.4.11 HIV-positive patients receiving anti-retroviral therapy are excluded from this study due 
to the possibility of pharmacokinetic interactions between antiretroviral medications 
and sorafenib or TRC105. HIV positive patients not receiving antiretroviral therapy are 
excluded due to the possibility that sorafenib or TRC105 may worsen their condition 
and the likelihood that the underlying condition may obscure the attribution of adverse 
events with respect to sorafenib or TRC105. 
2.1.4.12 History of hypersensitivity reaction to human or mouse antibody products 
2.1.4.13 Patients with a history of familial bleeding disorders 


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2.1.4.14 Patients with a history of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu 
Syndrome). 
2.1.4.15 Pregnancy and breast feeding are exclusion factors.  Enrolled patients must agree to use 
adequate contraception (hormonal or barrier method of birth control; abstinence) prior 
to study entry, the duration of study participation and 3 months after the end of the 
treatment. 
2.1.4.16 Patients with unhealed wounds for more than 30 days.   
2.1.5 Inclusion of Women and Minorities 
2.1.5.1 Men and women of all races and ethnic groups are eligible for this trial. 
2.2 
SCREENING EVALUATION 
This does not include the baseline correlative studies that will only be performed after the patient 
has signed the consent form. 
2.2.1 Imaging studies (baseline – obtained within one month prior to enrollment):  
• CT scan of chest, abdomen and pelvis 
• DCE-MRI will be obtained within 7 days of cycle 1 day 1 (optional based on 
availability).  
• Ultrasound evaluation of tumor volume  
2.2.2 Laboratory evaluation (baseline – obtained within 7 days prior to dosing) 
• Hematological profile: CBC with differential and platelet count, PT, aPTT, 
fibrinogen. 
• Biochemical profile: electrolytes, BUN, creatinine, urine protein-creatinine ratio 
(UPC), AST, ALT, total bilirubin, calcium, phosphorus, albumin, magnesium, uric 
acid, albumin, amylase. 
• Tumor marker profile: αFP (baseline – within 7 days prior to dosing) 
2.2.3 Laboratory evaluation (baseline- obtained within 28 days prior to dosing) 
• Hepatitis serology 
2.2.4 History and physical exam with vital signs within 1 week prior to dosing. 
2.2.5 Electrocardiogram (baseline – obtained within 28 days prior to dosing) 
2.2.6 Requirements for endoscopic evaluation: All patients with cirrhosis will be required to 
have had a screening endoscopy for varices within 6 months of study enrollment.  If this 
has not been done within the previous 6 months it will be performed by Dr. Heller and his 
team at NCI.  Varices identified on endoscopy will be treated as per standard of care.  All 
appropriate therapies for this are available here at NCI.  A history of prior variceal bleed 
in previous 1 year will be an exclusion factor.   


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2.2.7 Detailed cardiac history to be taken including known risk factors and the presence of 
symptoms such as exercise-induced chest discomfort. Suspicion of elevated cardiac risk 
will mandate referral and assessment to cardiology, unless patient is already under the 
care and surveillance of a cardiologist. 
2.3 
REGISTRATION PROCEDURES 
2.3.1 On-Study Registration 
Authorized staff must register an eligible candidate with NCI Central Registration Office (CRO) 
within 24 hours of signing consent.  A registration Eligibility Checklist from the web site 
(http://home.ccr.cancer.gov/intra/eligibility/welcome.htm) must be completed and sent via 
encrypted email to:  NCI Central Registration Office (HOIS) ncicentralregistration-
l@mail.nih.gov.  After confirmation of eligibility at Central Registration Office, CRO staff will 
call pharmacy to advise them of the acceptance of the patient on the protocol prior to the release 
of any investigational agents.  Verification of Registration will be forwarded electronically via e-
mail to the research team.  Please note, it is very important for all registrars to acquire encrypted 
e-mail from NIH Help Desk, since the verification of registration includes patient’s information.  
A recorder is available during non-working hours.  
3 
STUDY IMPLEMENTATION 
3.1 
STUDY DESIGN 
For both the phase I and phase II portions of this study TRC105 will be administered as an IV 
infusion every two weeks.  Sorafenib will be self-administered as a daily oral pill. Patients will 
be reviewed every week in clinic, with labs and routine history and physical performed.  Patients 
will be re-staged every 8 weeks.  Please see the Study Calendar for a detailed summary. 
3.2 
PHASE I (DOSE ESCALATION COMPLETE AS OF AMENDMENT L) 
The first part of this study is a standard 3+3 dose escalation phase I study with the primary 
objective of establishing MTD for the combination.  Sorafenib will be taken orally at a dose of 
400 mg twice daily.  TRC105 will be administered as an infusion every 2 weeks.  Patients will be 
re-staged every 8 weeks.  The TRC105 dose will be escalated as tolerated in cohorts of 3 to 6 
patients (see table below).  Intra-patient dose escalation is not allowed.  However, if a patient has 
had a dose reduction of sorafenib for toxicity and tolerates this dose for 28 days, the sorafenib 
may be re-escalated by one dose-level only, as per standard clinical practice.  
The planned dose-escalation schedule is as follows: 
Cohort 
Sorafenib 
(mg PO twice daily) 
TRC105 
(mg/kg IV every 2 
weeks) 
0 
400  
1 
1 
400  
3 


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Cohort 
Sorafenib 
(mg PO twice daily) 
TRC105 
(mg/kg IV every 2 
weeks) 
2 
400  
6 
3 
400  
10 
4 
400  
15 
Each cohort in the phase I portion of the study is planned to have at least 3 patients to evaluate 
for toxicity.  Three patients will be treated at a given dose level and observed for acute toxicity 
for one course of treatment before any more patients are entered.  The descriptions and grading 
scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) 
version 4.0 will be utilized for AE reporting. 
If none of the three patients at a given dose level experiences dose-limiting toxicity (DLT), 
accrual will proceed to the next cohort.  
If one of three patients treated at a dose level experiences DLT that is considered to be at least 
possibly related to TRC105, then three more patients will be enrolled at that same level.  If the 
incidence of DLT among those six patients is one in six, then the next cohort of three patients 
will be treated at the next higher dose.  
In general, if two or more of the six patients treated at a dose level experience DLT, then the 
MTD is considered to have been exceeded.  The MTD is defined as the highest dose studied for 
which the incidence of DLT was less than 33%.  
For MTD determination, dose-limiting toxicities will be evaluated throughout the first 28 days of 
treatment (Cycle 1).  Patients who exit the study for reasons other than drug-related toxicity prior 
to completion of the 28-day DLT evaluation period will be replaced to ensure an adequate safety 
assessment of each cohort.  If at the first dose level more than one DLT is observed in the first 
three subjects, or more than two DLTs in six subjects are observed, 3-6 patients will be accrued 
to Dose Level - 1. 
Number of Patients 
with DLT at a Given 
Dose Level 
Escalation Decision Rule 
0 out of 3 
Enter 3 patients at the next dose level 
> 2 
Dose escalation will be stopped.  This dose level will be declared 
the maximally administered dose (highest dose administered).  
Three (3) additional patients will be entered at the next lowest 
dose level if only 3 patients were treated previously at that dose. 
1 out of 3 
Enter at least 3 more patients at this dose level. 
• If 0 of these 3 patients experience DLT, proceed to the next 


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If >2 patients experience a DLT at any dose level, at any time in phase I, then subsequent 
patients will be enrolled at the next lower dose level. 
3.2.1 Dose Limiting Toxicities  
The following adverse event management guidelines are intended to ensure the safety of each 
patient while on the study.  The descriptions and grading scales found in the revised NCI 
Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for AE 
reporting.  All appropriate treatment areas should have access to a copy of the CTCAE version 
4.0.  A copy of the CTCAE version 4.0 can be downloaded from the CTEP web site 
(http://ctep.cancer.gov).   
3.2.2 Definition of Dose-limiting Toxicities (DLTs): 
3.2.2.1 Dose limiting toxicity 
• Grade 3 electrolyte toxicities unable to be corrected to Grade 1 or less within 24 hours 
will be considered dose limiting (proteinuria >3.5 g/24 hour will be defined as a DLT). 
• Drug-related Grade 4 hematological toxicity will be considered dose limiting.  
• Toxicity requiring a dose reduction or a delay in treatment for >7 days will be considered 
dose limiting.  
• Other Grade 3 or higher toxicity considered related to TRC105 will be considered dose-
limiting. 
3.2.2.2 Exclusions to Dose limiting toxicities 
• Grade 3 hypertension that can be controlled with oral medications and does not require 
treatment delay for > 7 days or dose reduction will not be considered a DLT.  Refer to 
Section 3.4.4.2 for guidelines on managing drug-induced hypertension.  
• Grade 3 diarrhea will only be considered dose-limiting if it is refractory to treatment.  
Grade 4 diarrhea will be dose limiting.  
• Nausea and vomiting Grade 3 will only be considered dose-limiting if it is refractory to 
anti-emetic therapy and unable to be corrected to Grade 1 or less within 48 hours. 
higher dose level. 
• If 1 or more of this group suffer DLT, then dose escalation 
is stopped, and this dose is declared the maximally 
administered dose.  Three (3) additional patients will be 
entered at the next lowest dose level if only 3 patients were 
treated previously at that dose. 
<1 out of 6 at highest 
dose level below the 
maximally administered 
dose 
This is generally the recommended phase 2 dose.  At least 6 
patients must be entered at the recommended phase 2 dose. 


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Abbreviated Title:  Sorafenib and TRC105 in HCC 
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• Grade 3 rise in creatinine, not corrected to Grade 1 or less after 2 liters of intravenous 
fluids within 24 hours, will be considered dose limiting.  All Grade 4 rises in creatinine 
will be dose limiting. 
• Any grade elevation in transaminases that is attributable as being likely related to 
sorafenib and/or disease alone and will be an exception to DLT. 
• Grade 3 rash will not be considered dose limiting unless it does not return to ≤ Grade 2 
after 1 week of symptomatic treatment.  
• Grade 3 hand-foot syndrome will not constitute DLT. 
• Grade 3 and 4 infusion reactions due to TRC105 administration will be considered to be 
dose-limiting toxicity.  
Three patients must complete at least 1 cycle of therapy prior to considering dose escalation in 
the next cohort of patients.  Determination of DLT for the purpose of dose escalation enrollment 
will be based on toxicities observed in the first 28 days of treatment (cycle 1) and must be 
considered as at least possibly related to study drug.  Evaluation for toxicity will continue 
throughout the study and should dose limiting toxicities occur beyond the cycle one, 
consideration will be given to halting the dose escalation and studying lower dose levels. 
3.3 
PHASE II  
The protocol will be reassessed by the IRB before proceeding to the phase II component of the 
study.  Specifically, data from the phase I that supports treatment of larger cohorts in the phase II 
at a specific dose will be presented to the IRB along with a revised consent document that will 
summarize updated results and toxicities. 
TRC105 and sorafenib will be administered at the 15 mg/kg TRC105 IV every 2 weeks and 400 
mg sorafenib PO twice per day (the recommended phase 2 dose defined from the phase I 
portion).  The sample size and interim stopping rule will be determined using a Simon optimal 
two-stage design.   
The first stage will initially enroll 6 evaluable patients, and if 0 of the 6 have a clinical response, 
then no further patients will be accrued. If 1 or more of the first 6 patients has a clinical response, 
then accrual would continue until a total of 23 patients have been enrolled. As it may take several 
weeks to determine if a patient has experienced a response, a temporary pause in the accrual may 
be necessary to ensure that enrollment to the second stage is warranted. If there are 1 to 2 clinical 
responses in 23 patients, this would be an uninterestingly low response rate. If there were 3 or 
more complete responses in 23 patients (13.0%), this would be sufficiently interesting to warrant 
further study in later trials. Under the null hypothesis (5% response rate), the probability of early 
termination is 73.5%.Drug Administration 
3.3.1 TRC105 Drug Administration 
All treatment will be administered on an outpatient basis.  
Thirty minutes to two hours prior to the start of each TRC105 infusion, all patients will receive 
the following premedications: 
• Acetaminophen 650 mg PO x 1  


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• Dexamethasone 20 mg IV x 1  
• Famotidine 50 mg IV x 1 (or similar H2 blocker) 
• Cetirizine 10 mg IV or PO x 1  (or similar oral or intravenous antihistamine) 
• Granisetron 1mg IV x 1 
After completing pre-medications, TRC105 will be administered intravenously utilizing an 
infusion pump.  TRC105 has been demonstrated to be compatible with polyethylene lined, non-
DEHP infusion sets and polyvinyl chloride, non-DEHP infusion sets.  TRC105 is required to be 
administered with a 0.2 micron downstream filter.  The attachment of the infusion pump 
administration set to the i.v. bag and transport of the TRC105 study drug to the patient will be 
performed as per standard study site procedures.   
On Cycle 1 Day 1, TRC105 will be infused over a period of four hours.  If a patient completes 
one 4 hour infusion without the development of an infusion reaction, then subsequent TRC105 
infusions may be reduced to 2 hours.  If a patient completes one 2 hour infusion without the 
development of an infusion reaction, subsequent TRC105 infusions may be reduced to a 
minimum of 1 hour (7 mg/mL TRC105 material) or 90 minutes (25 mg/mL TRC105 material).     
After the minimum TRC105 infusion duration of 1 hour (7 mg/mL TRC105 material) or 90 
minutes (25 mg/mL TRC105 material) has been safely administered, the dexamethasone should 
be gradually tapered as tolerated with each subsequent infusion and eventually discontinued if 
possible.  The dexamethasone dose should not be reduced unless the prior infusion was well-
tolerated (no infusion reaction of any grade).   
Recommended Dexamethasone Taper Schedule 
Infusion 
Dexamethasone Dose and Schedule 
First 1 hr infusion 
20 mg iv 30 minutes to two hours prior to each infusion 
Second 1 hr infusion 
10 mg iv 30 minutes to two hours prior to each infusion a 
Third 1 hr infusion 
5 mg iv 30 minutes to two hours prior to each infusion a 
Subsequent infusions 
No dexamethasonea 
aThe dexamethasone dose should not be reduced unless the prior infusion was well-tolerated (no infusion 
reaction of any grade).  
Patients with infusion–related events of any grade should be managed appropriately (Section 
3.3.1.1) and are not permitted to reduce infusion duration or pre-medications on the subsequent 
infusion.  Patients who experience a grade 3 or higher hypersensitivity reaction will be taken off 
treatment until toxicity resolution.  Each infusion of TRC105 must be completed within 8 hours 
of reconstitution.  Once the i.v. bag containing TRC105 is empty, the i.v. line should be flushed 
with 20 mL of normal saline at the same rate of infusion.  The dose level and infusion start and 
stop times must be recorded in the source documents.  
3.3.1.1 Management of TRC105 Infusion Reactions 
If a patient experiences a grade 2, 3 or 4 adverse reaction during infusion, the infusion should be 
stopped and the patient treated accordingly.  Antipyretic, antihistamine and other therapies 
should be administered as indicated.  If appropriate, the infusion may be restarted at half of the 


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previous rate when the patient is able to continue.  Infusion reactions will be recorded as AEs in 
the case report form.  Interventions should be documented as concomitant medications or 
concomitant treatments as appropriate.   
3.3.2 Sorafenib Administration 
Sorafenib will generally be administered on an outpatient basis except when admission is 
required for any reason.  No investigational or commercial agents or therapies other than those 
described in the protocol may be administered with the intent to treat the patient’s malignancy. 
Sorafenib is supplied as 200-mg tablets and is administered orally twice a day.  Patients are to 
swallow the tablets whole with approximately 250 ml (8 oz.) of water, each morning and evening 
(i.e., 12-hourly).  Tablets may be taken with or without food.  Sorafenib will be given as self-
administered oral doses at 400 mg bid continuously in a 28 days cycle 
3.3.2.1 Special Precautions: 
Sorafenib tosylate is metabolized by the P450 CYP3A enzyme and has been shown in preclinical 
studies to inhibit multiple CYP isoforms.  The following medications will be excluded prior to and 
during the study if is indicated: ketoconazole, itraconazole, ritonavir, products containing 
grapefruit juice, cyclosporine, carbamazepine, phenytoin, phenobarbital and prophylactic use of 
G-CSF, GM-CSF. 
Sorafenib has the ability to inhibit a variety of liver metabolic enzymes in vitro.  The clinical 
impact of this inhibition in humans taking drugs metabolized by these enzymes is unknown. 
Therefore, all patients enrolled onto this trial who are taking concomitant medications that are 
known to be metabolized by the liver should be closely observed for side effects of these 
concomitant medications.  Furthermore, patients taking narrow therapeutic index medications, 
(e.g. warfarin, quinidine, or digoxin) should be monitored proactively.  
3.4 
DOSING DELAYS AND DOSE MODIFICATIONS 
 
Grade 
Occurrence 
Immediate action 
Resumption of 
therapy 
1 
Any 
None 
No interruption 
2 
Any 
Hold therapy until ≤ 
G1 
No change in dose but 
initiate appropriate 
medical therapy. 
3 
1st 
Hold therapy until ≤ 
G1 
Initiate appropriate 
medical therapy and 
reduce either sorafenib 
or TRC105 to next 
lowest dose level per 
tables below in 


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Grade 
Occurrence 
Immediate action 
Resumption of 
therapy 
sections 3.4.1 and 
3.4.2 respectively. 
4 
1st 
Stop therapy 
Terminate therapy 
with experimental 
agents. Follow patient 
until 
resolution/stabilization 
of toxicity. 
#In the event that it is unclear which medication is responsible for the observed toxicity, the 
investigator should proceed to decrease doses of both study medications to the next lowest level. 
For all grade ≥2 non-hematologic toxicity and all grade ≥3 hematologic toxicities (excluding 
lymphopenia), sorafenib and TRC105 will be held until toxicities resolve to ≤ grade 1.  If 
treatment is delayed for > 7 days due to adverse events, treatment will be discontinued.  It will be 
in the clinical judgment of the investigator – based on an assessment of the adverse event and 
knowledge of both compounds – which of the agents to dose-reduce, unless specifically stated 
below for a particular toxicity (e.g., hand-foot syndrome). 
3.4.1 Sorafenib 
 
 
 
 
 
 
3.4.2 TRC105 
Dose Level 
TRC105 
(mg/kg IV every two weeks) 
0 
1 
Dose Level 
Sorafenib (by mouth) 
0 
400 mg twice daily 
-1 
600 mg daily (200 mg AM, 400 mg 
PM) 
-2 
400 mg daily 
-3 
400 mg every other day or 200 mg 
daily 


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Abbreviated Title:  Sorafenib and TRC105 in HCC 
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Version Date:  June 10, 2016 
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Dose Level 
TRC105 
(mg/kg IV every two weeks) 
1 
3 
2 
6 
3 
10 
4 
15 
 
3.4.3 Dosing Delays/Dose Modifications: General Guidelines (See section below for specific 
toxicities). 
3.4.3.1 Grade 1 Toxicity  
Treatment with sorafenib and TRC105 need not be interrupted.  For symptoms that last more 
than 7 days and have been found to be intolerable to the patient, the dose of sorafenib and 
TRC105 may be reduced to the next lower dose level.  
3.4.3.2 Grade 2 Non-Hematologic Toxicity 
Patients who have a grade 2 event may have a dose interruption.  However, re-initiation of 
sorafenib and TRC105 at the same dose is allowed provided the adverse event has resolved to 
grade 1 or baseline.  
3.4.3.3 Grade 3 Non-Hematologic Toxicity  
Hold sorafenib and TRC105 and re-evaluate at least bi-weekly until toxicity improves to ≤ grade 
1 or pre-treatment baseline.  Reduce dose of either sorafenib or TRC105 by one dose level based 
on the discretion of the investigator.  Treatment will be discontinued in patients who experience 
grade 3 non-hematologic toxicities that do not resolve to grade 1 or baseline within 4 weeks.  
3.4.3.4 Grade 4 Non-Hematologic Toxicity  
Patients with clinical grade 4 non-hematologic toxicity (except pulmonary embolism without 
significant hypoxia and hemodynamic instability) will be taken off treatment permanently. 
Patients with intolerable or limiting toxicity following two successive dose reductions will be 
removed from treatment.  Unacceptable toxicities that have not resolved at time of “off 
treatment” must be followed until stabilization or resolution, at which time they will continue in 
follow up for survival.  


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3.4.4 Dosing Delays/Dose Modifications for Specific Toxicities: 
3.4.4.1 Dermatologic Toxicities: 
Rash/dry skin: In patients experiencing grade 2 skin rash or grade 3 dry skin (there is no grade 4 
for dry skin), sorafenib will be held for 1-2 weeks (until rash less than grade 2, dry skin less than 
grade 3) and will be restarted at the same dose after the first occurrence.  Sorafenib will be 
reduced to dose level -1 after a second occurrence and dose level -2 after a third occurrence. 
Treatment will be discontinued and the patient taken off treatment if the patient does not improve 
from a previous episode or has a fourth occurrence in spite of dose reductions.  In patients 
experiencing grade ≥3 rash, dose reduction will begin with the first occurrence, and treatment 
will be discontinued and the patient taken off treatment if the patient does not improve from a 
previous episode or has a second occurrence.  
Hand/foot skin reaction: In patients experiencing grade 2 hand/foot skin reaction, sorafenib will 
be held for 1-2 weeks (until skin reaction less than grade 2) and will be restarted at the same dose 
after the first occurrence.  The dose of sorafenib will be reduced dose level -1 after the second 
occurrence and to dose level -2 after the third occurrence.  Treatment will be discontinued and 
the patient taken off treatment if the patient does not improve from a previous episode or has a 
fourth occurrence.  However, if a patient has had a dose reduction of sorafenib for toxicity and 
tolerates this dose for 28 days, the sorafenib may be re-escalated by one dose-level only, as per 
standard clinical practice.  TRC105 may be continued throughout the episode at the discretion of 
the PI, and its dose will not be reduced. 
3.4.4.2 Hypertension:  
Whilst hypertension is a potential side-effect of TRC105 this has not been seen so far in the 
phase I study.  On the other hand, this is a well-established side-effect of sorafenib.  Therefore, 
in the event of hypertension dose modifications will be made for sorafenib.  
Treatment and dose modification guidelines 
for sorafenib- induced hypertension: 
Grade of Event Management/ Next Dose 
grade 1 
No change 
grade 2 asymptomatic 
Treat patient with antihypertensives and 
continue sorafenib 
grade 2 symptomatic/ persistent 
OR 
diastolic BP > 110 mm/Hg 
OR 
grade 3 
Treat patient with antihypertensives and hold 
BAY 43-9006 until symptoms resolve and 
diastolic < 100 mmHg.* Resume treatment at 1 
dose level lower if further treatment is 
indicated** 
grade 4 
Off protocol therapy 
* Patients requiring a delay of > 2 weeks should go off protocol therapy. 


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Abbreviated Title:  Sorafenib and TRC105 in HCC 
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Version Date:  June 10, 2016 
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Treatment and dose modification guidelines 
for sorafenib- induced hypertension: 
Grade of Event Management/ Next Dose 
** Patients requiring > 2 dose reductions should go off protocol therapy. 
Grade 1: asymptomatic, transient (< 24 hours) increase by > 20 mmHg (diastolic) or to >150/100 if 
previously WNL; intervention not indicated. 
Grade 2: recurrent or persistent (> 24 hours) or symptomatic increase by > 20 mmHg (diastolic) or to > 
150/100 if previously WNL. 
Grade 3: requiring more than one drug or more intensive therapy than previously, including increasing 
dose of antihypertensive medication. 
Grade 4: life threatening (e.g. hypertensive crisis) 
3.4.4.3 Nausea/Vomiting:  
Grade 3 nausea and grade 3 vomiting will only require dose modification if it is refractory to 
antiemetic therapy.  In the case of refractory nausea/vomiting and grade 4 nausea or vomiting, 
sorafenib and TRC105 will be held until toxicities resolve to ≤grade 2 nausea and/or ≤grade 1 
vomiting, and then the dose of sorafenib will be reduced by one dose level. 
3.4.4.4 Diarrhea:  
Grade 3 diarrhea will only require dose modification if it is refractory to treatment.  In the case 
of grade 3 diarrhea, sorafenib will be held until diarrhea resolves to ≤grade 2 diarrhea.  Sorafenib 
will be reintroduced at the same dose unless the diarrhea is refractory to therapy in which case 
the dose of sorafenib will be reduced one dose level.  TRC105 may be continued throughout the 
episode, and TRC105 dose will not be reduced.  All patients will be carefully monitored for 
gastrointestinal adverse events. 
3.4.4.5 Electrolyte abnormalities:  
Grade 3 or greater hypokalemia, hypophosphatemia, or hypomagnesemia will require dose 
modification only if not correctable with oral or IV replacement therapy within 48 hours.  If the 
abnormality fails to correct to ≤grade 2 after ≤ 48 hours sorafenib and TRC105 will be held until 
the electrolyte abnormality resolves to ≤grade 2, and then the dose of both medications will be 
reduced by one dose level. 
Grade 3 or greater hyponatremia will require dose modification only if not correctable within 24 
hours by the administration of intravenous 0.9% Sodium Chloride Injection (0.9% NaCl Inj.). If 
the abnormality fails to correct to ≤ grade 2 after ≤ 24 hours of IV 0.9% Sodium Chloride 
Injection (0.9% NaCl Inj.), sorafenib and TRC105 will be held until the electrolyte abnormality 
resolves to ≤ grade 2, and then the dose of both medications will be reduced by one dose level. 
3.4.4.6 Transaminase abnormalities: 
Grade 3 elevation in transaminases will only require a therapy introduction and dose 
modification if they are also ≥ 1.5 times the baseline level. (This is because patients with Grade 2 
transaminase levels are eligible for study entry.) 
 


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Patients who experience grade 3 elevation (+ ≥ 1.5x baseline) in transaminases will have them 
rechecked within 96 hours to ensure that they are trending down following interruption of 
sorafenib. 
3.4.4.7 Uric acid:  
No dose modification will be necessary for any grade of hyperuricemia without physiologic 
consequences. 
3.4.4.8 Glucose:  
Grade 3 or greater hyperglycemia or hypoglycemia will require dose modification only if 
believed to be probably related to study medication(s). 
3.4.4.9 Hematologic abnormalities:  
Grade 3 or higher leucopenia (excluding lymphopenia), neutropenia or thrombocytopenia will 
require dose modification of sorafenib alone, the dose of TRC105 will be maintained.  
3.4.4.10 Proteinuria: 
Proteinuria, as demonstrated by a 24 hour protein of ≥ 2000 mg.  Urine protein will be 
screened by urine protein-creatinine ratio (UPC).  For UPC ratio > 1.0, a 24-hour urine 
protein will need to be obtained and the level should be < 2000 mg for patient enrollment. 
 
Proteinuria 
 
[Proteinuria should be monitored by urine analysis for urine protein creatinine (UPC) ratio 
prior to every other cycle of TRC105] 
UPC ratio  
< 3.5 
Continue TRC105 and sorafenib. 
UPC ratio  
> 3.5 
Hold TRC105 and sorafenib until it UPC recovers to < 3.5.   
Grade 4 or nephrotic 
syndrome 
Discontinue TRC105 and sorafenib. 
 
3.4.4.11 Bleeding episode: 
In the event of a bleeding episode both drugs will be held until resolution.  The patient will be 
closely monitored and the merits of continued participation in the study will be discussed.  We 
will only restart study medication if the source of bleeding has been remedied. 
3.4.4.12 Infusion-related toxicities:  
A permanent 50% decrease in the infusion rate of TRC105 will be required in patients 
experiencing a grade 1/2 (mild to moderate) infusion-related reaction.  TRC105 will be 
permanently discontinued in patients experiencing a grade 3/4 infusion-related reaction, and the 
patient will be taken off treatment.  All patients experiencing any grade of infusion reaction 
should be monitored for at least an hour after completion of infusion.  


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Abbreviated Title:  Sorafenib and TRC105 in HCC 
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3.5 
CORRELATIVE STUDIES FOR RESEARCH/PHARMACOKINETIC STUDIES 
The correlative studies which we wish to perform are outlined below and summarized in the 
table.  All blood and urine samples will be sent to Dr Figg’s laboratory for initial handling and 
processing, before being forwarded to the appropriate lab as indicated.  Tumor tissue will be 
handled by NCI Tissue Core.  
3.5.1 Molecular characterization of HCC using tumor tissue, blood and urine (Xin Wang lab): 
3.5.1.1 Description 
Investigators at the NCI have played a leading role in the molecular characterization of HCC36, 
37.  The heterogeneous nature of hepatocellular carcinoma (HCC) and the lack of appropriate 
biomarkers have hampered patient prognosis and treatment stratification.  Yamashita et al. have 
identified that a hepatic stem cell marker, epithelial cell adhesion molecule (EpCAM), which 
may serve as an early biomarker of HCC because its expression is highly elevated in 
premalignant hepatic tissues and in a subset of fully developed HCC. The same investigators 
have also identified novel HCC subtypes that resemble certain stages of liver lineages by 
searching for EpCAM-coexpressed genes. A unique signature of EpCAM-positive HCCs was 
identified by cDNA microarray analysis of 40 HCC cases and validated by oligonucleotide 
microarray analysis of 238 independent HCC cases, which was further confirmed by 
immunohistochemical analysis of an additional 101 HCC cases. EpCAM-positive HCC was 
found to display a distinct molecular signature with features of hepatic progenitor cells including 
the presence of known stem/progenitor markers such as cytokeratin 19, c-Kit, EpCAM, and 
activated Wnt-beta-catenin signaling, whereas EpCAM-negative HCC displayed genes with 
features of mature hepatocytes. Moreover, EpCAM-positive and EpCAM-negative HCC could 
be further subclassified into four groups with prognostic implication by determining the level of 
alpha-fetoprotein (AFP). These four subtypes displayed distinct gene expression patterns with 
features resembling certain stages of hepatic lineages.  
This information holds the promise of an easy classification system defined by EpCAM status 
and AFP to reveal HCC subtypes similar to hepatic cell maturation lineages, which may enable 
prognostic stratification and assessment of HCC patients in addition to providing new insights 
into the potential cellular origin of HCC and its activated molecular pathways. 
In order to perform this molecular analysis we will attempt to perform a baseline tumor biopsy. 
We will also attempt to perform a post-therapy biopsy at 2 months.  This biopsy will be 
performed to assess CD105 staining by IHC.  Molecular analysis will also be performed on this 
post-therapy sample by the Wang lab to identify any altered gene expression profile. Both 
biopsies are voluntary.  
3.5.1.2 Timing of Tumor Biopsies (Optional):  
Biopsies will be performed at the following time points:  
• At baseline i.e. after consent, prior to treatment.  
• During week 8 of therapy. 


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NCI Protocol #: 11-C-0102 
Version Date:  June 10, 2016 
Amendment: N 
3.5.1.3 Biopsy Procedure: 
The tumor biopsy will be obtained through Interventional Radiology by a percutaneous 
approach.  Location of the biopsy within tumor will be recorded.  A maximum of 2 core biopsies 
18-gauge in diameter and at least 1 cm in length will be obtained at each time point.  Only 
percutaneous biopsies will be performed on patients with solid tumors.  It is estimated that there 
will be between 2 to 5 million cells from each biopsy.  If a site is deemed appropriate for biopsy 
with minimal risk to the participant by agreement between the investigators and Interventional 
Radiology, an attempt at biopsy will be made.  The use of imaging to facilitate biopsies will be 
decided by members of the Interventional Radiology team and may include ultrasound, CT scan, 
or MRI.  Should CT scan be needed for biopsy, the number of scans for each procedure will be 
limited to the minimum number needed to safely obtain a biopsy.  Tumor biopsies will be 
performed under local anesthesia and conscious sedation only if they are considered to be of low 
risk to the participant as determined by the investigators and Interventional Radiology.   
All cases will be carefully reviewed with the interventional radiologists who have extensive 
experience in performing such procedures.  Only if the procedure is considered to be low risk 
then we will proceed with tumor biopsy in a given participant.  If the attempt is unsuccessful, the 
patient will still be eligible for treatment.  If a patient declines biopsy he/she will still be eligible 
for study. 
3.5.1.4 Sample Analysis: 
If two cores are obtained at each biopsy time point, they will be handled as follows: 
1) One core will be flash frozen and shipped on dry ice to Dr. Xin Wang’s laboratory for 
molecular characterization: 
2) The other core (or half of a core if only one is obtained will be divided in two) will be fixed 
in 10% formalin and submitted to Surgical Pathology, CCR/NCI (Bldg 10, 2N212) and for 
routine diagnostics.  The specimens will have routine H&E stains (including CD105) made 
as well as 5 additional unstained sections.  
3.5.1.5 Tumor tissue analysis at Dr. Wang’s lab: Gene expression analysis: 
1) Fresh-frozen tissue will be cut into serial 8μm sections 
2) Microdissect tissue into tumor and non-tumor tissue, using laser-captured microdissection 
(LCM). A pathologist will help with the procedure. The equipment for LCM is provided by 
the NCI core facility.  
3) Isolate, amplify and label RNA, using existing protocols. Currently, our laboratory uses a 
QIAGEN protocol for the isolation of total RNA from microdissected tissue and the small 
sample labeling protocol by Affymetrix to produce biotin-labeled cRNA. 
4) Hybridize cRNA onto the Affymetrix GeneChip Plus 2 arrays (gene expression) 
5) Array quality assessment will include array image inspection and in-house software 
packages developed by our bioinformatics staff 
6) Data analysis will be performed at Dr. Wang’s laboratory 


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Abbreviated Title:  Sorafenib and TRC105 in HCC 
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Version Date:  June 10, 2016 
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3.5.1.6 Collection of non-tumor tissue (blood, urine and mouthwash samples) for analysis in the 
Wang laboratory: 
We will collect blood (or mouth wash), urine and tissue specimens. The collected blood (or 
mouth wash) will be used for the analysis of genotypes, single nucleotide polymorphisms, 
methylation status, and the measurement of cytokine and microRNA concentrations in serum and 
plasma.  Urine samples are collected to study the association between metabolites in the liver and 
risk or progression of the disease.  The tissue specimens are collected for whole-genome gene 
expression analysis and the preparation of tissue arrays for immunohistochemical analysis of 
protein expression.  All non-tumor tissue samples will be initially collected and handled by the 
Figg laboratory and assigned a study ID number.  Personal identifiers will not be used on stored 
research samples.   
Genotyping will be performed from whole blood or buffy coat. The genotyping will be 
performed at the NCI Core Genotyping Facility using a global standard platform (currently, the 
HumanOmniExpress chip) which covers over 700K single nucleotude variants or through 
targeted Taqman assays based on genes of interest found in our gene expression analysis 
described elsewhere in this protocol.  Data will be analyzed and streamlined strictly for the 
purposes of the research aim(s) and results will not be shared with the patient.  Since samples are 
de-identified, researchers analyzing the data will be blind to the patient identifiers.  Thus, any 
additional findings that are incidental to the study will not be available to, nor benefit the patient 
whose sample was studied.   
3.5.1.6.1 Procedures for collection of blood (or MOUTH WASH) and urine 
Protocol for blood collection: 
1. 
Collect about 35cc of blood from each patient.  35cc of blood will be collected and divided 
into two 7 ml red top clot tubes (serum) and two 10ml green top sodium heparin tubes 
(plasma). Blood (separation of serum and blood clot; buffy coat; plasma and red blood cells) 
and urine to be processed within 8-24 hours at the Clinical Center. 
2. 
The date and exact time of each blood draw should be recorded on the blood tubes. Store the 
red tops, upright, at room temperature for 30-60min and then store at 4°C. Place the green 
tops on wet ice and store at 4°C in the refrigerator. 
3. 
Please page 102-11964 (Dr. Figg’s Lab) for immediate pick-up. Contact Dr. Figg’s Blood 
Processing Core (BPC) in 10/5A09 at 301-402-3622 or 301-594-6131 with any questions.  
4. 
Aliquots (1.5ml) will be frozen and – after initial handling and processing at the Figg 
laboratory – batch-shipped to Dr. Xin Wang’s Laboratory every three to four weeks.   
5. 
If a blood draw is not possible, a mouth wash is obtained. 
Protocol for mouthwash collection (optional if blood obtained): 
1. 
Rinse mouth with about 20ml water to wash out any food in mouth.  Discard. 
2. 
Rinse mouth with 30ml Blue color Listerine for 30 seconds and spit to a collection 
container. 
3.  Cover with lid and send to lab with ID label. 
4.  Complete Intake Form. 


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Abbreviated Title:  Sorafenib and TRC105 in HCC 
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Version Date:  June 10, 2016 
Amendment: N 
5.  Fill out Specimen Collection Form. 
6. 
Please page 102-11964 (Dr. Figg’s Lab) for immediate pick-up. Contact Dr. Figg’s Blood 
Processing Core (BPC) in 10/5A09 at 301-402-3622 or 301-594-6131 with any questions.  
Protocol for urine collection  
1. 
Collect approximately 50ml urine from each patient in a clean catch container. 
2. 
Store at 4°C in the refrigerator after collection.  
3. 
The date and time of collection should be recorded on the container. Please page 102-11964 
(Dr. Figg’s Lab) for immediate pick-up.  
3.5.2 Genotyping (Xin Wang lab): 
1) Isolate DNA from whole blood or buffy coat using a previously tested DNA isolation kit 
2) Determine DNA quality with Taqman-assays  and OD260/280 readings >1.8 
3) Perform genotype analysis with quality-controlled Taqman assays, using 384-well plates. 
Assays will be performed at the NCI Core Genotyping Facility. Each assay will contain 
negative and positive controls, and 10% blinded duplicates across and within Taqman plates.  
Greater than 90% concordance among duplicates will be required for inclusion in data 
analysis.   A >90% completion rate, >98% concordance rate and Hardy-Weinberg 
equilibrium tests will be used for inclusion.  Odds ratios for cases and controls will be 
assessed using logistical regression while association with survival among cases will be 
assessed by cox hazard regression using STATA.  Our survival assessment will be survival 
after date of study entry. 
3.5.3 Stem Cell Marker Analysis (Jane Trepel lab) 
1) Fresh blood which has been collected (~10mL) in green top tubes containing sodium heparin 
will be sent to NCI for immediate processing or stored at 4oc overnight.  Cancer stem cells 
will also be monitored in available fresh frozen tissue by IHC analysis of stem cell markers. 
2) Red blood cells will be removed with lysis buffer (25mL lysis buffer/1mL blood) with 5 
minute incubation followed by centrifugation at 300g. 
3) Circulating tumor cells (CTCs) will be isolated via negative enrichment to remove normal 
blood cells 
4) CTCs will be labeled for stem cell marker expression such as EpCAM, CD133 etc using 
commercial antibodies  and relative amounts will be determined by FACS 
3.5.4 Blood Product analysis (Xin Wang lab): 
1) Isolate small RNA from serum or plasma samples using commercially available kit 
(MirVANA, Invitrogen) 
2) Perform MicroRNA expression analysis using pre-made Taqman probes for specific 
microRNA purchased from Applied Biosystems; Each sample will be performed in triplicate 
and those with greater than 5% error in expression readings will be excluded from further 


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analyses.  Cycle readings under 36 will be considered good.  Differences between high and 
low RNA readings will be based upon the median, tertile or quartile cutoffs.   
3) Data analysis will be performed at the Dr. Wang’s laboratory. 
3.5.5 Cytokine expression analysis (Xin Wang lab) 
1) Incubate serum or plasma samples with cytokine probes using commercially available 
multiplexed human cytokine plate (MesoScale) 
2) Each assay will contain negative and positive controls, blanks and 10% blinded duplicates 
across and within Taqman plates.  Greater than 95% concordance among duplicates will be 
required for inclusion in data analysis.  Differences between high and low RNA readings will 
be based upon the median, tertile or quartile cutoffs.   
3) Data analysis will be performed at the Dr. Wang’s laboratory 
3.5.6 Metabolomics analysis (Xin Wang lab / Metabolon): 
Metabolomic profiling will be carried out at Metabolon (North Carolina, USA), using the general protocol 
outlined in Lawton et al (2008).  Liquid chromatography/mass spectrometry in both positive and negative 
modes (LC+/LC-) and gas chromatography/mass spectrometry (GC/MS) will be used. 
1) Urine samples from HCC cases (~150uL) will be prepared with neat HPLC grade acetonitrile 
(1:1) and centrifuged followed by processing by MS-based mass spectrometry in both 
positive and negative-ion mode.   
2) Quality will be assessed using control samples including pooled samples, blanks, duplicates 
and endogenous “spike-ins”. 
3) Data analysis will be performed at the Dr. Wang’s lab.  
3.5.7 Genotyping for SNPs in angiogenesis-related genes (eg VEGFR) (Figg lab):  
3.5.7.1 Description 
Of particular interest in studies evaluating anti-angiogenic agents in various cancers has been the 
finding (albeit often in an exploratory post-hoc analysis) of an improved median survival for 
those patients who experienced hypertension.  For example in a randomized phase II study of 
axitinib (an inhibitor of VEGFR) in pancreatic cancer those who experienced a single incident of 
diastolic hypertension (>90mm HG) during treatment visits had an improved median survival 
compared to those who also received the combination treatment but who didn’t experience any 
recorded hypertension (13.0m [95% CI 8.5 – 16.6] v 5.6m [95% CI 4.8 – 7.2])38.  This 
association between the onset of hypertension and improved therapeutic outcomes with anti-
angiogenic or anti-VEGF agents has also been found in other diseases and studies39-41. It is 
unclear whether the attainment of hypertension is a surrogate biomarker for those patients who 
would benefit from anti-VEGF therapy or indeed if it is a marker of efficacy that should be 
strived for. It appears that the former is more likely to be the case based on an analysis of patient 
tumor blocks from a study in breast cancer comparing paclitaxel with or without bevacizumab. 
In this study there was an association found between VEGF genotype and median overall 
survival as well as grade 3 or 4 hypertension41, 42.  Although the DNA evaluated in this study was 


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Abbreviated Title:  Sorafenib and TRC105 in HCC 
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derived from the primary tumor, it was host variability that was being evaluated, which is an 
important difference from other biomarkers, for example EGFR or KRAS mutations, which are 
tumor- related.  Because angiogenesis is a host-mediated process, germline genetic variability 
may be an important contributor to the heterogeneity of response seen and this variability has the 
potential to be used for better selection of patients for future studies evaluating anti-VEGF 
agents43.  
3.5.7.2 Procedure: 
A single blood test will be performed at baseline (after consent, prior to treatment initiation). 
One 6ml EDTA tube (BD, Franklin Lakes, NJ) will be collected from patients. 
1. Immediately after collection, invert the blood tube 8-10 times. Place the tube on wet ice 
and then refrigerate. The date and exact time of each blood draw should be recorded on 
the tube.  
2. Please page 102-11964 (Dr. Figg’s Lab) for immediate pick-up. Contact Dr. Figg’s Blood 
Processing Core (BPC) in 10/5A09 at 301-402-3622 or 301-594-6131 with any questions. 
Genomic DNA will be analyzed for polymorphisms in angiogenesis-related genes. Genotyping 
will be performed by sequencing analysis, RFLP or gene array analysis. 
3.5.8 Circulating endothelial cells (CECs), Circulating endothelial progenitor (CEP) cells, 
plasma levels of angiogenic factors, soluble CD105 (baseline) and Rat aortic ring 
bioassay. 
3.5.8.1 Brief description of background and rationale for performing this test:  
1. Both TRC105 and sorafenib inhibit angiogenesis and tumor growth.  However, there are 
no current human clinical data to support such biological activity in TRC105. 
2. Consistent fluctuations in plasma VEGF and PlGF (placenta-derived growth factor), as 
well as in CEC’s and CEP’s have been detected following an array of anti-angiogenic 
therapies, including the anti-VEGF antibody bevacizumab, VEGFR2 inhibitors, and their 
combinations in clinical studies.   
3. Such analysis in this study would provide the necessary support for the putative 
mechanism of action of the agent under investigation. 
4. Given the mechanism of TRC105 it is possible that efficacy is related to baseline soluble 
CD105. 
3.5.8.2  Implementation: 
3.5.8.2.1 CEPs and CECs (Jane Trepel lab):  
Two 7cc EDTA lavender tubes will be drawn for analysis of circulating endothelial 
progenitor cells (CEP) and mature circulating endothelial cells (CEC). Samples will be 
collected from patients at 30 min prior to dose on cycle 1 day 1, cycle 1 day 15 and cycle 
2 day 15.  
3.5.8.2.2 VEGF, PlGF, bFGF and sVEGFR1 (soluble VEGF receptor 1) (Liang Cao lab):  


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Abbreviated Title:  Sorafenib and TRC105 in HCC 
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One 4 ml EDTA plasma tube (BD, Franklin Lakes, NJ) is collected from each patient 
prior to drug administration at Day 1 of Cycle 1 (baseline), Day 15 of Cycle 1, at Day 1 
of Cycle 2, and at the end of the study.   
1. The date and exact time of each blood draw should be recorded on the blood tubes. 
Place the tubes on wet ice and store at 4°C in the refrigerator. 
2. Please page 102-11964 (Dr. Figg’s Lab) for immediate pick-up. Contact Dr. Figg’s 
Blood Processing Core (BPC) in 10/5A09 at 301-402-3622 or 301-594-6131 with any 
questions.  
The plasma will be transferred to Dr. Cao’s lab at Bldg 37, Rm. 6134 in batches (tel: 301-
435-9039). Plasma levels of angiogenic factors will be performed for VEGF, PlGF, bFGF 
and sVEGFR1 (soluble VEGF receptor 1).   The analysis will be done with assays 
developed on electrochemiluminescence platform that provides ultra-high sensitivity and 
very large signal dynamic range.   Purified protein standard will be used for generating 
standard curves for concentration determination.  Data analysis will be performed with 
Prism (GraphPad, San Diego, CA) to determine the medium value, interquartile range, 
and P value in paired t test.  If the induction of VEGF and PlGF can be observed, 
correlative studies will be performed between the induced levels of angiogenic factors 
and the dose levels of TRC105 in the phase I combination segment of the trial. In the 
phase II study, when the responses can be established, correlative studies will be 
performed between the initial levels of the angiogenic factors, or the degree of their 
induction with the clinical responses.  
3.5.8.2.3 Soluble CD105 (Seon Lab):  
A 5mL K2EDTA lavender top tube will be collected at Day 1 of Cycle 1 (baseline), Day 
15 of Cycle 1, at Day 1 of Cycle 2, and at the end of the study. 
1) Record the patient number on the collection and storage labels for each collection time 
point using a permanent marker.  Affix the completed collection and storage labels 
vertically on the 5mL K2EDTA (lavender top) blood collection tube and two 2mL clear 
polypropylene storage cryovials with lavender top, respectively, prior to specimen 
collection.  
2) Collect 5mL of blood into the K2EDTA (lavender top) blood collection tube. 
3) Gently invert the 5mL K2EDTA (lavender top) blood collection tube (~15 times) to 
completely mix the blood and anticoagulant.  
4) Please page 102-11964 (Dr. Figg’s Lab) for immediate pick-up. Contact Dr. Figg’s Blood 
Processing Core (BPC) in 10/5A09 at 301-402-3622 or 301-594-6131 with any questions.  
At the completion of the study samples will be shipped to Dr Seon’s lab at 
Roswell Park at the following address: 
 
Jill Duzen 
Seon Laboratory 
CGP bldg. Room L5-126 
Roswell Park Cancer Institute 


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Elm and Carlton Streets 
Buffalo, NY 14263  
Phone: 716-845-4482 
3.5.9 Rat aortic ring bioassay (Figg lab): 
At least 7 ml of blood in a red top clot tube for Dr. Figg’s lab will be collected at baseline 
and C3D1.  
1) The date and exact time of each blood draw should be recorded on the blood tubes. Store 
the red tops, upright, at room temperature for 30-60min and then store at 4°C.  
2) Please page 102-11964 (Dr. Figg’s Lab) for immediate pick-up. Contact Dr. Figg’s Blood 
Processing Core (BPC) in 10/5A09 at 301-402-3622 or 301-594-6131 with any questions. 
This assay as described by Ng et al utilizes a Matrigel system for optimal neovessel 
sprouts from implants of rat aortic sections44. After a 5-day incubation period, image 
analysis following photo microscopy allows for the quantization of sprout density. The 
assay conditions are able to use human serum as the stimulus source. The serum to be 
utilized will be allotted from the quantity sent to the Clinical Pharmacology Program. 
3.5.10 Fc receptor polymorphisms (Jane Trepel lab) 
Genotyping of CD16a will be performed using a TaqMan SNP probe assay.  The assay contains 
two primers for amplifying the sequence of interest and two TaqMan MGB (minor groove 
binding) probes for detecting specific alleles.  The genotyping assay determines the presence or 
absence of a SNP based on the change in fluorescence of the dyes associated with the probes.  
Pre-designed TaqMan SNP genotyping assays from the Applied Biosystems database 
(http://www.appliedbiosystems.com) will be used for rs396991, the relevant SNP of interest on 
CD16a (amino acid 158, V/F).   
 
Peripheral blood will be collected in one lavender top tube on C1D1 pre-therapy.  DNA will be 
isolated using the Qiagen Blood DNA isolation kit, and quantified using NanoDrop 
instrumentation.  For each DNA sample PCR amplification will be performed using the TaqMan 
SNP probe assay reagents.  After PCR amplification an endpoint plate read on an ABI 7500 
instrument will be performed and analyzed using SDS software provided by Applied 
Biosystems.  The results of the allelic discrimination assay will be displayed as a scatter plot of 
the fluorescence intensity of allele 1 versus allele 2. 
3.5.11 Immunogenicity Testing (Tracon): 
At each timepoint outlined in the schedule of assessments, a 5 mL blood sample will be collected 
to assess immunogenicity (Human Anti-Murine Antibodies/HAMA and Human Anti-Chimeric 
Antibodies/HACA).  Immunogenicity studies (both HAMA and HACA) will be collected at 
baseline and then 28 days following the end of the study treatment.  
The date and exact time of each blood draw should be recorded on the blood tubes. Store the red 
tops, upright, at room temperature for 30 min and then store at 4°C. Please page 102-11964 (Dr. 
Figg’s Lab) for immediate pick-up. Contact Dr. Figg’s Blood Processing Core (BPC) in 10/5A09 
at 301-402-3622 or 301-594-6131 with any questions. 


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Sera will be separated and stored at -70°C.  Samples will be batch shipped every 3 to 6 months to 
3rd party laboratory for analysis.  HAMA and HACA concentrations will be measured using 
validated ELISA methods and evaluated in the context of pharmacokinetic parameters and 
adverse event profiles.   
3.5.11.1 HAMA/HACA Serum Collection, Processing and Storage Instructions 
Step 1: Record the patient number on the collection and storage labels for each collection time 
point using a permanent marker.  Affix the completed collection and storage labels vertically on 
the 5mL red top blood collection tube and four 0.5mL clear polypropylene storage cryovials, 
respectively, prior to specimen collection.  
Label application instructions: 
 “HAMA Primary” & “HAMA Backup” labels – affix to 0.5mL clear polypropylene storage 
cryovials (vertically) 
“HACA Primary” & “HACA Backup” labels – affix to 0.5mL clear polypropylene storage 
cryovials (vertically) 
“HACA Extra” & “HAMA Extra” labels – to be used as replacement for damaged or lost label 
with corresponding assessment, collection time point and sample ID 
 
 
 
 
 
Step 2:  Collect 5mL of blood into the red top blood collection tube. 
Step 3:  Keep the blood specimen at room temperature for 30 minutes until clotted. 
Step 4:  Centrifuge the 5mL red top blood collection tube at 1700 g (~3,000 to 3,500 rpm) for 10 
to 15 minutes at 4°C in a refrigerated centrifuge or an unrefrigerated centrifuge with a centrifuge 
rotor/cups that have been pre-chilled to 4°C for 2 hours. 
Step 5:  Transfer the serum equally into four pre-labeled 0.5mL clear polypropylene storage 
cryovials.  Use a fresh transfer pipette for each time point. 
 
5mL red top blood collection tube                           4 x 0.5mL clear polypropylene storage cryovial 


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Step 6:  Place the 0.5mL clear polypropylene storage cryovials in the cryovial storage box 
provided and freeze immediately.  Store the specimens in a freezer at -70°C.  Once frozen, do not 
allow the specimens to thaw, including during shipment 
3.5.12 Immunomonitoring (Greten lab) 
3.5.12.1 Description 
Non-immune based therapies have been shown to have significant effects on tumor-specific 
immune responses.  While it was always a general believe that chemotherapy impairs immune 
responses in patients with cancer, there is increasing evidence demonstrating that under certain 
circumstances chemotherapy might have potential beneficiary effects on tumor specific immune 
responses45.  Until today the mechanism of how chemotherapy might support immune responses 
remains unclear.  While it has been shown in different mouse models that chemotherapy induced 
cell death supports T cell priming through cross-priming46 others have been able to demonstrate 
an effect of targeted therapies on different immune suppressor mechanisms including regulatory 
T cells as wells as MDSCs.  Sunitinib has been shown to impair both, the function of regulatory 
T cells as well as MDSCs47, 48.  Although the direct mechanism remains unclear how sunitinib 
impairs MDSCs and Treg function.  Previous studies have shown that VEGF plays a major role 
in abnormal dendritic cell differentiation and function in cancer.  It has been proposed that 
inhibition of VEGF may result in improved immune responses and that anti-VEGF based 
therapies improve immune responses in patients with cancer.  
In this study we plan to monitor immune effector function in detail.  For this PBMC will be 
analyzed from patients prior to first treatment and 4 and 10 weeks after initiation.  Blood will be 
collected and processed by the Figg lab and frozen until later analysis.  Frequency, phenotype 
and function of different immune cells (including B cells, CD8+ T cells, CD4+ T cells, NK cells, 
NKT cells, myeloid DCs, Macrophages, Monocytes, Tregs and MDSCs) will be analyzed in Dr. 
Greten’s laboratory. 
Peripheral blood will be collected in one 60cc heparinized syringe and stored at room 
temperature. The date and exact time of each blood draw should be recorded on the blood tubes. 
Please page 102-11964 (Dr. Figg’s Lab) for immediate pick-up. Contact Dr. Figg’s Blood 
Processing Core (BPC) in 10/5A09 at 301-402-3622 or 301-594-6131 with any questions. 
4 x 0.5mL clear polypropylene storage cryovial 
 
 
 
 


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3.5.13 TRC105 Pharmacokinetics 
3.5.13.1 TRC105 Pharmacokinetics Trough Concentration:  
A 5 mL blood sample to be collected C1D1, C1D15, C2D1 and C2D15, immediately prior to 
starting the TRC105 infusion.  Samples will be stored at approximately -70°C for shipment every 
3 months. See separate laboratory guide for further collection and shipment information. 
Additional PK samples may also be collected at the time of unexpected clinical events.  
 
3.7.13.2  
TRC105 Pharmacokinetics Peak Concentrations:  
A 5 mL blood sample to be collected within 5 minutes prior to the completion of the TRC105 
infusion on c C1D1, C1D15, C2D1, C2D15 and the end of the study.  Samples will be stored at 
approximately -70°C for shipment every 3 months. See separate laboratory guide for further 
collection and shipment information. Additional PK samples may also be collected at the time of 
unexpected clinical events. 
3.6 
IMAGING STUDIES 
An attempt will be made to perform all correlative imaging studies in accordance with the 
schedule; however, given scheduling issues and unforeseen circumstances which may result in 
treatment delays and patient inconvenience, these tests will be optional. 
3.6.1 Dynamic Contrast Enhanced – Magnetic Resonance Imaging (DCE-MRI) 
3.6.1.1 Description 
Dynamic Contrast Enhanced Magnetic Resonance Imaging (DCE-MRI) has been used 
extensively with novel antiangiogenic agents in phase I and II trials to monitor their effect on 
tumor vasculature through parameters reflecting both tumor perfusion and permeability. This 
protocol is limited to DCE-MRI using T1 weighted studies with low molecular weight 
gadolinium (Gd) chelates.  Other MRI techniques (which are not covered by this protocol) 
include the following:  DCE-MRI using T2* weighted images; contrast-enhanced MR with high 
molecular weight contrast agents; and non-contrast enhanced MRI techniques such as diffusion-
weighted MRI, T2* weighted MRI or BOLD. 
DCE-MRI studies will be interpreted by Dr. Peter Choyke, MD, Chief, NCI Molecular Imaging 
Department, 301.435.4046, 10/1B40.  Other members of the clinical imaging program may 
contact Dr. Choyke for information purposes regarding the imaging protocol and data capture 
methodology. 
3.6.1.2 DCE-MRI End Points  
• The primary end points of these DCE-MRI studies are the Initial Area Under the Gd 
Curve measured over 60 seconds (IAUC60) and the Transport Constant (Ktrans). 
• IAUC (initial area under the gadolinium concentration time curve). 
• Transport Constant (Ktrans). 
• Both Ktrans and IAUC60 require calculation of instantaneous tumor Gd concentration 
based on the change in relaxivity due to contrast uptake ΔR1.  The basic requirements 
for these calculations are: 
o An estimate of contrast agent relaxivity in tumor vasculature and tissue 


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o Measurement of tumor T1 immediately prior to contrast uptake 
o An accurate T1 measurement method verified for all spatial locations, 
coils and scanners used 
o Cardiac output (or arterial input function) for Ktrans (population based    
  
estimates may be appropriate) 
o Reproducible injection (ideally power injector) 
• All data including ROI definition and analysis should be recorded and traceable to 
support external review. 
• Additional end points may be generated at a study / protocol level in addition to these 
primary end points.  The production of the primary DCE-MRI end points for 
comparison between studies does not preclude other end points within studies such as 
parametric maps of IAUC/Ktrans, blood volume (Vb), extravascular space (Ve), Kep (a 
function of Ktrans and Ve), etc. 
3.6.1.3 Tumor Type and Location 
• Lesions within the lung are excluded from DCE-MRI studies due to “breathing” 
artifacts which make image data difficult to analyze reliably. 
• Recommendations for lesion selection: 
- 
Exclude lung lesions.  
- 
If possible, exclude lesions in close proximity to the heart or major 
vascular structures 
- 
If possible, choose lesions towards the center of the image volume. 
- 
If possible, choose lesions towards the center of the image plane. 
- 
Lesions should be at least 1.5 cm and preferably > 2 cm in longest in plane 
diameter  
- 
Lesions preferably should be < 7 cm in the z plane [the entire            
lesion(s) should be within the volume scanned]. 
- 
Lesions should be well defined on standard CT or MR imaging. 
3.6.1.4 Schedule of DCE-MRI Assessments 
• The use of DCE-MRI to assess tumor vascular factor parameters is exploratory is 
nature.  When possible, patients enrolled into the phase II portion of the study will be 
selected for enrollment based on appropriate lesions for pharmacodynamic imaging 
with planned DCE-MRI scans.   
• DCE-MRI scans should be obtained: 
- 
Prior to treatment (preferably within 7 days of treatment start) 
- 
24-36 hours after Cycle 1 Day 1   
- 
28 +/- 2 days after Cycle 1 Day 1  
- 
Further follow-up scans, depending on the study design 
3.6.1.5 Data to be collected 
• The following information on a per patient basis should be supplied to the NCI with 
the final study manuscript. 
- 
Study identifier (NCI protocol number) 
- 
Subject identifier (patient I.D.) 


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- 
TRC105 dosing information 
- 
Date of first dose of TRC105 
- 
Date of last dose of TRC105 
- 
Dose of TRC105 
- 
Any relevant dosing information, e.g., drug holidays 
• Tumor type 
• For each DCE-MRI scan 
- 
Location of lesion studied, e.g., liver metastases 
- 
Date of DCE-MRI scan 
- 
Tumor IAUC60 
- 
Tumor Ktrans 
• For each RECIST response assessment 
- 
Date of each RECIST assessment 
- 
Response assessment (if progression is recorded, then it should be             
specified whether the progression is in the lesion assessed by DCE-           
MRI) 
3.6.2 Doppler U/S of tumor vasculature. 
3.6.2.1 Ultrasound Evaluation Description 
Ultrasound evaluation of the patient’s liver tumor volume and tumor blood flow will be 
performed at the same time points as DCE-MRI 
3.6.2.2 Schedule: 
- 
Prior to treatment (preferably within 7 days of treatment start) 
- 
24-36 hours after Cycle 1 Day 1   
- 
28 +/- 2 days after Cycle 1 Day 1  
- 
56 +/- 2 days after Cycle 1, Day 1  
- 
Further follow-up scans, depending on the study design 


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3.7 
SUMMARY OF CORRELATIVE TESTS 
Tissue 
sample type 
Test 
Quantity 
Tube and storage 
Timing 
Blood 
Genotyping (Wang) 
Circulating Tumor cells, 
cytokines (Wang) 
35 mls 
2- 7mL red 
2- 10mL green (on 
ice) 
 
C1D1 
SNP for angiogenesis- related 
genes (Figg) 
6 mls 
EDTA (on ice) 
C1D1 
Serum PD 
(Trepel/Cao) 
 
CEP/CECs  
16 mls 
2-7 mL (on ice) 
Lavender 
C1D1, 
C1D15, 
C2D15 
VEGF,FGF,PIGF 
5 mls 
EDTA (on ice) 
C1D1, 
C1D15, C1, 
D1 and end 
of study 
Soluble CD105 
5 mls 
Lavender top tubes 
C1D1, 
C1D15, 
C2D1, and 
end of study 
Rat aortic ring 
assay 
7 mls 
Red (room temp) 
C1D1, 
C3D1 
HAMA/HACA (Figg) 
7mL 
Red top (room 
temp) 
C1D1, 
 28 days 
post end of 
study 
TRC 105 Pharmacokinetics 
5ml 
Red top (room 
temp) 
C1D1, 
C1D15, 
C2D1, 
C2D15 and 
end of study 
(trough 
only) 
pretreatment 
and 5 
minutes 
post 
completion 
of TRC 105 
infusion 


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Tissue 
sample type 
Test 
Quantity 
Tube and storage 
Timing 
Fc Receptor polymorphisms 
(Trepel) 
 
4 mls 
 
Lavender top tubes 
C1D1 
Immunomonitoring (Greten) 
60 mL 
1- 60cc Sodium 
Heparin Syringes 
(room temp) 
C1D1, 
4wks, 10 
wks  
Tumor 
tissue 
Molecular profiling (Wang) 
Histology for confirmatory 
diagnostics and CD105 
(Histopath.) 
Optional 
1-2 cores 
N/A 
Optional 
C1D1 and 
after 2 
cycles 
Urine 
Metabolomics (Wang) 
50 mLs 
13 ml plastic tubes 
(on ice) 
C1D1 
Mouthwash Genotyping (Wang) 
30mLs 
50 ml centrifuge 
tube 
C1D1 
Radiology 
DCE-MRI (Choyke) 
3 
N/A 
1) Prior to 
treatment 
(preferably 
within 7 
days of 
treatment 
start) 
2) 24-36 
hours after  
Cycle 1 Day 
1   
3) 28 +/- 2 
days after 
Cycle 1 
Day 1 
4) Doppler 
Only 56 +/- 
2 after 
Cycle 1 
Day 1   
Doppler U/S (Wood) 
4 
 
3.8 
SAMPLE STORAGE, TRACKING, AND DISPOSITION 
See Section 11.5 


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3.9 
ON-STUDY AND FOLLOW UP EVALUATIONS 
3.9.1 See study Calendar (Section 11.4) 
3.9.2 All study subjects will be followed for overall survival only once active treatment has 
been completed. 
3.9.3 If toxicities cause discontinuation of therapy, patients will be followed until resolution of 
toxicity to at least Grade 1. This may be done by phone if appropriate. 
3.9.4 Follow-up will be annual telephone contact to assess survival status.  Every attempt will 
be made to contact patient/subject including: contacting referring physician, contacting 
emergency contact patient identified on admission, checking SSDI (Social Security Death 
Index) 
3.10 CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA 
3.10.1 Criteria for removal from protocol therapy 
In the absence of treatment delays due to adverse event(s), treatment may continue until one of 
the following criteria applies: 
3.10.1.1 Progressive disease as defined in Section 5.2 
3.10.1.2 Intercurrent illness that prevents further administration of treatment, 
3.10.1.3 Unacceptable adverse event(s) 
3.10.1.4 Patient decides to withdraw from treatment 
3.10.1.5 General or specific changes in the patient’s condition render the patient unacceptable 
for further treatment in the judgment of the investigator. 
3.10.2 Off-Study Criteria 
3.10.2.1 Voluntary withdrawal of consent to participate in the study or the follow up period. 
3.10.2.2 Patient noncompliance with the study. 
3.10.2.3 Patient death 
3.10.3 Off Study Procedure 
Authorized staff must notify Central Registration Office (CRO) when a subject is taken off-
study. An off-study form from the web site 
(http://home.ccr.cancer.gov/intra/eligibility/welcome.htm) main page must be completed and 
sent via encrypted email to:  NCI Central Registration Office (HOIS) ncicentralregistration-
l@mail.nih.gov. 
3.11 EARLY STOPPING RULES FOR SAFETY/ACCRUAL 
The following stopping rules for safety and accrual/futility will be implemented in the protocol: 


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i. 
In the event of more than 1 variceal bleeding event during the phase I part of the study or 
more than 2 variceal bleeding events in the phase II part the study, the study will be 
suspended pending full investigation of the bleeding cause.  
ii. 
In the event of 1 other major bleeding complication (CTC grade 3), apart from variceal 
hemorrhage, during the phase I part or more than 2 bleeding events in the phase II part 
the study, the study will be suspended pending full investigation of the bleeding cause. 
iii. 
A screening log will be initiated to identify those in/exclusion criteria, which are most 
likely hindering patients to enroll into the studies.  This log will not only help us for the 
design of other future trials, but we can also use it to evaluate if we need to amend the 
protocol to allow for a better (but still safe, accrual).  Should we notice that not enough 
patients are referred to NCI, we will open a second center at a location outside of the 
Washington/Baltimore area, possibly at Memorial Sloan-Kettering Cancer Center or 
Harvard.  
4 
SUPPORTIVE CARE 
Patients will receive appropriate supportive care medications at the investigator's discretion. See 
section 3.4 for management of specific toxicities.  
5 
DATA COLLECTION AND EVALUATION  
5.1 
DATA COLLECTION 
Data will be prospectively collected and entered into the NCI C3D database.  Medical records 
will be maintained to include but not limited to: 
• 
Signed, Dated Consent Form 
• 
Completed Eligibility Checklist 
• 
Source documents verifying eligibility criteria 
• 
Pre-study lab, radiology, pathology reports, histopathological results 
• 
Interim monitoring test results 
• 
Physician notes/progress notes documenting physical evaluations, PS, history, prior 
therapy 
• 
Physician/Nursing notes documenting vital signs, adverse event assessment, 
• 
Treatment administration forms-In-patient/Out-patient 
• 
Response evaluation- results/tumor measurements 
• 
Research DCE-MRI Scan/biologic correlate sample collection/analysis 
• 
Off study summary 
See also the CCR Standard Operating Procedure: Conducting and Documenting Drug 
Accountability for Oral Investigational Agents that are Self-Administered by Patients 
(http://ccrintra.cancer.gov/clin_ops/policies/SOPCLIN1.pdf). 
All data will be kept secure. The PI will be responsible for overseeing entry of data into an in-
house password protected electronic system and ensuring data accuracy, consistency and 
timeliness. The principal investigator, associate investigators/research nurses and/or a contracted 
data manager will assist with the data management efforts. All human subjects personally 


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identifiable information (PII) as defined in accordance to the Health Insurance Portability and 
Accountability Act, eligibility and consent verification will be recorded. Primary data obtained 
during the conduct of the protocol will be kept in secure network drives or in approved 
alternative sites that comply with NIH security standards. Primary and final analyzed data will 
have identifiers so that research data can be attributed to an individual human subject participant. 
End of study procedures: Data will be stored according to HHS and FDA regulations as 
applicable.  
Loss or destruction of data: Should we become aware that a major breech in our plan to protect 
subject confidentiality and trial data has occurred, the IRB will be notified. 
5.2 
RESPONSE CRITERIA 
Re-staging CT scan of chest, abdomen, and pelvis will be required every two months of 
treatment.  Confirmatory scans should also be obtained 4 weeks following initial documentation 
of objective response (CR or PR)  
Objective 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 
[Eisenhauer EA, et al. New response evaluation criteria in solid tumours: Revised RECIST 
guideline (version 1.1) 2009; Eur J Ca 45:228-247]. 
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. 
5.2.1 Response Criteria for Radiographic Studies 
5.2.1.1 Measuring of Soft Tissue Disease 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline 
(version 1.1) [Eur J Ca 45:228-247, 2009] as well as – in an exploratory fashion as a secondary 
endpoint – the EASL-modified RECIST criteria (Lencioni and LLovet Semin Liv dis 2010). 
Changes in the largest diameter (unidimensional measurement) of the tumor lesions and the 
shortest diameter in the case of malignant lymph nodes are used in the RECIST criteria. 
a. Evaluation of Target Lesions  
 
 
Complete Response (CR)  
Disappearance of all target lesions.  Any pathological lymph nodes (whether target or 
non-target) must have reduction in short axis to <10 mm 
 
 
Partial Response (PR)  
At least a 30% decrease in the sum of the diameters of target lesions, taking as 
reference the baseline sum of diameters 
 
 
Progressive Disease (PD)  


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At least a 20% increase in the sum of the diameters of target lesions, taking as 
reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study).  In addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm.  (Note:  the appearance of one or 
more new lesions is also considered progressions) 
 
 
Stable Disease (SD)  
 Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for 
PD, taking as reference the smallest sum of diameters while on study 
b. Evaluation of Non-Target Lesions  
 
 
Complete Response (CR)  
Disappearance of all non-target lesions and normalization of tumor marker level.  All 
lymph nodes must be non-pathological in size (<10 mm short axis) 
Note:  If tumor markers are initially above the upper normal limit, they must 
normalize for a patient to be considered in complete clinical response. 
 
 
Non-CR/Non-PD (Stable Disease, SD) 
Persistence of one or more non-target lesion(s) and/or maintenance of tumor marker 
level above the normal limits. 
 
 
Progressive Disease (PD)  
Appearance of one or more new lesions and/or unequivocal progression of existing 
non-target lesions. Unequivocal progression should not normally trump target lesion 
status.  It must be representative of overall disease status change, not a single lesion 
increase.     
 Although a clear progression of “non-target” lesions only is exceptional, the opinion 
of the treating physician should prevail in such circumstances, and the progression 
status should be confirmed at a later time by the review panel (or Principal 
Investigator). 
c. 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 
Best Overall Response 
when Confirmation is 
Required* 
CR 
CR 
No 
CR 
>4 wks. Confirmation** 


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CR 
Non-CR 
Non-PD 
No 
PR 
 
>4 wks. Confirmation** 
CR 
Not 
evaluated 
No 
PR 
PR 
Non-CR 
Non-PD 
Not 
evaluated 
No 
PR 
SD 
Non-CR 
Non-PD 
Not 
evaluated 
No 
SD 
Documented at least once >4 
wks. from baseline** 
PD 
Any 
Yes or 
No 
PD 
 
No prior SD, PR or CR 
Any 
PD*** 
Yes or 
No 
PD 
Any 
Any 
Yes 
PD 
      *See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
      **Only for non-randomized trials with response as primary endpoint. 
      ***In exceptional circumstances, unequivocal progression in non-target lesions may be accepted 
as disease progression 
 
 
d. 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. 
e. In some circumstances, it may be difficult to distinguish residual disease from normal 
tissue.  When the evaluation of complete response depends on this determination, it is 
recommended that the residual lesions be investigated (fine needle aspirate/biopsy) 
before confirming the complete response status. 
5.2.1.2 Confirmatory Measurement/Duration of Response 
a. Confirmation 
To be assigned a status of PR or CR, changes in tumor measurements must be 
confirmed by repeat assessments that should be performed at least 4 weeks after the 
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b. Duration of Overall Response 
The duration of overall response is measured from the time measurement criteria are 
met for CR or 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 CR is measured from the time measurement criteria are first 
met for CR until the first date that progressive disease is objectively documented. 
5.2.1.3 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 by chest x-ray, as >10 mm with CT 
scan, or >10 mm with calipers by clinical exam.  All tumor measurements must be recorded in 
millimeters (or decimal fractions of centimeters). 
Note:  Tumor lesions that are situated in a previously irradiated area might or might not be 
considered measurable.  If the investigator thinks it appropriate to include them, the conditions 
under which such lesions should be considered must be defined in the protocol. 
5.2.1.4 Malignant Lymph Nodes  
To be considered pathologically enlarged and measurable, a lymph node must be >20 mm in 
short axis when assessed by CT scan (CT scan slice thickness recommended to be no greater 
than 5 mm).  At baseline and in follow-up, only the short axis will be measured and followed. 
5.2.1.5 Non-Measurable Disease 
All other lesions (or sites of disease), including small lesions (longest diameter <10 mm or 
pathological lymph nodes with ≥ 10 to <15 mm short axis), are considered non-measurable 
disease.  Bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, 
lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not followed 
by CT or MRI), are considered as non-measurable. 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts should not 
be considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts. 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable lesions, 
if they meet the definition of measurability described above. However, if non-cystic lesions are 
present in the same patient, these are preferred for selection as target lesions. 
5.2.1.6 Target Lesions 
All measurable lesions up to a maximum of 2 lesions per organ and 5 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), be representative of all involved organs, but in addition should be those 
that lend themselves to reproducible repeated measurements.  It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement in which 
circumstance the next largest lesion which can be measured reproducibly should be selected.  A 


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sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters.  If lymph nodes are to be 
included in the sum, then only the short axis is added into the sum.  The baseline sum diameters 
will be used as reference to further characterize any objective tumor regression in the measurable 
dimension of the disease. 
Progressive disease by RECIST criteria [1] noted after the first re-staging scan may represent 
disease that was not detected on the pre-study scan, and a confirmatory scan will be required at 
the next scheduled re-staging evaluation unless clinically not indicated.  If confirmed, 
progression should be dated by the initial time when the lesions are first detected. If progressive 
disease by RECIST criteria is seen after cycle 2, but not confirmed on subsequent restaging scan, 
the scans from after cycle 2 would serve as the baseline scan to evaluate for disease progression,  
(ref: Scher, HI et al. J Clin Onc, 26 (7), 2008) 
5.2.1.7 Non-Target Lesions 
All other lesions (or sites of disease) including any measurable lesions over and above the 5 
target lesions should be identified as non-target lesions and should also be recorded at baseline. 
Measurements of these lesions are not required, but the presence, absence, or in rare cases 
unequivocal progression of each should be noted throughout follow-up.  
5.2.1.8 Metastatic Bone Lesions 
Disease progression is considered if a minimum of two new lesions is observed on bone scan. 
New lesions seen by the end of cycle 2 or before cycle 3 (with the first re-staging bone scan) 
may represent disease that was not detected on the pre-study scan, and a confirmatory scan will 
be required at the next scheduled re-staging bone scan unless clinically not indicated.  If 
confirmed, progression should be dated by the initial time when the lesions are first detected. If 
new lesions are seen after cycle 2, but no additional lesions are seen on confirmatory scans, the 
scans from post-cycle 2 would serve as the baseline scan to evaluate for disease progression,  
(ref: Scher, HI et al. J Clin Onc, 26 (7), 2008) 
5.2.1.9 Clinical Lesions  
Clinical lesions will only be considered measurable when they are superficial (e.g., skin nodules 
and palpable lymph nodes) and ≥10 mm diameter as assessed using calipers (e.g., skin nodules).  
In the case of skin lesions, documentation by color photography, including a ruler to estimate the 
size of the lesion, is recommended.  
5.2.1.10  Guidelines for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler or calipers.  All 
baseline evaluations should be performed as closely as possible to the beginning of treatment and 
never more than 4 weeks before the beginning of the treatment. 
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 unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam. 


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5.2.1.11  Methods of Measurement 
Chest X-ray - Lesions on chest x-ray are acceptable as measurable lesions when they are clearly 
defined and surrounded by aerated lung.  However, CT is preferable.  
CT and MRI - CT and MRI are the best currently available and reproducible methods to measure 
target lesions selected for response assessment. For this study helical Multi-detector CT will be 
performed with cuts of 5 mm in slice thickness for chest, abdomen and pelvis lesions and 2-3 
mm thickness for head and neck lesions. 
5.2.2 EASL-modified RECIST criteria. 
5.2.2.1 Background 
The Amercian Association for the Study of Liver Disease (AASLD) convened an expert panel to 
reach consensus on issues relating to trial design in HCC, a particular challenge given the almost 
invariable existence of underlying cirrhosis49.  A number of recomendations were made 
including:  
• The Barcelona Clinic Liver Cancer Staging System (BCLCS) was recommeded for 
selection of the target population in an effort to standardise inclusion criteria and make 
data interpretation easier.  
• For phase II studies the panel recommended a randomized design with a time-to-event 
endpoint, such as time to tumor progression (TTP).  This is in place of a composite 
endpoint, such as progression-free survival, which may be influenced by the underlying 
cirrhosis and mask any potential anti-cancer efficacy of the drug.  
• The use of smarter correlative endpoints which better reflect the mechanistic effect of the 
investigational agent can also be useful, especially given the lack of randomized studies 
in this disease.  
• The AASLD panel also recommended that new agents be tested in patients with well-
preserved liver function (Child-Pugh Class A).  
In addition, the panel addressed the deficiencies in the standard RECIST criteria as they apply to 
HCC, particularly in the era of molecular therapies where changes in tumor viability, as 
determined by contrast-enhanced techniques, are important. This is especially relevant given the 
vascularity of HCC. Certain amendments to the RECIST criteria were therefore proposed which 
are centred on the concept of measuring viable tumor, defined as the uptake of contrast agent in 
the arterial phase of dynamic CT or MRI.  These EASL-modified RECIST criteria will used to 
evaluate response as a secondary endpoint of this study. 
The mRECIST for HCC has introduced the following amendments to RECIST in the 
determination of tumor response for target lesions: 
• 
Complete response: the disappearance of any intratumoral arterial enhancement in all 
target lesions 
• 
Partial response: at least a 30% decrease in the sum of diameters of viable (contrast 
enhancement in the arterial phase) target lesions, taking as reference the baseline sum of 
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• 
Progressive disease: an increase of at least 20% in the sum of the diameters of viable 
(enhancing) target lesions, taking as reference the smallest sum of the diameters of viable 
(enhancing) target lesions recorded since the treatment started 
• 
Stable disease: any cases that do not qualify for either partial response or progressive 
disease 
The measurement of the longest diameter of the viable tumor may be challenging in lesions 
showing partial internal necrosis. The following points should be taken into account in such 
cases: 
• 
The measurement of the viable tumor should be performed on CT or MRI obtained in the 
arterial phase, when the contrast between viable vascularized tumor tissue and 
nonenhancing necrotic tissue is the highest. 
• 
The longest diameter of the viable tumor is not necessarily located in the same scan plane 
in which the baseline diameter was measured: a thorough careful evaluation of the CT or 
MRI scans is required. 
• 
The measurement of the viable tumor diameter should not include any major intervening 
areas of necrosis. 
5.2.2.2 NONTARGET LESIONS RESPONSE 
The RECIST guideline provides the following definitions of the criteria used to determine the 
objective tumor response for nontarget lesions: complete response is the disappearance of all 
nontarget lesions; incomplete response/stable disease is the persistence of one or more nontarget 
lesions; and progressive disease is the appearance of one or more new lesions and/or unequivocal 
progression of existing nontarget lesions. 
According to mRECIST for HCC, tumor necrosis should be taken into account when assessing 
the response of nontarget lesions. The disappearance of intratumoral arterial enhancement in 
nontarget lesions should be considered equivalent to the disappearance of nontarget lesions, and 
therefore, should declare complete response of nontarget lesions. The persistence of intratumoral 
arterial enhancement in one or more nontarget lesions should be considered equivalent to 
persistence of one or more nontarget lesions, and therefore, should declare incomplete response / 
stable disease. The appearance of one or more new lesions and/or unequivocal progression of 
existing nontarget lesions should declare progressive disease. 
Special recommendations for the assessment of tumor response in nontarget lesions in patients 
with HCC and cirrhosis can be made regarding the following points: 
1. Portal vein thrombosis. Malignant portal vein thrombosis should be considered a 
nonmeasurable lesion due to the difficulty in performing consistent measurements of the 
malignant thrombus during the course of the treatment. Measurements of the extent of the 
malignant thrombus may be impaired by the possible presence of a bland component of 
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2. Porta hepatis lymph node. Lymph nodes detected at the portal hepatis can be considered 
as malignant if the lymph node short axis is at least 20 mm. Evidence of reactive lymph 
nodes at the porta hepatis, in fact, is a common finding in patients with cirrhosis 
regardless of the presence of an HCC. The short axis of the node is the diameter normally 
used by radiologists to judge if a node is involved by solid tumor. 
3. Pleural effusion and ascites. The original RECIST publication specifies that cytologic 
confirmation of the neoplastic nature of any effusion that appears or worsens during 
treatment is required when the measurable tumor has met criteria for response or stable 
disease. Under such circumstances, the cytologic examination of the fluid collected will 
permit differentiation between response or stable disease (an effusion may be a side 
effect of the treatment) and progressive disease (if the neoplastic origin of the fluid is 
confirmed). The mRECIST for HCC panel of experts considered this issue to be of high 
importance in the setting of HCC in cirrhosis. The emergence or the increase in ascites is 
a common event during the course of treatment in a cirrhotic patient, which may be due 
to worsening of the underlying chronic liver disease and be unrelated to cancer 
progression. Other effusions, such as pleural effusion, may also be unrelated to cancer 
progression and be caused by the liver insufficiency. Thus, the mRECIST for HCC 
emphasizes that cytopathologic confirmation of the neoplastic nature of any effusion 
(particularly ascites) that appears or worsens during treatment is required when the 
measurable tumor has met criteria for response or stable disease. It has to be underlined 
that peritoneal carcinomatosis is a very rare event in HCC. 
5.2.2.3 NEW LESIONS 
Characterization of a newly detected focal liver lesion as true HCC is a challenging issue in the 
setting of cirrhosis because pathologic abnormalities related to cirrhosis changes—such as large 
regenerative nodules and dysplastic nodules—may be indistinguishable from a small tumor. 
Moreover, the clear-cut separation of the hepatic phases of liver enhancement routinely achieved 
by state-of-the-art CT or MRI creates additional problems in a cirrhotic liver, mostly related to 
the presence of perfusion abnormalities resulting in areas of abnormal liver enhancement. In 
most cases, such perfusion abnormalities are detected as arterially hyperenhancing areas caused 
by a selective impairment of the portal venous feeding. Such perfusion abnormalities may 
ultimately mimic or conceal focal liver lesions; hence, they represent an additional major source 
for interpretation errors. 
The AASLD practice guideline for the clinical management of HCC has recommended strict 
criteria for the imaging diagnosis of HCC in cirrhosis. Noninvasive diagnostic criteria of HCC 
can be made without histology in lesions of at least 1 cm in diameter showing characteristic 
vascular features of HCC—arterial hypervascularization with washout in the portal venous or the 
late phase—at dynamic imaging studies. For diagnostic purposes, two imaging techniques—CT 
and MRI—are required for such a confirmation in tumors of 1 to 2 cm in diameter, and one 
imaging technique in tumors beyond 2 cm in cirrhotic patients. 
In the assessment of tumor progression, these concepts have been adopted by the mRECIST 
assessment proposal, considering some specificities for the frame of progression mode: 


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• 
A newly detected hepatic nodule will be classified as HCC—and therefore will be 
declared as evidence of progression—when its longest diameter is at least 1 cm and the 
nodule shows the typical vascular pattern of HCC on dynamic imaging, that is, 
hypervascularization in the arterial phase with washout in the portal venous or late 
venous phase. 
• 
Liver lesions larger than 1 cm that do not show a typical vascular pattern can be 
diagnosed as HCC by evidence of at least 1-cm-interval growth in subsequent scans. 
• 
An individual radiologic event will be adjudicated in retrospect as progression at the time 
it was first detected by imaging techniques, even if strict criteria were fulfilled only on 
subsequent radiologic testing. 
5.2.2.4 Overall Response Assessment 
In mRECIST for HCC, identical to conventional RECIST, overall patient response is a result of 
the combined assessment of target lesions, nontarget lesions, and new lesions. It is important to 
point out that appearance of one or more new lesions declares progression whatever the response 
of target and nontarget lesions. Overcalling of equivocal lesions as new HCC, therefore, has a 
major impact on the outcome of studies with a radiologic endpoint, such as tumor response or 
time to progression. Hence, any newly detected focal liver lesion that does not meet the criteria 
reported above should be considered equivocal and not conclusive for disease progression. 
5.3 
TOXICITY CRITERIA 
The following adverse event management guidelines are intended to ensure the safety of each 
patient while on the study.  The descriptions and grading scales found in the revised NCI 
Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for AE 
reporting.  All appropriate treatment areas should have access to a copy of the CTCAE version 
4.0.  A copy of the CTCAE version 4.0 can be downloaded from the CTEP web site 
(http://ctep.cancer.gov).  All appropriate treatment areas should have access to a copy of the 
CTEP Active Version of CTCAE. 
5.4 
SAMPLE STORAGE, TRACKING AND DISPOSITION 
See Section 11.5 
6 
STATISTICAL CONSIDERATIONS   
The primary purpose of this study is to evaluate the ability of a combination of sorafenib and 
TRC105 to improve upon the time to progression of patients with HCC. 
The study will be conducted with both a phase I trial and then a phase II trial.   
6.1 
PHASE I PORTION 
In the phase I trial, a conventional 3+3 design was used and required a maximum of 6 patients 
per dose level.  


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As of July 24, 2014, we completed accrual to the phase I portion of this study and established a 
recommended phase II dose of TRC-105 15mg/kg every two weeks in combination with 
sorafenib 400mg bid. 
6.2 
PHASE II PORTION 
Based upon the largest reported trial of sorafenib in an identical patient population, the median 
time to progression in patients with this disease was shown to be 5.5 months.  Patients enrolled 
on this study will receive scans every 8 weeks.  Thus, the third scan would take place at 
approximately 6 months.  If the median time to progression were 5.5 months, this would be 
equivalent to having 47% without progression at 6 months.  Thus, the primary endpoint of this 
study will be the proportion of patients who are progression-free after 6 months on-study.  
The sample size and interim stopping rule will be determined using a Simon optimal two-stage 
design.  A median 5.5 month time to progression, translating into a 6 month progression free 
survival rate of 47%, would be considered not promising (p0=0.47), while a 67%  6-month PFS 
rate (corresponding to a median time to progression of 10.5 months) would be considered 
promising (p1=0.67). With alpha=0.10 and beta=0.10, 21 patients will be accrued to the study in 
the first stage.  
If 10 or fewer patients demonstrate lack of progression on imaging after 6 months (three scans) 
on-study, the accrual to the study will be terminated early and the trial declared to have a 
negative result.  A pause in the accrual may be necessary to ensure that enrollment may continue 
to the second stage.  If 11 or more patients are progression-free at 6 months, enrollment will be 
extended to accrue a total of 45 patients.  If 11-25 have not progressed by 6 months, this will be 
considered insufficient to warrant further study, while if 26 or more of 45 patients are 
progression-free after their third scan (at 6  months)  the treatment will be declared effective and 
worthy of further testing.  Under the null hypothesis (47% without progression by 6 months), the 
probability of early termination is 61%.  A Kaplan-Meier curve of progression free survival and 
of survival will also be constructed in addition to evaluating the proportions without progression 
by the third scan.  
Amendment L, version dated July 31, 2014: 
Starting with Amendment L version dated July 31, 2014, patients will be enrolled on the phase II 
portion and will be evaluated according to the language below.  
Results from previous studies suggest that an overall response rate for sorafenib alone in this 
patient population was between 2 and 8%. The primary objective of this portion of the trial is to 
establish if the combination of sorafenib and TRC105 is able to be associated with an improved 
overall response rate. This trial will be conducted using an optimal two-stage phase II trial design 
(Simon R, Controlled Clinical Trials 10:1-10, 1989) in order to rule out an unacceptably low 
PR+ CR rate of 5% (p0=0.05) in favor of an improved PR + CR rate of 25% (p1=0.25). With 
alpha=0.10 (probability of accepting a poor treatment=0.10) and beta = 0.20 (probability of 
rejecting a good treatment=0.20). The first stage will initially enroll 6 evaluable patients, and if 0 
of the 6 have a clinical response, then no further patients will be accrued. If 1 or more of the first 
6 patients has a clinical response, then accrual would continue until a total of 23 patients have 
been enrolled. As it may take several weeks to determine if a patient has experienced a response, 
a temporary pause in the accrual may be necessary to ensure that enrollment to the second stage 


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is warranted. If there are 1 to 2 clinical responses in 23 patients, this would be an uninterestingly 
low response rate. If there were 3 or more complete responses in 23 patients (13.0%), this would 
be sufficiently interesting to warrant further study in later trials. Under the null hypothesis (5% 
response rate), the probability of early termination is 73.5%. 
6.3 
ACCRUAL AND STUDY DURATION 
This trial has accrued 19 patients in phase I and no additional patients will be accrued as accrual 
for the phase I portion is complete. An additional 23 patients may be required for the phase II 
portion of the study. Thus, a total of 19+23 patients may be needed to complete the accrual for 
this study. In order to allow for the possibility of a small number of inevaluable patients, the 
accrual ceiling will be set at 44 patients. If 1-2 patients are accrued onto this trial per month, 
accrual for the phase II portion is expected to be completed within 1 to 2 years. 
7 
HUMAN SUBJECTS PROTECTIONS  
7.1 
RATIONALE FOR SUBJECT SELECTION 
Subjects treated on this study, will be individuals with advanced hepatocellular carcinoma 
(HCC), which has recurred (or persisted) after appropriate standard treatment.  Individuals of any 
race or ethnic group will be eligible for this study.  Eligibility assessment will be based solely on 
the patient’s medical status.  Recruitment of patients onto this study will be through standard 
CCR mechanisms.  No special recruitment efforts will be conducted. 
7.2 
PARTICIPATION OF CHILDREN 
Individuals under the age of 18 will not be eligible to participate in this study because they are 
unlikely to have hepatocellular carcinoma, and because of unknown toxicities in pediatric 
patient. 
7.3 
EVALUATION OF BENEFITS AND RISKS/DISCOMFORTS 
The potential benefit to a patient that goes onto study is a reduction in the bulk of their tumor 
which may or may not have favorable impact on symptoms and/or survival.  Potential risks 
include the possible occurrence of any of a range of side effects which are listed in the Consent 
Document.  The procedure for protecting against or minimizing risks will be to medically 
evaluate patients on a regular basis as described. 
7.4 
RISKS/BENEFITS ANALYSIS 
For patients with hepatocellular carcinoma cancer, median survival is in the range of 6 months. 
Potential risks include the possible occurrence of any of a range of side effects listed.  Risk of 
baseline biopsy: All care will be taken to minimize risks that may be incurred by tumor 
sampling.  However, there are procedure-related risks (such as bleeding, infection and visceral 
injury) that will be explained fully during informed consent.  If patients suffer any physical 
injury as a result of the biopsies, immediate medical treatment is available at the NIH’s Clinical 
Center in Bethesda, Maryland.  Although no compensation is available, any injury will be fully 


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evaluated and treated in keeping with the benefits or care to which patients are entitled under 
applicable regulations. 
7.5 
CONSENT PROCESS AND DOCUMENTATION 
Patients will meet with an associate or principal investigator on the trial in the GI oncology 
Clinic, during the initial evaluation for this study.  During that meeting, the investigator will 
inform patients of the purpose, alternatives, treatment plan, research objectives and follow-up of 
this trial.  The investigator will then provide a copy of the IRB-approved informed consent 
document that is included in this protocol.  The patient will be allowed to take as much time as 
he wishes, in deciding whether or not he wishes to participate.  If a prolonged period of time 
expires during the decision making process (several weeks, as an example), it may be necessary 
to reassess the patient for protocol eligibility. The original signed consent goes to Medical 
Records; copy placed in research record (NIH policy). 
All patients must have a signed informed consent form and an on-study (confirmation of 
eligibility) form filled out and signed by a participating investigator before entering on the study. 
7.5.1 Reconsent via Telephone 
The informed consent document will be sent to the subject.  An explanation of the study will be 
provided over the telephone after the subject has had the opportunity to read the consent form.  
The subject will sign and date the informed consent. A witness to the subject’s signaturewill sign 
and date the consent. 
The original informed consent document will be sent back to the consenting investigator who 
will sign and date the consent form with the date the consent was obtained via telephone.   
A fully executed copy will be returned via mail for the subject’s records. 
The informed consent process will be documented on a progress note by the consenting 
investigator and a copy of the informed consent document and note will be kept in the subject’s 
research record. 
7.5.2 Informed Consent of non-English Speaking Subjects 
If there is an unexpected enrollment of a research participant for whom there is no translated 
extant IRB approved consent document, the principal investigator and/or those authorized to 
obtain informed consent will use the Short Form Oral Consent Process as described in MAS 
Policy M77-2, OSHRP SOP 12, 45 CFR 46.117 (b) (2), and 21 CFR 50.27 (b) (2). The summary 
that will be used is the English version of the extant IRB approved consent document.  Signed 
copies of both the English version of the consent and the translated short form will be given to 
the subject or their legally authorized representative and the signed original will be filed in the 
medical record. 
Unless the PI is fluent in the prospective subject’s language, an interpreter will be present to 
facilitate the conversation (using either the long translated form or the short form). Preferably 
someone who is independent of the subject (i.e., not a family member) will assist in presenting 
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the relevant consent documents well before the consent conversation with the subject (24 to 48 
hours if possible).  
We request prospective IRB approval of the use of the short form process for non-English 
speaking subjects and will notify the IRB at the time of continuing review of the frequency of the 
use of the Short Form. 
8 
SAFETY REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING 
PLAN   
8.1 
DEFINITIONS 
8.1.1 Adverse Event 
An adverse event is defined as any reaction, side effect, or untoward event that occurs during the 
course of the clinical trial associated with the use of a drug in humans, whether or not the event 
is considered related to the treatment or clinically significant. For this study, AEs will include 
events reported by the patient, as well as clinically significant abnormal findings on physical 
examination or laboratory evaluation. A new illness, symptom, sign or clinically significant 
laboratory abnormality or worsening of a pre-existing condition or abnormality is considered an 
AE.  All AEs must be recorded on the AE case report form. 
All AEs, including clinically significant abnormal findings on laboratory evaluations, regardless 
of severity, will be followed until satisfactory resolution. Serious adverse events that occur more 
than 30 days after the last administration of investigational agent/intervention and have an 
attribution of at least possibly related to the agent/intervention should be recorded and reported 
as per sections 8.2 and 8.3.  
An abnormal laboratory value will be considered an AE if the laboratory abnormality is 
characterized by any of the following: 
• Results in discontinuation from the study 
• Is associated with clinical signs or symptoms  
• Requires treatment or any other therapeutic intervention 
• Is associated with death or another serious adverse event, including hospitalization.  
• Is judged by the Investigator to be of significant clinical impact 
• If any abnormal laboratory result is considered clinically significant, the investigator 
will provide details about the action taken with respect to the test drug and about the 
patient’s outcome. 
8.1.2 Suspected adverse reaction 
Suspected adverse reaction means any adverse event for which there is a reasonable possibility 
that the drug caused the adverse event. For the purposes of IND safety reporting, ‘reasonable 
possibility’ means there is evidence to suggest a causal relationship between the drug and the 
adverse event. A suspected adverse reaction implies a lesser degree of certainty about causality 
than adverse reaction, which means any adverse event caused by a drug. 


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8.1.3 Unexpected adverse reaction 
An adverse event or suspected adverse reaction is considered “unexpected” if it is not listed in 
the investigator brochure or is not listed at the specificity or severity that has been observed; or, 
if an investigator brochure is not required or available, is not consistent with the risk information 
described in the general investigational plan or elsewhere in the current application. 
"Unexpected”, also refers to adverse events or suspected adverse reactions that are mentioned in 
the investigator brochure as occurring with a class of drugs or as anticipated from the 
pharmacological properties of the drug, but are not specifically mentioned as occurring with the 
particular drug under investigation. 
8.1.4 Serious 
An Unanticipated Problem or Protocol Deviation is serious if it meets the definition of a Serious 
Adverse Event or if it compromises the safety, welfare or rights of subjects or others. 
8.1.4.1 Serious Adverse Event 
An adverse event or suspected adverse reaction is considered serious if in the view of the 
investigator or the sponsor, it results in any of the following: 
• 
Death, 
• 
A life-threatening adverse drug experience 
• 
Inpatient hospitalization or prolongation of existing hospitalization 
• 
Persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions  
• 
A congenital anomaly/birth defect. 
• 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. 
8.1.5 Disability 
A substantial disruption of a person’s ability to conduct normal life functions. 
8.1.6 Life-threatening adverse drug experience 
Any adverse event or suspected adverse reaction that places the patient or subject, in the view of 
the investigator or sponsor, at immediate risk of death from the reaction as it occurred, i.e., it 
does not include a reaction that had it occurred in a more severe form, might have caused death. 
8.1.7 Protocol Deviation (NIH Definition) 
Any change, divergence, or departure from the IRB approved research protocol. 


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8.1.8 Non-Compliance (NIH Definition) 
The failure to comply with applicable NIH Human Research Protections Program (HRPP) 
policies, IRB requirements, or regulatory requirements for the protection of human research 
subjects.  
8.1.9 Unanticipated Problem 
Any incident, experience, or outcome that: 
•  Is unexpected in terms of nature, severity, or frequency in relation to  
(a) the research risks that are described in the IRB-approved research protocol and 
informed consent document; Investigator’s Brochure or other study documents, and 
(b) the characteristics of the subject population being studied; AND 
• Is related or possibly related to participation in the research; AND 
• Suggests that the research places subjects or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized. 
8.2 
NCI-IRB REPORTING 
8.2.1 NCI-IRB Expedited Reporting of Unanticipated Problems and Deaths 
The Protocol PI will report to the NCI-IRB: 
• All deaths, except deaths due to progressive disease  
• All Protocol Deviations 
• All Unanticipated Problems 
• All non-compliance 
Reports must be received by the NCI-IRB within 7 working days of PI awareness via iRIS. 
8.2.2 NCI-IRB Requirements for PI Reporting at Continuing Review 
The protocol PI will report to the NCI-IRB:  
1. A summary of all protocol deviations in a tabular format to include the date the deviation 
occurred, a brief description of the deviation and any corrective action. 
2. A summary of any instances of non-compliance 
3. A tabular summary of the following adverse events: 
• All Grade 2 unexpected events that are possibly, probably or definitely related to the 
research;  
• All Grade 3 and 4 events that are possibly, probably or definitely related to the research;  
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• All Serious Events regardless of attribution.  
NOTE: Grade 1 events are not required to be reported.  
8.2.3 NCI-IRB Reporting of IND Safety Reports 
Only IND Safety Reports that meet the definition of an unanticipated problem will need to be 
reported to the NCI IRB. 
8.3 
IND SPONSOR REPORTING CRITERIA 
An investigator must immediately report to the sponsor, using the mandatory MedWatch form 
3500a, any serious adverse event, whether or not considered drug related, including those listed 
in the protocol or investigator brochure and must include an assessment of whether there is a 
reasonable possibility that the drug caused the event.  
Study endpoints that are serious adverse events (e.g. all-cause mortality) must be reported in 
accordance with the protocol unless there is evidence suggesting a causal relationship between 
the drug and the event (e.g. death from anaphylaxis).  In that case, the investigator must 
immediately report the death to the sponsor. 
Events will be submitted to Dr. William Dahut, authorized representative for the IND Sponsor 
(CCR) at: 
William Dahut, M.D. 
Bldg 10, Room 3-2571 MSC 1206 
10 Center Drive 
Bethesda, MD 20892 
Telephone: 301-496-4251 
William.Dahut@nih.gov 
Copy all MedWatch forms to: nciprotocolsupportoffice@mail.nih.gov 
8.4 
FDA REPORTING CRITERIA 
8.4.1 IND Safety Reports to the FDA (Refer to 21 CRF 312.32) 
8.4.1.1 Expedited reporting to the FDA 
The Sponsor will notify the FDA of any unexpected fatal or life-threatening suspected adverse 
reactions as soon as possible but no later than 7 calendar days of initial receipt of the 
information.  
The Sponsor is also responsible for reporting any:  
• suspected adverse reaction that is both serious and unexpected  
• any findings from clinical, epidemiological, or pooled analysis of multiple studies or any 
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• clinically important increase in the rate of a serious suspected adverse reaction over that 
listed in the protocol or investigator brochure  
to the FDA and to all investigators no later than 15 calendar days after determining that the 
information qualifies for reporting using the MedWatch Form 3500a. If FDA requests any 
additional data or information, the sponsor must submit it to the FDA as soon as possible, but no 
later than 15 calendars days after receiving the request.FDA Annual Reports (Refer to 21 CRF 
312.32) 
8.4.2 FDA Annual Reports (Refer to 21 CFR 312.33)  
The study Sponsor will submit a brief report annually of the progress of the trial within 60 days 
of the anniversary date that the IND went into effect as indicated in 21CFR 312.33 and any 
associated FDA correspondences regarding the IND annual report.  
8.4.3 Expedited Adverse Event Reporting Criteria to the IND Manufacturer (Tracon 
Pharmaceuticals, Inc.) 
The initial telephone/facsimile report should contain as much information as is available 
concerning the event in order to permit Tracon Pharmaceuticals, Inc. to file a report, which 
satisfies regulatory requirements.  Initial telephone report of SAE must be followed-up by a 
completed SAE report (Medwatch form 3500a signed by the investigator) faxed to the Medical 
Monitor at Tracon Pharmaceuticals, Inc. or designee.  The event should also be entered into the 
source documents and case report forms, as appropriate.  
If only limited information is initially available, follow-up reports will be required. A completed 
SAE form report should follow the initial phone call or incomplete fax report within 5 working 
days for all SAEs.  
When additional information is available, a follow-up SAE report form should be faxed to the 
Medical Monitor at Tracon Pharmaceuticals, Inc. or designee.  
Any adverse events that are initially ‘non-serious’ but become ‘serious’ shall be reportable 
according to the time of the most recent classification. 
One serious adverse event report (SAER) form will be completed per serious adverse event 
(SAE).  The SAE term should match with the term captured on the AE page of the CRF.  In 
order to avoid vague, ambiguous, or colloquial expressions, the AE term should be recorded in 
standard medical terminology. 
For all serious adverse events, the Principal Investigator or an Associate Investigator will be 
responsible for completing the SAE Report Form and will fax the SAE Form within 24 hours of 
their knowledge of the event to the Medical Monitor at Tracon Pharmaceuticals, Inc: 
Charles Theuer, MD, PhD 
Tracon Pharmaceuticals, Inc.  
8910 University Center Lane, Suite 700 
San Diego, CA 92122 
Direct Phone:  (858) 550-0780 x233 
Cell Phone:  (858) 344-9400                                    


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                        Facsimile:  (858) 550-0786 
8.5 
RECORDING OF ADVERSE EVENTS  
Adverse events will be assessed from the time the patient receives the first dose of TRC105 
through completion of the final end-of-treatment assessment.  All new events, as well as those 
that worsen in intensity or frequency relative to baseline, must be captured.  All adverse events 
will be recorded on case report forms.  The Investigator or his staff should elicit information 
regarding the occurrence of adverse events through information volunteered by the patient, open-
ended questioning of the patient, physical examination results and review of laboratory results.  
Information to be recorded for each adverse event includes: 
•  CTC AE Term 
• The date and time of onset of the event  
• The date and time of resolution of the event  
• Assessments of severity, causal relationship to study drug, and seriousness of the 
adverse event. 
• Action(s) taken (if any) for management of the adverse event, including but not 
limited to change in the study drug administration (e.g., temporary interruption in 
dosing, dose reduction); drug treatment; non-drug treatment; diagnostic procedures 
performed  
• Outcome of the adverse event:  patient recovered without sequelae; patient recovered 
with sequelae; event ongoing; patient died  
If a laboratory abnormality is one component of a diagnosis or syndrome, then only the diagnosis 
or syndrome should be records on the AE page of the CRF. If the abnormality was not a part of a 
diagnosis or syndrome, then the abnormality should be recorded as the AE. 
For causality assessment, the Investigator must assess whether the event was related to the study 
medications, concurrent drug therapy, underlying cancer, concurrent illness, a combination of 
these factors, or if it is unknown.   
Adverse events characterized as intermittent require documentation of onset and duration of each 
episode. 
Events resulting from concurrent illnesses, reactions to concurrent illnesses, reactions to 
concurrent medications, or progression of disease states must be reported as adverse events.  
Any medical condition that is present at the time that the patient is screened but does not 
deteriorate should not be reported as an adverse event.  However, if it deteriorates at any time 
during the study, it should be recorded as an adverse event.  
All adverse events will be followed to adequate resolution/stabilization. An adverse event will be 
considered to have resolved if either of the following events has occurred: 
• The principal investigator has documented that all abnormal symptoms, physical 
signs, and laboratory abnormalities associated with the adverse event have returned to 
normal (normal is defined as the baseline conditions for that individual established at 
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• In cases where resolution/stabilization is not obvious, the Investigator should obtain 
written confirmation from the sponsor that the event can be considered resolved and 
that further follow-up is unnecessary.  
8.5.1 Reported Adverse Events Related to TRC105 
See Section 1.2.3.5 
8.6 
DATA AND SAFETY MONITORING PLAN 
8.6.1 Principal Investigator/Research Team 
A formal DSMB will not be required for this study; the principal investigator, research nurse, 
and research team will monitor the study for AEs on an ongoing basis for determining DLTs and 
MTD.  All data will be collected in a timely manner and reviewed by the principal investigator or 
an associate investigator for adverse events.  In addition, stopping rules are in place for ensuring 
safe conduct of the trial.  The principal investigator will personally conduct or supervise the 
investigation and provide appropriate delegation of responsibilities to other members of the 
research staff.  
8.6.2 Sponsor Monitoring Plan 
This trial will be monitored by personnel employed by Harris Technical Services on contract to 
the NCI, NIH, who are qualified by training and experience to monitor the progress of clinical 
trials. Personnel monitoring this study will not be affiliated in any way with the trial conduct.  
At least 25% of enrolled patients’ records will be randomly selected and monitored biannually or 
as needed, based on accrual rate.  The patients selected will have 100% source document 
verification done. Additional monitoring activities will include: adherence to protocol specified 
study eligibility, treatment plans, data collection for safety and efficacy, reporting and time 
frames of adverse events to the NCI IRB and FDA, and informed consent requirements. Written 
reports will be generated in response to the monitoring activities and submitted to the Principal 
Investigator and Clinical Director or Deputy Clinical Director, CCR, NCI.  
9 
PHARMACEUTICAL INFORMATION   
9.1 
TRC105 (NSC #754227) 
TRC105 is an IgG1, kappa immunoglobulin containing murine light- and heavy-chain variable 
region sequences and human constant region sequences.  TRC105 has an approximate molecular 
weight of 148 kDa.  
9.1.1 TRC105 Packaging and Labeling 
TRC105 may be provided in one or more of the following presentations. 
 
Phosphate Buffered Saline Formulation (7 mg TRC105/mL) 
 
210 mg TRC105/30 mL single-use vial 


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20 mM L-Histidine/L-Histidine Monohydrochloride, 240 mM Trehalose, 0.01% 
Polysorbate 20 Formulation (25 mg TRC105/mL) 
100 mg TRC105/4mL single-use vial 
400 mg TRC105/16 mL single-use vial  
Vials of TRC105 are labeled with one of the following:  
TRC105 
NSC# 754227 
210 mg per vial (7 mg/mL, 30 mL vial) 
Store refrigerated at 2-8˚C. 
For Intravenous Use Only.     Single-use vial. 
Lot:  XXXXXXX     Mfg Date: XX/XX/XXXX 
Caution: New Drug Limited by 
Federal (or United States) law to investigational use. 
TRACON Pharmaceuticals Inc., San Diego, CA 92122 USA 
 
TRC105 
NSC# 754227 
100 mg per vial (25 mg/mL, 4 mL vial) 
Store refrigerated at 2-8°C. 
For Intravenous Use Only. Single-use vial. 
Lot:  XXXXXXX 
Mfg Date:  XX/XX/XXXX 
Caution:  New Drug Limited by 
Federal (or United States) law to investigational use. 
TRACON Pharmaceuticals Inc., San Diego, CA 92122 USA 
 
TRC105 
NSC# 754227 
400 mg per vial (25 mg/mL, 16 mL vial) 
Store refrigerated at 2-8°C. 
For Intravenous Use Only. Single-use vial. 
Lot:  XXXXXXX 
Mfg Date:  XX/XX/XXXX 
Caution:  New Drug Limited by 
Federal (or United States) law to investigational use. 
TRACON Pharmaceuticals Inc., San Diego, CA 92122 USA 
 
 For information regarding current formulation, please refer to Section 1.2.3.6, TRC105 Physical, 
Chemical, and Pharmaceutical Properties and Formulations. 
9.1.2 TRC105 Storage and Shipping 
TRC105 must be stored upright between 2 °C and 8 °C (36 °F to 46 °F). 


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9.1.3 TRC105 Preparation 
TRC105 will be prepared in the pharmacy and diluted into normal saline using appropriate 
aseptic technique.  TRC105 will be administered using an in-line 0.2 micron filter.  No 
incompatibilities between TRC105 and polyvinyl chloride or polyolefin bags have been 
observed.  Multiple vials will be required for a single dose.  The following formulae should be 
used to calculate the volume of TRC105 to be added to normal saline: 
• 
Patient weight (kg) × dose level (mg/kg) divided by TRC105 concentration (mg/mL) 
= volume of TRC105 (mL) to be administered. 
The volume of TRC105 that is to be administered can be rounded up or down to the nearest 1.0 
mL; in the case of an increment of 0.5 mL the volume should be rounded up.  The maximum 
weight that should be used for dose calculation in this study is 85 kg for women and 100 kg for 
men (note: there is not a weight restriction for enrollment purposes).  If the patient’s weight 
changes by > 10% during the study, the dose of TRC105 will be recalculated.  At that time a new 
baseline weight will be established such that subsequent weight changes by >10% from the new 
baseline weight would require further recalculation of the TRC105 dose. The calculated volume 
of TRC105 will be diluted with normal saline.  Appropriate judgment should be exercised in 
withdrawing an adequate amount of saline necessary to permit injection of the appropriate 
volume of antibody into a normal saline bag in accordance with the dose needed.  The final 
TRC105 concentration must be between 0.3 mg/mL and 10 mg/mL.  The prepared TRC105 must 
be gently inverted several times in order to ensure a homogeneous solution. The diluted infusion 
solution of TRC105 should be used within 8 hours of preparation if stored at room temperature, 
or within 24 hours of dilution if stored at 2° to 8°C (36º to 46ºF). The expiration time should be 
labeled on the bag.  If the diluted infusion solution of TRC105 cannot be infused within 8 hours 
of preparation (i.e.: the prepared infusion is at room temperature for more than 8 hours), a second 
bag will be prepared that contains the balance of the planned dose that was not already delivered. 
The prepared solution should not be frozen. 
9.1.4 TRC105 Handling and Disposal 
The Investigator should not return clinical study materials to TRACON unless specifically 
instructed to do so by TRACON.  All used or expired vials of TRC105 should be retained.  A 
TRACON representative will periodically conduct an accountability of the used or expired vials 
and authorize their destruction. 
If the participating pharmacy is prohibited by institutional policy from retaining open or expired 
vials, the Site Pharmacist will then be responsible for documenting the destruction of the vials 
and completing an Investigational Drug Product Destruction Form. 
9.1.5 Adverse Events and potential safety risks based on ongoing and completed studies of 
TRC105 
Grade 3 anemia has occurred with TRC105 therapy at the recommended phase 2 dose of 10 
mg/kg weekly.  All patients treated with TRC105 should be monitored closely for anemia and 
treated appropriately, including the possibility of TRC105 dose reductions.  Anemia may be 
caused by correctable mineral or vitamin deficiency. The anemia related to TRC105 is 


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hypoproductive in nature and is reversible with interruption of treatment, transfusion, 
erythropoietin, and other interventions as appropriate. 
Gastrointestinal hemorrhage has occurred with TRC105 therapy.  Patients with active ulcer 
disease or risk factors for ulcer disease are excluded from this study.    
Grade 1 and 2 cutaneous telangiectasia related to TRC105 occur early in the course of therapy 
and have been the source of gingival bleeding and epistaxis.  Telangiectasia are also seen in 
patients with hereditary hemorrhagic telangiectasia (HHT), a disease of CD105 haplotype 
insufficiency.  Patients with HHT are at risk of hemorrhage from abnormal blood vessels and this 
could be exacerbated by treatment with TRC105.  Other contraindications to TRC105 therapy 
include a history of significant hemorrhage or tumors located in the central chest or another 
location where bleeding is associated with high morbidity.  All patients treated with TRC105 
should be monitored for signs of hemorrhage and the risks and benefits of drug treatment 
reevaluated in any patient with hemorrhage. 
Premedication including the use of glucocorticoids is required prior to infusion of TRC105 to 
reduce the frequency and severity of infusion reactions.  Infusion reactions following TRC105 
dosing generally occur with the first TRC105 dose and include a grade 4 vasovagal reaction that 
resolved without sequelae.  Signs and symptoms of TRC105 infusion reactions include 
hypertension, hypotension, dyspnea, bronchospasm, chills/rigors, chills, sweats, fever, nausea, 
tachycardia, bradycardia, EKG changes, flushing, urticaria, pruritus, and headache, generally of 
grade 1 and 2 severity. Potential infusion reactions seen with other therapeutic antibodies include 
angioedema, asthenia, throat irritation, rhinitis, vomiting, joint pain, fatigue and neurologic 
disorders including inflammation of the spine and/or brain.  
Hypersensitivity reactions with infusions are a potential risk for sensitized patients, and TRC105 
should be used with caution in patients with known hypersensitivity to any component of the 
drug product.  Host anti-TRC105 antibodies to the murine or human portions of CHO-produced 
TRC105 are rare.  In general, the risk of immunogenicity to therapeutic chimeric antibodies is 
small (<10%) and the clinical significance of immunogenicity is not well defined.  The current 
trial will collect serial blood samples for anti-product antibody concentrations to further 
characterize the immunogenicity of TRC105 and potential clinical implications. 
Grade 3 cerebrovascular hemorrhage resulting in hemiparesis occurred in one patient with 
hepatocellular cancer who was thrombocytopenic (who entered the study with a platelet count of 
60,000/uL) in a study of TRC105 with sorafenib.  Patients must have a platelet count of > 
100,000/uL to enter this study (see inclusion criteria).  Transient Grade 3 hepatic encephalopathy 
occurred in one patient with cirrhosis and hepatocellular carcinoma who received TRC105 in 
combination with sorafenib.   Additionally, Grade 5 intracranial hemorrhage occurred in one 
glioblastoma patient with markedly abnormal blood clotting parameters in a study of TRC105 
with bevacizumab. A patient with glioblastoma developed temporary confusion and slurred 
speech following treatment with TRC105 and bevacizumab that required hospitalization for 
observation. Another patient with glioblastoma, who underwent resection and had a history of an 
abnormal collection of cerebral spinal fluid, developed a grade 2 cerebral spinal fluid leak. 
Grade 3 myocardial infarction (non-Q wave infarct associated with hypertension following an 
infusion reaction) was observed in a patient with hepatocellular cancer following treatment with 


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TRC105 that resolved without sequelae.  In addition, a Grade 5 myocardial infarction occurred in 
a patient with coronary artery disease who received TRC105 in combination with sorafenib. 
Patients with evidence of active coronary artery disease are excluded from participation in this 
trial (see exclusion criteria).   
Adult respiratory distress syndrome that required temporary intubation occurred in one patient 
who received TRC105 with pazopanib, from which the patient recovered. Of note, interstitial 
lung disease has been added as an adverse drug reaction and warning/precaution to the core 
safety information for pazopanib. 
Infections have been observed rarely. Grade 3 infected lipoma/cyst was observed in a Phase 2 
study of TRC105 as a single agent in patients with metastatic bladder cancer. Grade 3 orbital 
cellulitis and grade 3 brain abscess were observed in patients treated with TRC105 and 
bevacizumab and considered possibly related to TRC105.  Grade 1 and 2 gingivitis including 
infection and ulceration has also been observed.  Overall, infections have been observed in fewer 
than 5% of patients and have largely been considered unrelated to treatment with TRC105. 
Grade 1-3 headaches have been observed following TRC105 treatment, generally within hours 
following completion of the initial infusion.  Headaches are throbbing in nature, are not 
associated with radiographic abnormalities, and have responded to treatment with non-steroidal 
anti-inflammatory agents and to triptans. Headaches were particularly common when TRC105 
and bevacizumab were initially dosed on the same day and were ameliorated when TRC105 was 
dosed one week following bevacizumab dosing and given over two days during the initial week 
of dosing. 
Nasal congestion and periorbital edema have been observed with TRC105 dosing, particularly 
when dosed in combination with bevacizumab.  The edema has been transient in nature and 
treated with corticosteroids.  
9.1.6 Fatigue of grade 1- 3 severity has been reported following dosing with TRC105. 
Maculopapular rash and skin flushing of grade 1 and grade 2 severity have also been 
reported.  A patient receiving treatment with TRC105 and sorafenib developed self-
limited pancreatitis of grade 2 severity.TRC105 Drug Accountability 
The Investigator must maintain an accurate accounting of TRC105 supplied by TRACON.  
During the study, the following information must be recorded: 
• Date of receipt, quantity and identification of the study drug received from TRACON 
• ID number of the patient to whom the product is dispensed 
• The date(s) and quantity of the product dispensed 
• Dates and quantity of product returned, lost or accidentally or deliberately destroyed 
Investigational Drug Accountability Logs should be maintained by the site and must be readily 
available for inspection. 
9.1.7 Agent Ordering  
TRC105 will be supplied by Tracon Pharmaceuticals.  


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9.2 
SORAFENIB (NEXAVAR ®; BAY 43-9006; NSC 724772) 
9.2.1 Product Description 
Chemical Name: 4–{4-[3-(4-chloro-3-trifluoromethyl-phenyl) ureido]-phenoxy}-pyridine-
2carboxylic acid methylamide-4-methylbenzensulfonate. 
Other Names: BAY 54-9085 is the tosylate salt of BAY 43-9006; Nexavar®. 
Classification: Kinase inhibitor (Raf, VEGF-R, and PDGF-R) 
Mechanism of Action: The ras/raf signaling pathway is an important mediator of responses to 
growth signals and angiogenic factors. This pathway is often aberrantly activated in human tumors 
due to presence of activated ras, mutant b-raf, or over expression of growth factor receptors.  
BAY 43-9006 is a potent inhibitor of c-raf, and wild-type and mutant b-raf in vitro. Additionally, 
further characterization of BAY 43-9006 tosylate revealed that this agent inhibits several receptor 
tyrosine kinases (RTKs) that are involved in tumor progression (VEGF-R, PDGF-R, Flt3, and c-
KIT) and p38α, a member of the MAPK family. 
Molecular Formula: C12H16CIF3N4O3 X C7H8O3S 
 
M.W.: BAY 43-9006 tosylate: 637 Daltons; BAY 43-9006 (free base): 465 Daltons  
Approximate Solubility: 0.19 mg/100 mL in 0.1 N HCl, 453 mg/100 mL in Ethanol, and 2971 
mg/100 mL in PEG 400.  
9.2.2 Storage Requirements 
Store at controlled room temperature (15ºC – 25ºC).  Storage conditions should not exceed 25ºC. 
9.2.3 Stability  
Stability studies with the 200 mg dosage form are ongoing. The current shelf life is 24 months when 
stored at controlled room temperature.  
9.2.4 Administration 
Oral sorafenib tosylate should be taken with at least 250 mL of water and can be given without 
regards to meals.  Food does not appear to have a clear effect on sorafenib tosylate 
pharmacokinetics. 
Sorafenib tosylate is supplied as an immediate-release film-coated, round, and salmon color tablet 
containing 200 mg of the free base, BAY 43-9006, and the excipients croscarmellose sodium, 
microcrystalline cellulose, hydroxypropylmethylcellulose, sodium lauryl sulfate, and magnesium 
stearate.  The film-coat consists of hydroxypropylmethyl cellulose, polyethylene glycol, titanium 
dioxide and red iron oxide.  The film coating has no effect on the rate of release of the active 
sorafenib tosylate.  
Sorafenib tosylate 200 mg tablets are supplied in bottles of 140 tablets. 
9.2.5 Reported Adverse Events and Potential Risks:   
Comprehensive Adverse Events and Potential Risks list (CAEPR) for Sorafenib (BAY 43-9006, NSC 724772) 


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 Adverse Events with Possible  
 Relationship to Sorafenib (BAY 43-9006) 
 (CTCAE 4.0 Term) 
[n= 2157] 
 
 
 
 EXPECTED AEs FOR ADEERS 
REPORTING  
Agent Specific Adverse Event 
List 
(ASAEL) 
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
Expected 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
 
Anemia 
 
 Anemia 
 
Febrile neutropenia 
 
  
CARDIAC DISORDERS 
  
 
 
Acute coronary syndrome 
  
 
 
Left ventricular systolic 
dysfunction 
  
 
 
Myocardial infarction 
  
GASTROINTESTINAL DISORDERS 
  
Abdominal pain 
 
 
 Abdominal pain 
 
Anal mucositis 
 
  
 
Ascites 
 
  
 
Constipation 
 
 Constipation 
Diarrhea 
 
 
 Diarrhea 
 
Gastrointestinal hemorrhage2  
 Gastrointestinal hemorrhage2 
 
 
Gastrointestinal perforation3 
  
 
Mucositis oral 
 
  
Nausea 
 
 
 Nausea 
 
Rectal mucositis 
 
  
 
Small intestinal mucositis 
 
  
 
Vomiting 
 
 Vomiting 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
 
Edema limbs 
 
  
Fatigue 
 
 
 Fatigue 
 
Fever 
 
 Fever 
 
Non-cardiac chest pain 
 
  
IMMUNE SYSTEM DISORDERS 
  
 
 
Anaphylaxis 
  
INFECTIONS AND INFESTATIONS 
  
 
Infection4 
 
 
 
  
INVESTIGATIONS 
  
 
Activated partial 
thromboplastin time 
prolonged 
 
 Activated partial 
thromboplastin time prolonged 
Alanine aminotransferase 
increased 
 
 
 Alanine aminotransferase 
increased 
Alkaline phosphatase 
increased 
 
 
 Alkaline phosphatase 
increased 
Aspartate aminotransferase 
increased 
 
 
 Aspartate aminotransferase 
increased 
Blood bilirubin increased 
 
 
 Blood bilirubin increased 
 
Cholesterol high 
 
  
Creatinine increased 
 
 
 Creatinine increased 
 
GGT increased 
 
  


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INR increased 
 
 
 INR increased 
 
Investigations - Other 
(bicarbonate, serum-low) 
 
  
Lipase increased 
 
 
 Lipase increased 
Lymphocyte count decreased  
 
 Lymphocyte count decreased 
 
Neutrophil count decreased 
 
 Neutrophil count decreased 
Platelet count decreased 
 
 
 Platelet count decreased 
Serum amylase increased 
 
 
 Serum amylase increased 
Weight loss 
 
 
 Weight loss 
White blood cell decreased 
 
 
 White blood cell decreased 
METABOLISM AND NUTRITION DISORDERS 
  
Anorexia 
 
 
 Anorexia 
 
Hypercalcemia 
 
  
Hyperglycemia 
 
 
 Hyperglycemia 
 
Hyperkalemia 
 
 Hyperkalemia 
 
Hypernatremia 
 
  
 
Hyperuricemia 
 
  
Hypoalbuminemia 
 
 
 Hypoalbuminemia 
Hypocalcemia 
 
 
 Hypocalcemia 
 
Hypoglycemia 
 
 Hypoglycemia 
 
Hypokalemia 
 
 Hypokalemia 
Hyponatremia 
 
 
 Hyponatremia 
Hypophosphatemia 
 
 
 Hypophosphatemia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthralgia 
 
 Arthralgia 
 
Back pain 
 
 Back pain 
 
Bone pain 
 
  
 
Musculoskeletal and 
connective tissue disorder -  
Other (muscle spasms) 
 
  
 
Myalgia 
 
  
 
Pain in extremity 
 
 Pain in extremity 
NERVOUS SYSTEM DISORDERS 
  
 
Dizziness 
 
  
 
Headache 
 
 Headache 
 
 
Intracranial hemorrhage 
  
 
Peripheral sensory 
neuropathy 
 
  
 
 
 
 
Reversible posterior 
leukoencephalopathy 
syndrome 
  
PSYCHIATRIC DISORDERS 
  
 
Insomnia 
 
  
RENAL AND URINARY DISORDERS 
  
 
Acute kidney injury 
 
  
 
Hematuria 
 
  
 
Renal hemorrhage 
 
  
REPRODUCTIVE SYSTEM AND BREAST DISORDERS 
  
 
Hematosalpinx 
 
  
 
Ovarian hemorrhage 
 
  
 
Prostatic hemorrhage 
 
  
 
Spermatic cord hemorrhage  
  
 
Testicular hemorrhage 
 
  


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Uterine hemorrhage 
 
  
 
Vaginal hemorrhage 
 
  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Bronchopulmonary 
hemorrhage 
 
  
 
Cough 
 
 Cough 
 
Dyspnea 
 
 Dyspnea 
 
Epistaxis 
 
  
 
Laryngeal mucositis 
 
  
 
Pharyngeal mucositis 
 
  
 
Tracheal mucositis 
 
  
 
Voice alteration 
 
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
Alopecia 
 
 
 Alopecia 
 
Dry skin 
 
 Dry skin 
 
 
Erythema multiforme 
  
Palmar-plantar 
erythrodysesthesia syndrome 
 
 
 Palmar-plantar 
erythrodysesthesia syndrome 
 
Pruritus 
 
 Pruritus 
Rash maculo-papular 
 
 
 Rash maculo-papular 
 
 
Stevens-Johnson syndrome   
VASCULAR DISORDERS 
  
 
Hypertension 
 
 Hypertension 
 
Thromboembolic event 
 
  
 
1This table will be updated as the toxicity profile of the agent is revised.   
2Gastrointestinal hemorrhage includes Anal hemorrhage, Cecal hemorrhage, Colonic hemorrhage, Duodenal hemorrhage, 
Esophageal hemorrhage, Esophageal varices hemorrhage, Gastric hemorrhage, Hemorrhoidal hemorrhage, Ileal hemorrhage, 
Intra-abdominal hemorrhage, Jejunal hemorrhage, Lower gastrointestinal hemorrhage, Oral hemorrhage, Pancreatic hemorrhage, 
Rectal hemorrhage, Retroperitoneal hemorrhage, and Upper gastrointestinal hemorrhage under the GASTROINTESTINAL 
DISORDERS SOC. 
 
3Gastrointestinal perforation includes Colonic perforation, Duodenal perforation, Esophageal perforation, Gastric perforation, 
Ileal perforation, Jejunal perforation, Rectal perforation, and Small intestinal perforation under the GASTROINTESTINAL 
DISORDERS SOC. 
 
4Includes all 75 infection sites under the INFECTIONS AND INFESTATIONS SOC. 
Also reported on sorafenib (BAY 43-9006) trials but with the relationship to sorafenib (BAY 43-9006) still undetermined: 
 
CARDIAC DISORDERS - Atrial fibrillation; Atrial flutter; Chest pain - cardiac; Sinus bradycardia; Sinus tachycardia; 
Supraventricular tachycardia 
EAR AND LABYRINTH DISORDERS - Tinnitus 
ENDOCRINE DISORDERS - Hyperthyroidism; Hypothyroidism 
EYE DISORDERS - Blurred vision; Cataract; Extraocular muscle paresis  
GASTROINTESTINAL DISORDERS - Abdominal distension; Dyspepsia; Dysphagia; Flatulence; Ileus; Pancreatitis; Rectal 
fistula; Small intestinal obstruction 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills; Edema face; Flu like symptoms; Pain 
IMMUNE SYSTEM DISORDERS - Allergic reaction 
INVESTIGATIONS - Fibrinogen decreased 
METABOLISM AND NUTRITION DISORDERS - Dehydration; Hypermagnesemia; Hypertriglyceridemia; 
Hypomagnesemia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthritis; Generalized muscle weakness 
NERVOUS SYSTEM DISORDERS - Dysgeusia; Encephalopathy; Ischemia cerebrovascular; Memory impairment; Syncope 
PSYCHIATRIC DISORDERS - Confusion; Depression 
RENAL AND URINARY DISORDERS - Proteinuria 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Erectile dysfunction 


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RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Hypoxia; Pleural effusion; Pneumonitis; 
Pneumothorax 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Hyperhidrosis; Purpura; Rash acneiform; Skin and subcutaneous 
tissue disorders - Other (non-life threatening squamous cell carcinoma of skin:  keratoacanthoma type); Skin hypopigmentation 
VASCULAR DISORDERS - Flushing; Hypotension; Vasculitis 
 
Note: Sorafenib (BAY 43-9006) in combination with other agents could cause an exacerbation of any adverse event currently 
known to be caused by the other agent, or the combination may result in events never previously associated with either agent. 
 
Body as a whole:  
Fatigue, flu-like syndromes, fever, arthralgia 
Gastrointestinal:  
Diarrhea, pancreatitis, elevated amylase/lipase, 
abdominal pain/cramping, nausea, flatulence, 
dyspepsia 
Hepatic: 
Increased bilirubin, ALT, AST, GGT, LDH, and 
alkaline phosphatase 
Metabolic and Nutritional:  
Anorexia 
Skin:  
Hand-foot syndrome, characterized by palmar and 
plantar erythema; rash/desquamation, 
hypersensitivity reactions, dry skin, alopecia, nail 
changes, vitiligo 
Cardiovascular: 
Hypertension. 
The following adverse events have been reported on trials but the relationship to 
Sorafenib still undetermined: Arthritis, brain stem stroke, dyspnea, increase PT/PTT, 
and weight loss. 
9.2.6 Drug interactions 
Sorafenib is metabolized by the P450 CYP3A enzyme and has been shown in preclinical studies to 
inhibit multiple CYP isoforms.  Therefore, it is possible that BAY43-9006 tosylate may interact 
with drugs that are metabolized by the P450 CYP isoenzymes or with drugs that inhibit CYP 3A.  
Close monitoring is recommended for patients taking agents with narrow therapeutic indices and 
metabolized by the liver, such as warfarin, quinidine and digoxin.  Additionally, Sorafenib is 97% 
to 99% protein bound; however, no drug interactions have been reported in studies, thus far. 
9.2.7 Availability 
Sorafenib is FDA approved for the indication used in this study, and will be purchased by the 
Clinical Center Pharmacy from commercial sources. 
9.2.8 Agent Accountability 
Sorafenib, an oral self-administered investigational agent, will be accounted for, handled, and 
disposed of in accordance with CCR Policy # Clin-1, “Policy on Documenting, Handling and 


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Disposing of Oral Investigational Agents that are Self-Administered by NCI CCR patients.”  The 
Standard Operating Procedure # Clin-1, “Standard Operating Procedure for Conducting and 
Documenting Drug Accountability for Oral Investigational Agents that are Self-Administered by 
Patients at the CCR” identifies activities associated with drug accountability and compliance 
monitoring for orally self-administered investigational agents.  Study drug will be dispensed in 
bottles of 140 tablets.  Each patient will be instructed to document in a study diary the daily 
intake of sorafenib, including the time the dose is taken and whether or not any doses are missed, 
and to date and sign the entry. They will bring the study diary and any unused drug to their next 
scheduled clinic appointment. Clinic staff will (1) collect all “old” [i.e., empty bottle(s), partial 
bottle(s) or full bottle(s)] of study drug; (2) perform a capsule count and record the results on the 
approved CCR Pill Count Case Report Form which is to be maintained in the research record; 
and (3) dispense the new partial and full bottle(s) of sorafenib to the patient.  Unused study drugs 
are to be returned to the research nurse who will dispose of them according to the SOP. 


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11 APPENDICES 
11.1 APPENDIX 1:  PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, 
able to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no 
evidence of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of 
disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; 
some signs or symptoms of 
disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active 
work. 
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and 
about more than 50% of waking 
hours. 
60 
Requires occasional assistance, 
but is able to care for most of 
his/her needs. 
50 
Requires considerable assistance 
and frequent medical care. 
3 
In bed >50% of the time.  
Capable of only limited self-care, 
confined to bed or chair more 
than 50% of waking hours. 
40 
Disabled, requires special care 
and assistance. 
30 
Severely disabled, 
hospitalization indicated.  Death 
not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization 
indicated. Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 


92 
Abbreviated Title:  Sorafenib and TRC105 in HCC 
NCI Protocol #: 11-C-0102 
Version Date:  June 10, 2016 
Amendment: N 
11.2 
APPENDIX 2:  CHILD-PUGH CLASSIFICATION SYSTEM 
 
 
 
 
 
 


93 
Abbreviated Title:  Sorafenib and TRC105 in HCC 
NCI Protocol #: 11-C-0102 
Version Date:  June 10, 2016 
Amendment: N 
11.3 
APPENDIX 3:  CORRELATIVE STUDY SPECIMEN PROCESSING PROCEDURES 
11.3.1 Molecular characterization of HCC using tumor tissue, blood and urine (Xin Wang lab): 
Processing of Blood Samples: 
1) Centrifuge green top tube(s) and red top tube(s), approximately 850 g (2000 rpm on 
Sorval T 6000) for 10 minutes to separate components. 
2) Withdraw plasma (green tops) and aliquot into sterile cryovials at 1.5 ml per vial; 
withdraw serum (red tops) and aliquot into sterile cryovials at 0.5 ml per vial. 
3) Label each vial appropriately with printed bar code label (i.e., plasma normal [from green 
top tube], serum normal [from red top tube]).  
4) From the green top tubes, remove the buffy coat from the red blood cell pellet; this 
appears as a white/pink layer on top of the RBCs, and can be done with a serological 
pipette or a transfer pipette.  Place buffy coat in a cryovial, wash once with Phosphate 
Buffered Saline (PBS), and centrifuge as above to precipitate cells into a pellet.  Aspirate 
supernatant, label vial appropriately (as buffy coat normal) with printed bar code label.  
5) From the red top tube, pour the RBC/clot into a 15 ml plastic tube, label appropriately 
with a bar code label, and place in cryobox in -80 C freezer. 
6) For collection of RBCs, add PBS to green top tubes to resuspend the RBC pellet, and 
centrifuge for 5 min. at 850 g (2000 rpm).   Aspirate PBS and repeat this wash step.  
After the second wash, re-suspend the cells in an equal volume of PBS, aliquot 1.5 ml 
each into up to 10 cryovials, and centrifuge as above.  Aspirate PBS, and label vials 
appropriately (as RBC normal). 
7) Place all plasma, serum, buffy coat, and RBC vials in cryobox in -80 C freezer. 
Processing of mouthwash: 
1) Transfer specimen from the container to a 50 ml centrifuge tube. 
2) Rinse container with about 10 ml of Listerine or PBS (Phosphate Buffered Saline) and 
add to 50 ml tube. 
3) Centrifuge tube at 2700 rpm for 15 minutes to pellet cells. 
4) Discard the supernatant carefully so as not to disturb pellet. 
5) Wash the cell pellet in 25 ml of 1 X TE buffer and again centrifuge at 2700 rpm for 15 
minutes to pellet cells. 
6) Discard the supernatant and re-suspend the pellet in 100 ul 1 X TE  
7) buffer facilitated by vortexing. 
8) Aliquot the sample into two 1.8 ml labeled NUNC Cryovials and store samples in 
cryobox in -80 C freezer. 
Processing of urine: 
1) Using a 25 ml serological pipette, aliquot urine into 13 ml plastic tubes, with up to10 ml 
into each tube, using up to 5 tubes. 
2) Label tubes with printed bar code labels and place in cryobox in -80C freezer. 


94 
Abbreviated Title:  Sorafenib and TRC105 in HCC 
NCI Protocol #: 11-C-0102 
Version Date:  June 10, 2016 
Amendment: N 
 
11.3.2 Genotyping for SNPs in angiogenesis-related genes (eg VEGFR)(Figg lab):  
1. Samples will be stored at 4C until time of extraction.  
2. A Qiagen Maxi Prep Kit will be used for extraction. 
3. Resulting DNA will be stored at -80C until time of analysis. 
11.3.3 Circulating endothelial cells (CECs), Circulating endothelial progenitor (CEP) cells, 
soluble CD105 (baseline) and Rat aortic ring bioassay. 
11.3.3.1 Processing of CECs and CEPs:  
11.3.3.2 Processing of VEGF samples: 
1. Centrifuge at 1200xg for 5 minutes at 4°C.   
2. Transfer plasma to 2X 1ml tubes and immediately freeze on dry ice 
3. Store at -80°C. 
11.3.3.3 Processing of soluble CD105 samples: 
1. Centrifuge the 5mL K2EDTA (lavender top) blood collection tube at 2500 x g for 
15 minutes. 
2. Transfer the plasma into a 5mL plastic test tube and repeat centrifuge at 2500 x g for 
15 minutes.  Use a fresh plastic test tube for each time point. 
3. Transfer the plasma equally into two pre-labeled 2mL lavender top clear 
polypropylene storage cryovials.  Use a fresh transfer pipette for each time point. 
4. Place the 2mL clear polypropylene storage cryovials with lavender top in the cryovial 
storage box provided and freeze immediately.  Store the specimens in a freezer at -80°C.  
Once frozen, do not allow the specimens to thaw, including during shipment. 
11.3.3.4 Processing of Rat aortic ring assay samples: 
1. Centrifuge at 1200xg for 5 minutes at 4°C.   
2. Transfer serum to 2X 1ml tubes  
3. Store at -80°C. 
11.3.4 Immunomonitoring (Greten lab). 
1)Pour the heparinized blood from the blood sample tubes into 50 ml Falcon tubes and spin 
at 1800 rpm, 10', 21°C 
2)Transfer the plasma (SN) of the centrifugated Falcon tubes into a fresh Falcon tube make 
aliquots in 1,8 ml cryotubes, store at -80°C 
3)Resuspend pellet with RPMI to a total volume of 35 ml and overlay the Ficoll slowly with 
the diluted blood. Spin at 2100 rpm, 17', 21°C without brake. 
4)Remove the lymphocyte ring and also the media and Ficoll with a 10 ml shorty-pipette and 
transfer to a new 50 ml Falcon tube (discard only the pellet) fill up to 50 ml with RPMI. 
Spin at 1600 rpm, 13', 21°C, discard the SN transfer the cells (of the same individual, 


95 
Abbreviated Title:  Sorafenib and TRC105 in HCC 
NCI Protocol #: 11-C-0102 
Version Date:  June 10, 2016 
Amendment: N 
from multiple Falcon tubes) to a single Falcon in 25 ml RPMI. Spin at 1600 rpm, 13', 
21°C, discard the SN resuspend the pellet in 25 ml RPMI and spin at 1300 rpm, 5', 21°C, 
discard the SN. 
5) Resuspend the pellet in 10 ml or 20 ml RPMI (according to the pellet) count the cells in a 
counting chamber (1/2 or 1/5 in Trypan Blue) separate the cells according to the aliquots 
that you want to freeze. Spin 1500 rpm, 5', 21°C, discard the SN. Prepare fresh freezing 
media use 1ml freezing media/cryotube store the cryotubes in ““Mr. Frosty”” at -80°C 
for one day, then store in liquid N2. 


96 
Abbreviated Title:  Sorafenib and TRC105 in HCC 
NCI Protocol #: 11-C-0102 
Version Date:  June 10, 2016 
Amendment: N 
 
11.4 APPENDIX 4: STUDY CALENDAR 
All baseline and follow-up evaluations can be performed during the last week of the prior cycle 
(+/- 48 hours).  
 
Pre-
study 
Cycle 1 
Cycle 2 + 
Cycle 3 
Day 1 
Off 
Treatment 
Day 
 
1 
15 
1 
15 
1 
 
TRC105a 
 
X 
X 
X 
X 
X 
 
Sorafenib 
 
Daily continuous self-administration 
Premedicationsb 
 
X 
X 
X 
X 
X 
 
Informed 
consent 
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
Medical history 
X 
X 
X 
X 
X 
X 
X 
Adverse event 
evaluation 
 
X 
X 
X 
X 
X 
X 
Physical exam 
X 
X 
X 
X 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
Weight 
X 
X 
X 
X 
X 
X 
 
Performance 
Status 
X 
X 
X 
X 
X 
X 
X 
CBC 
w/differential, 
Platelets 
X 
X 
X 
X 
X 
X 
X 
PT, PTT, 
Fibrinogen 
X 
X 
X 
X 
X 
X 
X 
Serum 
chemistry c 
X 
X 
X 
X 
X 
X 
X 
Serum AFP 
X 
 
 
X 
 
X 
 
ECG 
X 
 
 
 
 
 
 
Urine 
Protein-
creatinine 
Ratio (UPC)d 
X 
 
 
X 
 
X 
 
Restaging 
radiologic 
Evaluatione 
X 
 
 
 
 
X 
 
DCE-MRIh,i 
X 
X 
 
X 
 
 
 
Ultrasoundi 
X 
X 
 
X 
 
X 
 
Angiogenic 
biomarkersf 
X 
 
X 
 
X 
 
 
Tumor biopsy 
 
X 
 
 
 
X 
 
HAMA/HACAg 
X 
 
 
 
 
 
X 


97 
Abbreviated Title:  Sorafenib and TRC105 in HCC 
NCI Protocol #: 11-C-0102 
Version Date:  June 10, 2016 
Amendment: N 
 
Pre-
study 
Cycle 1 
Cycle 2 + 
Cycle 3 Day 1 
Off 
Treatment 
TRC105 
Pharmacokineti
c  
 
X 
Xj 
 
 
 
Xk 
Urine for 
Metabolomic 
Analysis 
 
X 
 
 
 
 
 
a: TRC105: Dose as assigned; administered I.V. every two week without planned rest/break. One cycle = 28 days 
b: Premedications: Thirty minutes to two hours prior to the start of each TRC105 infusion, all patients will receive 
the following pre-medications: Acetaminophen 650 mg PO x 1; Dexamethasone 20 mg IV x 1; Famotidine 20 mg 
IV x 1 (or similar H2 blocker); cetirizine 10  mg IV x 1  For details please see section 3.5. 
c: Sodium, potassium, chloride, bicarbonate, BUN, creatinine, glucose, amylase, albumin, total protein, calcium, 
magnesium, phosphorous, AST, ALT, alkaline phosphatase, total bilirubin, uric acid 
d: For UPC ratio > 1.0, a 24-hour urine protein will need to be obtained and the level should be < 2000 mg for 
patient enrollment . UPC will be performed every other cycle. 
e: CT chest, abdomen, pelvis every 8 weeks. 
f: see section 3.5 for details as to pharmacodynamic timepoints/angiogenic biomarkers to be drawn. 
g: see section 3.5 for details; draw prestudy, pre-dose every 3rd cycle, at end of study, and at month 3 and 6 after end 
of study.  If still positive, draw at month 9 and 12 after end of study. 
h. DCE-MRI will be performed at the following timepoints: 1) Prior to treatment (preferably within 7 days of 
treatment start; 2) 24-36 hours after Cycle 1 Day 1  and 3) 28 +/- 2 days after Cycle 1 Day 1 
i. Optional Studies  
j. Pretreatment and 5 minutes post completion of TRC 105 infusion 
k. Trough Only 


98 
Abbreviated Title:  Sorafenib and TRC105 in HCC 
NCI Protocol #: 11-C-0102 
Version Date:  June 10, 2016 
Amendment: N 
11.5 APPENDIX 5: CORRELATIVE STUDY SPECIMEN AND DATA STORAGE PROCEDURES 
11.5.1 Sample Data Collection  
All samples sent to the Blood Processing Core (BPC) will be barcoded, with data entered and 
stored in the LABrador (aka LabSamples) utilized by the BPC. This is a secure program, with 
access to LABrador limited to defined Figg lab personnel, who are issued individual user 
accounts. Installation of LABrador is limited to computers specified by Dr. Figg. These 
computers all have a password restricted login screen. All Figg lab personnel with access to 
patient information annually complete the NIH online Protection of Human Subjects course.  
 
LABrador creates a unique barcode ID for every sample and sample box, which cannot be traced 
back to patients without LABrador access. The data recorded for each sample includes the 
patient ID, name, trial name/protocol number, time drawn, cycle time point, dose, material type, 
as well as box and freezer location. Patient demographics associated with the clinical center 
patient number are provided in the system. For each sample, there are notes associated with the 
processing method (delay in sample processing, storage conditions on the ward, etc.). 
11.5.2 Sample Storage and Destruction 
Barcoded samples are stored in barcoded boxes in a locked freezer at either -20 or -80°C 
according to stability requirements.  These freezers are located onsite in the BCP and offsite at 
NCI Frederick Central Repository Services (Fisher BioServices) in Frederick, MD. Visitors to 
the laboratory are required to be accompanied by laboratory staff at all times.  
Access to stored clinical samples is restricted. Samples will be stored until requested by a 
researcher named on the protocol. All requests are monitored and tracked in LABrador. All 
researchers are required to sign a form stating that the samples are only to be used for research 
purposes associated with this trial (as per the IRB approved protocol) and that any unused 
samples must be returned to the BPC. It is the responsibility of the NCI Principal Investigator to 
ensure that the samples requested are being used in a manner consistent with IRB approval. 
Following completion of this study, samples will remain in storage as detailed above. Samples 
will remain in storage only for those patients who have provided consent for their samples to be 
collected for future research. Access to these samples will only be granted following IRB 
approval of an additional protocol, granting the rights to use the material.  
If, at any time, a patient withdraws from the study and does not wish for their existing samples to 
be utilized, the individual must provide a written request. Following receipt of this request, the 
samples will be destroyed (or returned to the patient, if so requested), and reported as such to the 
IRB. Any samples lost (in transit or by a researcher) or destroyed due to unknown sample 
integrity (i.e. broken freezer allows for extensive sample thawing, etc.) will be reported as such 
to the IRB. 
Sample barcodes are linked to patient demographics and limited clinical information. This 
information will only be provided to investigators listed on this protocol, via registered use of the 
LABrador. It is critical that the sample remains linked to patient information such as race, age, 


99 
Abbreviated Title:  Sorafenib and TRC105 in HCC 
NCI Protocol #: 11-C-0102 
Version Date:  June 10, 2016 
Amendment: N 
dates of diagnosis and death, and histological information about the tumor, in order to correlate 
genotype with these variables. 
Any new uses of human subject samples collected during the course of this trial must be 
reviewed and approved by the NCI IRB. Any loss or unintentional destruction of the samples 
will be reported to the IRB. 
 


MEDICAL RECORD 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
INSTITUTE: 
National Cancer Institute 
STUDY NUMBER: 
11-C-0102 
PRINCIPAL INVESTIGATOR: 
Tim Greten, M.D. 
STUDY TITLE:  
A Phase I/II Study of TRC105 in Combination with Sorafenib in Hepatocellular 
Carcinoma (HCC) 
Continuing Review Approved by the IRB on 09/14/15 
Amendment Approved by the IRB on 07/07/16 (N) 
Date posted to web:  07/13/16 
Standard 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
NIH-2514-1 (07-09) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent (1) 
 
INTRODUCTION 
We invite you to take part in a research study at the National Institutes of Health (NIH). 
First, we want you to know that: 
Taking part in NIH research is entirely voluntary.  
You may choose not to take part, or you may withdraw from the study at any time.  In 
either case, you will not lose any benefits to which you are otherwise entitled.  However, 
to receive care at the NIH, you must be taking part in a study or be under evaluation for 
study participation. 
You may receive no benefit from taking part.  The research may give us knowledge that 
may help people in the future. 
Second, some people have personal, religious or ethical beliefs that may limit the kinds of 
medical or research treatments they would want to receive (such as blood transfusions).  If you 
have such beliefs, please discuss them with your NIH doctors or research team before you agree 
to the study. 
Now we will describe this research study.  Before you decide to take part, please take as much 
time as you need to ask any questions and discuss this study with anyone at NIH, or with family, 
friends or your personal physician or other health professional.   
Why is this study being done?  
This study is divided into two phases. In the phase 1 portion, we determined the highest safe 
dose of an experimental cancer drug called TRC105, when given with another cancer drug, 
sorafenib (also called Nexavar).  You are being asked to participate in Phase 2 of this study.  
To our knowledge, this is the first time TRC105 has been given with sorafenib in humans.   


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 11-C-0102 
CONTINUATION: page 2 of 18 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
 
Sorafenib has been approved by the FDA for treatment of kidney and liver cancer (hepatocellular 
carcinoma - HCC).  It has been shown to prolong survival in patients with HCC. Unfortunately, 
we know that after a period of time the cancer tends to start growing again. This study will try to 
improve the cancer fighting ability of sorafenib by giving it in combination with TRC105.  This 
study is being done in collaboration with Tracon Pharmaceuticals, Inc., the makers of TRC105.   
TRC105 is not approved by the U.S. Food and Drug Administration (FDA) and is experimental.  
TRC105 is a man-made antibody (a special immune system protein) that blocks the body’s steps 
for making new blood vessels grow, a process called angiogenesis.  All solid tumors require new 
blood vessels to grow.  Sorafenib is in a class of medications call ‘multikinase inhibitors’ and 
works by slowing the spread of cancer cells.  It is thought therefore, that giving patients with 
HCC tumors TRC105 in combination with sorafenib, we will stop the growth of their tumors or 
cause tumors to shrink, better than with sorafenib alone.   
Why are you being asked to take part in this study? 
You are being asked to participate because you have hepatocellular carcinoma (HCC) that has 
not responded to other types of therapy, and your doctor has determined that you are not a 
candidate for liver transplantation.   
How many people will take part in this study?  
To date, the phase 1 portion of this study has enrolled 19 patients. The phase 2 portion of this 
study will enroll up to a maximum of 23 patients. 
Description of Research Study 
What will happen if you take part in this research study?   
Before you begin the study 
All research studies have specific criteria for entry to allow for valid interpretation of the study 
results and safety of participants, known as eligibility criteria.  Before you begin this study you 
will need to have the following exams and tests to make sure you are eligible for this study.  The 
exams and tests are part of regular cancer care and may be done even if you do not join the 
study.  If you recently had some of the tests, they may not need to be repeated.   
• History and physical examination, including vital signs (height, weight, blood pressure, 
heart rate, temperature, breathing rate) 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 11-C-0102 
CONTINUATION: page 3 of 18 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
 
• Standard blood tests to measure your liver and kidney function, white blood cells, red 
blood cells and platelets, your blood sugar and blood electrolytes.  If you are a woman 
able to get pregnant, you will also have a pregnancy test done. 
• Scans, x-rays and an ultrasound of your tumors to measure your disease.   
• Electrocardiogram within 16 days prior to your first dose of TRC105. 
• HIV Testing:  As part of this study, we will test you for infection with the human 
immunodeficiency virus (HIV), the virus that causes AIDS.  If you are infected with 
HIV you will not be able to participate in this study.  We will tell you what the results 
mean, how to find care, how to avoid infecting others, how we report newly diagnosed 
HIV infection, and the importance of informing your partners at possible risk because of 
your HIV infection. 
• Endoscope exam of your esophagus to look for varices (swollen or enlarged blood 
vessels).  Because bleeding is a possible side effect of all cancer drugs that limit blood 
vessel growth, patients with varices will not be eligible to participate. 
If you meet the eligibility criteria for this study you will be offered the option of participating. 
During the study 
Everyone enrolled in the study will take the same dose of sorafenib (two pills) two times every 
day, in the morning and at night.  The TRC 105 will be given through a vein (intravenously) 
once every two weeks on days 1 and 15 of a 28 day cycle.  In the phase 1 portion of the study we 
found the highest dose that will be given in the phase 2 portion.  Everyone enrolled in phase 2 
portion of the study will receive the same dose of sorafenib and TRC 105. The TRC 105 dose 
was determined in the phase 1 part of this study.   
The TRC105 infusion will be given to you in the outpatient clinic, while the nurses and doctors 
watch you closely for any side effects.  The sorafenib pills should be swallowed whole with a 
full glass (8 ounces) of water in the morning and night every day for the 28 days of the cycle.  
You can take it with or without food.   
To help prevent known side effects of the TRC105 you will be given a steroid, Dexamethasone, 
through your vein 30 minutes to 2 hours before you receive TRC105.  Infusion of any antibody 
has the potential to cause an allergic-type of infusion reaction, and giving the steroid helps 
prevent this.  In addition, 30 minutes before you receive the TRC105 you will be given cetirizine 
(or similar drug) to help prevent infusion reactions, in addition to acetaminophen (Tylenol) to 
prevent chills and fever and famotidine (or similar drug) to prevent stomach upset.  The first 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 11-C-0102 
CONTINUATION: page 4 of 18 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
 
dose of TRC105 will be given over a period of 4 hours, and if you do not have side effects, the 
next dose may be given over two hours.  If the second dose is tolerated, subsequent doses can be 
given over at least one hour.   
If you experience side effects (described later in this consent) during the TRC105 infusion, the 
infusion may be slowed or stopped, or treated with additional medicines, if necessary.  If the side 
effects are too severe, the doctor may decide to stop all further doses of TRC105.  If the side 
effects are not too severe, subsequent doses may be delayed until you have time to recover.  The 
dosages of both TRC105 and sorafenib may be adjusted after the first cycle to reduce the severity 
of your side effects, if the doctor determines your side effects are not too severe.  
At each visit during the first cycle you will have a physical examination and blood tests, which 
are the same as what you would have done with your regular cancer care, including blood tests 
for blood counts and chemistries.  We will also do a urine test every cycle to evaluate your 
kidney functions.  We will ask you questions about how you are feeling and any medications you 
may have taken to treat your symptoms.  Every third cycle (about every three months) you will 
have standard scans and x-rays to evaluate your tumor(s).  After the first cycle the physical 
examination and blood tests will be repeated at the beginning of each new cycle (each month).   
Research Tests  
An important part of this study is testing the effects of TRC105 in combination with sorafenib on 
your body and your cancer.  We would also like to do research studies on the characteristics and 
genetic analysis of your type of cancer (HCC). These studies will study the DNA or genes that 
are important in your cancer and may be causing it to grow. We will not be studying your 
‘normal’ genes however. In other words, we will only be studying the genes or DNA in your 
cancer and not those in normal parts of your body. We therefore will not be able to look at 
hereditary genes, or ones that cause conditions to ‘run in families’. To do these studies we will 
collect blood, mouth wash, urine, and tissue specimens (optional).  We will also look at the blood 
levels of various markers of angiogenesis (blood vessel growth).  These tests are being done for 
research purposes only, and therefore the results will be preliminary and will not be reported 
back to you or your referring physician. 
To do these tests, we would like to take blood samples before your first infusion, on Day 15 of 
your first cycle, Day 1 and 15 of your second cycle, Day 1 of your third cycle, and after your last 
treatment.  We may ask you to give us a mouth wash sample before starting therapy. 
In addition, we will take 1 teaspoon of blood before your first dose and then on Day 1 of every 
3rd cycle, and 3 and 6 months after you stop TRC105 to see if your body is making immune cells 
against the antibody.  


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 11-C-0102 
CONTINUATION: page 5 of 18 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
 
In total we would draw about 31 tablespoons of blood over the course of this study.  The amount 
of blood taken for these research tests is within the safe guidelines for research blood volumes 
set by the NIH.  In adults that limit is 37 tablespoons in an 8-week period. 
If the doctors think that we can obtain a piece of your tumor (biopsy) through a needle 
(percutaneously) with minimal risk to you, we will take a biopsy when you start the study and 
during week 8 of therapy.  You will be given the chance to decide if you want to participate at 
the time of the procedure. If you decide to have the biopsy, you will be given local anesthesia 
(numbing medicine) and a sedative prior to the biopsy.  The biopsy will be taken through a 
needle put through the skin into your liver tumor.  After the procedure you will have to lay on 
your right side for 2-4 hours, and the nurses will watch your blood pressure and other vital signs. 
Research Scans 
DCE-MRI:  To study the changes in the tumor vessels you will be asked to undergo an MRI, 
called a dynamic contrast enhanced magnetic resonance imaging (or DCE-MRI) before starting 
treatment, 24 to 36 hours after your first dose of TRC105 and then at the end of the first cycle.  
MRI is a scan that uses a powerful magnetic field, radio frequency pulses and computer to take 
pictures of your bones, organs and tumor inside the body.  DCE is a special test that uses contrast 
fluid to better see these body structures, including blood vessels.  The radiologist will make sure 
it is safe for you to have this test, as you may not have any metal objects on or in your body.   
Ultrasound of tumor blood vessels: Ultrasound imaging, also called ultrasound scanning or 
sonography, uses high-frequency sound waves to produce pictures of your tumor blood vessels 
inside of the body.  Ultrasound exams do not use ionizing radiation (as used in x-rays).  This test 
will be done before starting treatment, 24 to 36 hours after your first dose of TRC105 and then at 
the end of the first cycle.   
When you are finished taking the drugs (treatment) 
After completing treatment with TRC105, a nurse or doctor will contact you or your physician to 
get an update of your condition, at least every year. 
Study Chart 
Each Cycle  
Day 
 
 
 
What to do and what will happen to you 
Before 
starting 
TRC105 and 
Get routine blood tests. 
Provide a history of how you feel and undergo a physical examination by the 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 11-C-0102 
CONTINUATION: page 6 of 18 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
 
sorafenib 
research team’s Health Care Provider. 
Research blood, urine and mouthwash samples will be taken, and a tumor biopsy 
(optional). 
DCE-MRI and ultrasound may be done. 
 
Day 1 
Routine blood tests will be drawn; urine test will be done. 
30 minutes to two hours before TRC105, take the premedications 
(acetaminophen, dexamethasone, cetirizine, famotidine and granisetron) 
Receive 1st dose of TRC105 in the vein (IV) in the Day Hospital over 4 hours 
Report any side effects to the research team.  
Research blood samples will be taken. 
Start sorafenib twice a day, with a full glass of water (8 oz). 
24-36 hours 
after first 
dose of 
TRC105 
DCE-MRI and ultrasound may be done. 
Continue taking sorafenib twice a day, with a full glass of water (8 oz). 
Day 15 
Return to the NIH clinic to see your doctor.  Provide a history of how you feel 
and have a physical exam by your Health Care Provider. 
Blood will be taken for routine cancer care tests. 
If you are tolerating the TRC105, the next dose of the cycle will be given. 
Research blood samples will be taken. 
Continue taking sorafenib twice a day, with a full glass of water (8 oz). 
Day 28 or 29 
(also Day 1 
of the next 
Cycle) 
Return to the NIH clinic to see your doctor.  Provide a history of how you feel 
and have a physical exam by your Health Care Provider. 
Blood will be taken for routine cancer care tests. 
If you are tolerating the drug well, a new treatment cycle will begin. 
Research blood samples will be taken. 
Continue taking sorafenib twice a day, with a full glass of water (8 oz). 
DCE-MRI and ultrasound may be done. 
After every 
2-3 Cycles 
CT scan of the chest, abdomen and pelvis. 
After 
stopping 
TRC105 and 
sorafenib 
Return to the NIH clinic to see your doctor.  Provide a history of how you feel 
and have a physical exam by your Health Care Provider. 
Blood will be taken for routine cancer care tests. 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 11-C-0102 
CONTINUATION: page 7 of 18 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
 
Research blood samples will be taken. 
Follow Up 
At least yearly, a member of the research team will contact you or your referring 
physician to ask about your condition. 
 
Birth Control 
If you are a woman who is breast feeding or pregnant, you may not take part in the study because 
we don’t know how this medicine would affect your baby or your unborn child.  If you are a 
woman who can become pregnant, or are the partner of a woman who can become pregnant, you 
will need to practice an effective form of birth control before starting study treatment, during 
study treatment, and for 3 months after you finish study treatment.  If you think that you or your 
partner is pregnant, you should tell your study doctor or nurse at once.   
Effective forms of birth control include:  
• abstinence  
• intrauterine device (IUD) 
• hormonal [birth control pills, injections, or implants] 
• tubal ligation 
• vasectomy 
 
Risks or Discomforts of Participation 
What side effects or risks can I expect from being in this study?  
You may have side effects while you are taking the study drugs.  Everyone taking part in the 
study will be watched carefully for any side effects.  However, doctors don’t know all the side 
effects that may happen, so it is important to report any changes that you may notice, even if 
your study team does not ask specifically about them.  Side effects may be mild or severe.  Your 
study team will give you medicines to help lessen side effects.  Many side effects go away with 
those medicines and others may go away soon after you stop the study drugs.  In some cases, 
side effects can be serious, long lasting, or may never go away.  There are no known long-lasting 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 11-C-0102 
CONTINUATION: page 8 of 18 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
 
side effects from TRC105 or sorafenib at this time.  If new information about side effects 
becomes available, we will make you aware of this new information.  
During the phase I portion of the study one patient died related to a cardiac event. This patient 
had a preexisting heart condition and this is the suspected cause of death. We cannot exclude 
100% that the protocol therapy could have contributed to the death.  
TRC105 
There have been about 50 patients treated with TRC105 so far in other studies. Generally, the 
side effects have been mild. The most common side effects that patients have mentioned were 
fatigue, chills, and diarrhea. The table below lists both the common and uncommon side-effects 
that have been seen with TRC105.  
Risks and side effects related to TRC105 are detailed in the table below: 
SIDE 
EFFECT 
Mild 
Severe, but not life 
threatening 
Life Threatening 
Common 
• Fatigue 
• Back Pain* 
• Lip Pain 
• Anemia (low red blood 
cell count) 
• Abdominal pain* 
• Abdominal distension 
• Constipation 
• Diarrhea 
• Nausea 
• Infusion related reaction 
(chills, fever, flushing 
during the TRC105 
infusion) 
 
 
Uncommon 
• Loss of Appetite* 
• Vomiting 
• Joint pain 
• Headache 
• Abnormal blood tests 
related to liver function 
• Chills 
• Wheezing* 
• Fever 
• Infusion related 
reaction (chills, fever, 
flushing during the 
TRC105 infusion) 
• Sinusitis 
• Cellulitis 
 
 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 11-C-0102 
CONTINUATION: page 9 of 18 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
 
• Heartburn* 
• Changes in taste 
• Flushing 
• Protein in the urine 
• Swelling of the legs* 
• Low potassium in the 
blood* 
• Difficulty sleeping* 
• Cough* 
• Coughing up blood* 
• Vaginal bleeding 
• Anal discomfort 
• Dry mouth 
• Gas and bloating 
• Chest pain 
• Thirst 
• Eye infection 
• Herpes zoster (viral 
infection which can affect 
nerves and cause pain, i.e. 
shingles) 
• infection and sores on the 
gums 
Rare 
 
• Gastric ulcer 
• Small intestine 
blockage 
• Perforation of the 
intestine requiring 
surgery 
• Collapsed lung 
• Spinal fluid leak in a 
patient who 
underwent resection 
of a brain tumor and 
had a history of 
abnormal collection 
of spinal fluid 
• Liver failure 
• Kidney failure 
• Mycardioal 
Infarction* 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 11-C-0102 
CONTINUATION: page 10 of 18 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
 
*These side effects are events that have occurred during clinical studies using TRC105, but it has 
not yet been determined whether the events were caused by TRC105. 
Sorafenib 
SIDE 
EFFECT 
Mild 
Severe, but not life 
threatening 
Life Threatening 
Common 
• Hair loss 
• Inflammation of the skin on the 
palms of the hands or soles of the 
feet  
• Rash / flaking or shedding of 
outer layer of skin* 
• Fatigue or tiredness 
• Loss of appetite 
• Diarrhea 
• Nausea 
• Low levels of blood protein 
called albumin 
• Low blood phosphate level 
• Stomach ache 
• Laboratory test-related: increased 
liver enzymes or abnormal liver 
enzyme levels 
 
 
Uncommon 
• Low blood counts:  decrease in a 
red blood cell protein that carries 
oxygen in the body, decreased 
total number of white blood cells, 
decreased number of a type of 
white blood cell, decreased 
number of blood cells that help 
clot blood. 
• Stomach / Intestine Related: 
constipation, painful 
inflammation and ulceration of 
the lining of the mouth and 
digestive tract, vomiting. 
• Laboratory test-related:  abnormal 
bone enzyme levels, abnormal 
digestive enzyme level, high 
• Bleeding: 
Bleeding in the 
digestive tract; 
bleeding in the 
reproductive 
organs or urinary 
system (such as 
the bladder or 
kidney) 
• Breathing-
related: shortness 
of breath, cough, 
fluid 
accumulation 
around the lungs 
(pleural 
 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 11-C-0102 
CONTINUATION: page 11 of 18 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
 
blood levels of a liver pigment 
indicative of abnormal liver 
function, low blood calcium level, 
high blood sugar, low blood 
sugar, abnormal level of fat-
digesting enzyme, high blood 
potassium level, low blood 
potassium level, low blood 
sodium level. 
• Voice changes (for example 
hoarseness, loss or change in 
voice)  
• Dry skin, itching. 
• General: dizziness, fever (with or 
without a dangerously low white 
blood cell count), weight loss, 
infection (with or without a low 
white blood cell count), pain 
throughout the body (such as 
back pain, chest pain, leg pain, 
headache, joint pain, muscle 
pain), difficulty sleeping or 
falling asleep. 
• Swelling of the arms and legs 
effusion), 
bleeding of the 
respiratory tract 
or lungs. 
•  High blood 
pressure* 
• Nerve damage 
causing 
numbness, 
tingling, or 
burning 
• Allergic reaction 
 
Rare 
 
 
• Kidney failure 
• Formation or 
presence of a 
blood clot inside 
a blood vessel, 
i.e. heart, lung 
• Heart failure 
• Hole in the 
bowel with 
Gastrointestinal 
(GI) bleeding 
• Bleeding into 
the brain 
• Neurological 
problem: 
leukoencephalop


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 11-C-0102 
CONTINUATION: page 12 of 18 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
 
athy syndrome 
including 
reversible 
posterior 
leukoencephalop
athy syndrome 
[RPLS] 
*The skin rash, fatigue, diarrhea, and high blood pressure are reversible, and can usually be 
alleviated by reducing the dose of sorafenib.  We will monitor your blood pressure carefully on 
the study, and if found to be elevated, a medication to lower your blood pressure can be used. If 
you have uncontrolled high blood pressure, this elevated pressure can cause damage to other 
organs including the heart, kidneys, or brain. Having uncontrolled high blood pressure increases 
the risk of heart attack and stroke in adults. Usually there are no symptoms of high blood 
pressure; however, dizziness, headache, or nose bleed can occur.  
We will monitor your blood pressure carefully on the study, and if found to be elevated, a 
medication to lower your blood pressure can be used.  If you have uncontrolled high blood 
pressure, this elevated pressure can cause damage to other organs including the heart, kidneys, or 
brain.  Having uncontrolled high blood pressure increases the risk of heart attack and stroke in 
adults. Usually there are no symptoms of high blood pressure; however, dizziness, headache, or 
nose bleed can occur.  
Dexamethasone: 
Common 
Occasional 
Rare and Serious 
• High blood pressure 
which 
may 
cause 
headaches, dizziness  
• Skin changes, rash, 
acne  
• Swelling of the body, 
tiredness, bruising  
• Weight gain in belly, 
face, 
back 
and 
shoulders  
• Pain in belly  
• Infection  
• Damage to the bone  
 
• 
Cloudiness of the eye, 
visual disturbances 
• 
Non-healing wound 
• 
Heartburn 
• 
Kidney stones 
• Blurred vision 
• Bleeding from sores in 
stomach 
• Broken bones 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 11-C-0102 
CONTINUATION: page 13 of 18 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
 
 
Biopsy of Liver Tumor: 
The most common side effect of a liver biopsy is pain.  Other rare complications include 
bleeding, which may rarely be severe enough to require a transfusion, puncturing a nearby organ, 
or very rarely (less than 1%) death. We will monitor you for 24 hours after your liver biopsy to 
rule-out bleeding. 
DCE-MRI: 
Most MRI exams are painless, however, some patients find it uncomfortable to remain still 
during MR imaging.  Others experience a sense of being closed-in (claustrophobia).  Therefore, 
sedation can be arranged for those patients who anticipate anxiety, but fewer than one in 20 
require it.  It is normal for the area of your body being imaged to feel slightly warm, but if it 
bothers you, notify the radiologist or technologist.  It is important that you remain perfectly still 
while the images are being recorded, which is typically only a few seconds to a few minutes at a 
time.  For some types of exams, you may be asked to hold your breath.  When the contrast 
material is injected, it is normal to feel coolness and a flushing sensation for a minute or two.  
The intravenous needle may cause you some discomfort when it is inserted and once it is 
removed, you may experience some bruising.  There is also a very small chance of irritation of 
your skin at the site of the IV tube insertion. 
Ultrasound of tumor blood vessels: 
This procedure is painless and requires no preparation. 
Potential Benefits of Participation 
Are there benefits to taking part in this study? 
The aim of the study is to determine the highest safe dose of TRC105 when given in combination 
with sorafenib.  We do not know if you will receive personal, medical benefit from taking part in 
this study.  The potential benefits could include shrinking of your tumor or lessening of your 
symptoms, such as pain, that are caused by the cancer.  Because there is not much information 
about the effects of this combination on HCC, we do not know if you will benefit from taking 
part in this study, although the knowledge gained from this study may help others in the future 
who have cancer.   


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 11-C-0102 
CONTINUATION: page 14 of 18 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
 
Alternative Approaches or Treatments 
What other choices do I have if I do not take part in this study?  
Instead of being in this study, you have these options: 
• Getting treatment or care for your cancer without being in a study 
• Taking part in another study 
• Getting comfort care, also called palliative care.  This type of care helps reduce pain, 
tiredness, appetite problems and other problems caused by the cancer.  It does not treat 
the cancer directly.  Instead, it tries to improve how you feel.  Comfort care tries to keep 
you as active and comfortable as possible. 
Please talk to your doctor about these and other options. 
Research Subject’s Rights 
What are the costs of taking part in this study?  
If you choose to take part in the study, the following will apply, in keeping with the NIH policy: 
• 
You will receive study treatment at no charge to you. This may include 
surgery, medicines, laboratory testing, x-rays or scans done at the 
Clinical Center, National Institutes of Health (NIH), or arranged for you 
by the research team to be done outside the Clinical Center, NIH if the 
study related treatment is not available at the NIH.  
• 
There are limited funds available to cover the cost of some tests and 
procedures performed outside the Clinical Center, NIH.  You may have 
to pay for these costs if they are not covered by your insurance company. 
• 
Medicines that are not part of the study treatment will not be provided or 
paid for by the Clinical Center, NIH. 
• 
Once you have completed taking part in the study, medical care will no 
longer be provided by the Clinical Center, NIH. 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 11-C-0102 
CONTINUATION: page 15 of 18 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
 
Will your medical information be kept private?  
We will do our best to make sure that the personal information in your medical record will be 
kept private.  However, we cannot guarantee total privacy.  Organizations that may look at 
and/or copy your medical records for research, quality assurance, and data analysis include: 
• The National Cancer Institute (NCI) and other government agencies, like the Food and 
Drug Administration (FDA), which are involved in keeping research safe for people. 
• National Cancer Institute Institutional Review Board 
• The study Sponsor (Center for Cancer Research) or their agent(s). 
• Qualified representatives from TRACON Pharmaceuticals, Inc., the pharmaceutical 
company who produces TRC105. 
A description of this clinical trial will be available on http://www.Clinicaltrials.gov, as required 
by U.S. Law.  This Web site will not include information that can identify you.  At most the 
Web site will include a summary of the results.  You can search this Web site at any time. 
Stopping Therapy  
Your doctor may decide to stop your therapy for the following reasons: 
• if he/she believes that it is in your best interest 
• if your disease comes back during treatment 
• if you have side effects from the treatment that your doctor thinks are too severe 
• if new information shows that another treatment would be better for you 
In this case, you will be informed of the reason therapy is being stopped. 
You can stop taking part in the study at any time.  However, if you decide to stop taking part in 
the study, we would like you to talk to the study doctor and your regular doctor first. 
If you decide at any time to withdraw your consent to participate in the trial, we will not collect 
any additional medical information about you. However, according to FDA guidelines, 
information collected on you up to that point may still be provided to Tracon Pharmaceticals, 
Inc. or designated representatives. If you withdraw your consent and leave the trial, any samples 
of yours that have been obtained for the study and stored at the NCI can be destroyed upon 
request. However, any samples and data generated from the samples that have already been 
distributed to other researchers or placed in the research databases cannot be recalled and 
destroyed. 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 11-C-0102 
CONTINUATION: page 16 of 18 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
 
 
Conflict of Interest 
The National Institutes of Health (NIH) reviews NIH staff researchers at least yearly for conflicts 
of interest.  This process is detailed in a Protocol Review Guide.  You may ask your research 
team for a copy of the Protocol Review Guide or for more information.  Members of the research 
team who do not work for NIH are expected to follow these guidelines but they do not need to 
report their personal finances to the NIH. 
 
Members of the research team working on this study may have up to $15,000 of stock in the 
companies that make products used in this study.  This is allowed under federal rules and is not a 
conflict of interest.  
The National Institutes of Health and the research team for this study are using a drug developed 
by Tracon Pharmaceuticals through a joint study with your researchers and the company.   The 
company also provides financial support for this study.  
Use of Specimens and Data for Future Research 
To advance science, it is helpful for researchers to share information they get from studying 
human samples.  They do this by putting it into one or more scientific databases, where it is 
stored along with information from other studies. A researcher who wants to study the 
information must apply to the database and be approved.  Researchers use specimens and data 
stored in scientific databases to advance science and learn about health and disease.   
We plan to keep some of your specimens and data that we collect and use them for future 
research and share them with other researchers. We will not contact you to ask about each of 
these future uses.  These specimens and data will be stripped of identifiers such as name, address 
or account number, so that they may be used for future research on any topic and shared broadly 
for research purposes. Your specimens and data will be used for research purposes only and will 
not benefit you.  It is also possible that the stored specimens and data may never be used.  
Results of research done on your specimens and data will not be available to you or your doctor.  
It might help people who have cancer and other diseases in the future.   
If you do not want your stored specimens and data used for future research, please contact us in 
writing and let us know that you do not want us to use your specimens and/or data.  Then any 
specimens that have not already been used or shared will be destroyed and your data will not be 
used for future research. However, it may not be possible to withdraw or delete materials or data 
once they have been shared with other researchers. 
 


MEDICAL RECORD 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
STUDY NUMBER: 11-C-0102 
CONTINUATION: page 17 of 18 pages 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH 
STUDY (Continuation Sheet) 
• 
Adult Patient or 
• Parent, for Minor Patient 
NIH-2514-1 (07-09) 
P.A.:  09-25-0099 
 
File in Section 4:  Protocol Consent 
 
 
OTHER PERTINENT INFORMATION 
1. Confidentiality.  When results of an NIH research study are reported in medical journals or 
at scientific meetings, the people who take part are not named and identified.  In most cases, the 
NIH will not release any information about your research involvement without your written 
permission.  However, if you sign a release of information form, for example, for an insurance 
company, the NIH will give the insurance company information from your medical record.  This 
information might affect (either favorably or unfavorably) the willingness of the insurance 
company to sell you insurance. 
The Federal Privacy Act protects the confidentiality of your NIH medical records.  However, you 
should know that the Act allows release of some information from your medical record without 
your permission, for example, if it is required by the Food and Drug Administration (FDA), 
members of Congress, law enforcement officials, or authorized hospital accreditation 
organizations. 
2. Policy Regarding Research-Related Injuries.  The Clinical Center will provide short-term 
medical care for any injury resulting from your participation in research here.  In general, no 
long-term medical care or financial compensation for research-related injuries will be provided 
by the National Institutes of Health, the Clinical Center, or the Federal Government.  However, 
you have the right to pursue legal remedy if you believe that your injury justifies such action. 
3. Payments.  The amount of payment to research volunteers is guided by the National 
Institutes of Health policies.  In general, patients are not paid for taking part in research studies at 
the National Institutes of Health.  Reimbursement of travel and subsistence will be offered 
consistent with NIH guidelines. 
4. Problems or Questions.  If you have any problems or questions about this study, or about 
your rights as a research participant, or about any research-related injury, contact the Principal 
Investigator, Tim Greten, M.D., Building 10, Room 12N226 Telephone:  301-451-4723.  You 
may also call the Clinical Center Patient Representative at (301) 496-2626. If you have any 
questions about the use of your specimens or data for future research studies, you may also 
contact the Office of the Clinical Director, Telephone:  301-496-4251.  
5. Consent Document.  Please keep a copy of this document in case you want to read it again. 
 
 


MEDICAL RECORD 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
STUDY NUMBER: 11-C-0102 
CONTINUATION: page 18 of 18 pages 
 
PATIENT IDENTIFICATION 
 
 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH 
STUDY (Continuation Sheet) 
• 
Adult Patient or 
• Parent, for Minor Patient 
NIH-2514-1 (07-09) 
P.A.:  09-25-0099 
 
File in Section 4:  Protocol Consent 
 
 
 
COMPLETE APPROPRIATE ITEM(S) BELOW: 
A. Adult Patient’s Consent 
B. Parent’s Permission for Minor Patient. 
I have read the explanation about this study 
and have been given the opportunity to discuss 
it and to ask questions.  I hereby consent to 
take part in this study. 
I have read the explanation about this study 
and have been given the opportunity to discuss 
it and to ask questions.  I hereby give 
permission for my child to take part in this 
study.   
(Attach NIH 2514-2, Minor’s Assent, if 
applicable.) 
 
  
  
 
 
 
Signature of Adult Patient/ 
Legal Representative 
Date 
Signature of Parent(s)/ Guardian Date 
 
 
Print Name 
 
 
Print Name 
C. Child’s Verbal Assent (If Applicable) 
The information in the above consent was described to my child and my child agrees to 
participate in the study. 
 
  
  
 
Signature of Parent(s)/Guardian 
Date 
Print Name 
THIS CONSENT DOCUMENT HAS BEEN APPROVED FOR USE  
FROM SEPTEMBER 14, 2015 THROUGH SEPTEMBER 13, 2016.  
 
 
 
 
 
 
 
 
Signature of Investigator 
Date 
Signature of Witness 
Date 
 
 
Print Name 
 
 
Print Name