Clinical trial NCT02560779
Conditions: Hepatocellular Carcinoma
Keywords: TRC105 CD105 Endoglin Angiogenesis inhibitor HCC TKI Tyrosine Kinase Inhibitor Sorafenib Nexavar
Sponsor: Tracon Pharmaceuticals Inc.
Start date: 2016-11-01; Completion date: 2019-08-01
Enrollment: 27 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of the phase 1b portion is to evaluate safety and tolerability and determine a recommended phase 2 dose for TRC105 when added to standard dose sorafenib in patients with hepatocellular carcinoma. Up to 18 patients will be treated.

The purpose of the phase 2 portion is to estimate the ORR of patients with hepatocellular carcinoma by RECIST 1.1. Up to 21 patients will be treated in phase 2.

Detailed description:
Sorafenib is an oral multikinase inhibitor targeting several receptor tyrosine kinases, including the VEGF receptor (VEGFR), implicated in pathologic angiogenesis, tumor growth, and cancer progression. Sorafenib is approved for the treatment of unresectable hepatocellular carcinoma (HCC). TRC105 is an antibody to endoglin, an important angiogenic target on proliferating endothelial cells that is distinct from VEGFR. TRC105 inhibits angiogenesis, tumor growth and metastases and complements the activity of bevacizumab and multi-kinase inhibitors that target the VEGFR in preclinical models. Together, the use of TRC105 with sorafenib may result in more effective angiogenesis inhibition and improved clinical efficacy over that seen with sorafenib alone.

Arms: arm 1: Carotuximab (TRC105) in combination with standard dose Sorafenib.
Interventions: intervention 1: Carotuximab (TRC105) intervention 2: Sorafenib
Intervention descriptions: intervention 1: Bi-weekly iv TRC105 (15 mg/kg) will be given with 400mg sorafenib twice daily in the phase 1B portion of the study. Weekly iv TRC105 (10 mg/kg) will be given with 400mg sorafenib twice daily in the phase 2 portion of the study. intervention 2: 400 mg of sorafenib will be given twice daily.

Protocol documents:
Prot_SAP_000.pdf: 


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The information in this document is confidential and proprietary.  Any other distribution, copying or disclosure is strictly prohibited unless 
required by federal regulations or state law.  Persons receiving this information must be notified that it is confidential and may not be further 
disclosed. 


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PROCEDURES IN CASE OF EMERGENCY 
Table 1: 
Emergency Contact Information 
Role in Study 
Name 
Address and Telephone number 
Medical Monitor 
Charles Theuer MD PhD 
4350 La Jolla Village Drive, Suite 800 
San Diego, CA 92122 
Office: (858) 550-0780 x233 
Mobile Phone: (858) 344-9400 
Email: ctheuer@traconpharma.com 
Secondary Medical Monitor 
James Freddo MD 
4350 La Jolla Village Drive, Suite 800 
San Diego, CA 92122 
Mobile Phone: (858) 472-2330 
Email: jfreddo@traconpharma.com 
 


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1. 
SYNOPSIS 
Name of Sponsor/Company: TRACON Pharmaceuticals, Inc.  
Name of Investigational Product: TRC105 
Name of Active Ingredient: TRC105 
Title of Study:  
AN OPEN LABEL PHASE 1B/2 TRIAL OF TRC105 AND SORAFENIB IN PATIENTS WITH 
HEPATOCELLULAR CARCINOMA (HCC) 
Study center(s): This study will be performed at approximately 5 US centers (sites to be 
determined). 
Investigators: To be determined 
Studied period (years):  
Date first patient enrolled phase 1b portion: Nov 2016 
Estimated Date phase 1b MTD obtained: January 2018 
Estimated date first patient enrolled phase 2 portion: March 2018 
Estimated date phase 2 endpoint obtained: May 2019 
Estimated date last patient completed: May 2019 
Phase of development: 1b/2 
 
Rationale:  
Sorafenib is an oral multikinase inhibitor targeting several receptor tyrosine kinases, including the VEGF 
receptor (VEGFR), implicated in pathologic angiogenesis, tumor growth, and cancer progression.  
Sorafenib is approved for the treatment of unresectable hepatocellular carcinoma (HCC). TRC105 is an 
antibody to endoglin, an important angiogenic target on proliferating endothelial cells that is distinct 
from VEGFR.  TRC105 inhibits angiogenesis, tumor growth and metastases and complements the 
activity of bevacizumab and multi-kinase inhibitors that target the VEGFR in preclinical models.  
Together, the use of TRC105 with sorafenib may result in more effective angiogenesis inhibition and 
improved clinical efficacy over that seen with sorafenib alone.   
A phase 1b/2 study of TRC105 with standard dose sorafenib was conducted by the NCI.  Twenty 
patients were treated with sorafenib (400 mg BID) and 3, 6, 10 or 15mg/kg TRC105 every 2 weeks. The 
majority of patients had HCC with cirrhosis and compensated liver dysfunction (Childs Pugh A/B7) and 
an ECOG of 0/1. Overall, treatment was tolerable and the study proceeded as per protocol to the 
maximum planned dose level of TRC105 (15mg/kg every 2 weeks) in combination with 400 mg BID of 
sorafenib. Dose limiting transaminase elevation was encountered in a single patient at 10 mg/kg of 
TRC105 every 2 weeks and the cohort was expanded. One grade 5 cardiac event of myocardial 
infarction in a patient with preexisting coronary artery disease was observed in which the contribution of 
protocol treatment could not be excluded. The most common side-effect was hand-foot skin reaction 
attributed to sorafenib. Four of 10 patients (40%) treated at the top two dose levels of TRC105 (10 
mg/kg every two weeks and 15 mg/kg every two weeks) had RECIST defined partial responses and the 
majority of patients had tumor reductions.  


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An additional partial response was reported in one of the initial four patients treated in the Phase 2 
portion of the study. Median time on study was 4 months and one patient remained on treatment for 22 
months.  
Given the results from the phase 1b portion of the NCI study, TRACON is conducting this multicenter 
phase 1b/2 study to assess the safety, tolerability and activity of TRC105 with standard dose sorafenib.  
This study includes an initial phase 1b dose escalation portion in order to assess the safety of TRC105 
given at 10 mg/kg weekly for four weeks followed by 15 mg/kg every 2 weeks by i.v. infusion with daily 
sorafenib. A maximum of 21 additional patients will be treated in the phase 2 portion to assess the 
overall response rate to TRC105 and sorafenib. The recommended phase 2 dose of TRC105 is 10 mg/kg 
weekly in combination with 400 mg sorafenib twice daily.  Ongoing patients in the Phase 1b portion 
of this study may, at the discretion of the investigator, be treated at the Phase 2 TRC105 dose of 
10 mg/kg weekly. 
Objectives:  
Phase 1b: 
Primary: 
• 
To determine a recommended phase 2 dose for TRC105 by i.v. infusion when given with 
standard dose sorafenib in patients with hepatocellular carcinoma 
Secondary: 
• 
To determine the frequency and severity of adverse events as assessed by NCI CTCAE 
(Version 4.03) 
• 
To characterize the pharmacokinetic profile of TRC105 and sorafenib when given together 
• 
To evaluate TRC105 immunogenicity as assessed by Anti-Product Antibody (APA)  
• 
To assess preliminary evidence of antitumor activity when TRC105 is added to sorafenib, by 
assessing overall response rate (ORR), progression-free survival (PFS) and overall survival 
(OS) 
• 
To explore changes in circulating angiogenic biomarkers following treatment with TRC105 
and sorafenib 
Phase 2: 
Primary: 
• 
To estimate the ORR by RECIST 1.1 of patients with unresectable hepatocellular carcinoma 
given TRC105 and sorafenib 
Secondary: 
• 
To determine duration of response by RECIST 1.1  
• 
To estimate PFS by RECIST 1.1, and determine overall survival (OS)   
• 
To determine the frequency and severity of adverse events as assessed by NCI CTCAE 
(Version 4.03) 
• 
To characterize the pharmacokinetic profile of TRC105 and sorafenib when given together 


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• 
To evaluate TRC105 immunogenicity as measured by APA 
• 
To explore changes in circulating angiogenic biomarkers following treatment with TRC105 
and sorafenib 
• 
To prospectively assess IGF-1-modified Child-Pugh score [1] and outcomes in patients with 
HCC treated with sorafenib and TRC105 
Methodology:  
Phase 1b: 
This is a multicenter, open-label, nonrandomized, phase 1b, dose-finding study of TRC105 in 
combination with standard dose sorafenib in patients with unresectable HCC.  Escalating doses of i.v. 
TRC105 will be administered weekly or every two weeks, beginning with Dose Level 1 in combination 
with oral sorafenib given at 400 mg twice daily of each 28-day cycle.  Sorafenib dose modifications are 
allowed starting in cycle 1, per the package insert and as outlined in section Section 7.8.6. 
Dose Levela 
Number of Evaluable 
Subjects 
Sorafenib mg p.o., 
b.i.d. days 1-28 
TRC105 
mg/kg 
IV 
-1 
3-6 
400 
10 (weekly C1), 10 
(every 2 weeks C2+)  
1 
(starting dose) 
3-6 
400 
10 (weekly C1), 15 
(every 2 weeks C2+)b 
aAdditional intermediate doses (below the MTD established during the trial) may be explored based upon clinical, 
PK, and/or biomarker data 
bTRC105 will be administered weekly during cycle 1. The first weekly TRC105 dose will be split into two doses 
whereby 3 mg/kg is administered on cycle 1 day 1 and the balance is administered on cycle 1 day 4. Starting on 
cycle 2 day 1 and beyond, TRC105 will be administered every two weeks on days 1 and 15. 
Patients will be initially enrolled and treated at dose level 1. If <33% of patients experience a dose-
limiting toxicity (DLT) during the 56-day evaluation period (cycle 1through the end of cycle 2), dose 
escalation will proceed following review of safety data with appropriate site staff including the principal 
investigators at all sites.  At least 6 patients will be evaluated at the MTD (or highest dose administered 
if MTD is not reached) to confirm safety and tolerability. Additional patients may be enrolled at Dose 
Level 1 (as long as it does not exceed the MTD) to obtain additional safety and PK information. 
If 1 of 3 patients experiences DLT, the dose level will be expanded to 6 patients.  The maximum 
tolerated dose (MTD) will have been exceeded if ≥ 33% of patients experience DLT at a given dose 
level.  DLT will have occurred when a patient has 1 or more toxicity listed in the table below that is at 
least possibly related to TRC105 during the first 56 days (cycle 1 and 2).  Patients who exit the study for 
reasons other than DLT prior to completion of the 56-day DLT evaluation period will be replaced to 
ensure an adequate safety assessment at each dose level.  Patients who experience DLT and those 
without DLT who receive less than the prescribed dose of sorafenib due to documented toxicity in Cycle 
1 or 2 will be considered evaluable for dose escalation purposes.  Upon agreement of the study 
investigators, a given TRC105 dose level may be reenrolled at 400 mg daily or 400 mg every other day 
of sorafenib and/or the first dose of TRC105 may be delayed by one week (i.e., delayed to cycle 1 
day 8).   


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Toxicity Category Drug-Related Toxicity/Grade 
Hematologic 
Grade 4 neutropenia for ≥ 5 days 
Febrile neutropenia: grade 4 neutropenia with fever > 38.5 ºC both sustained 
over a 24 hour period. 
Neutropenic infection: grade ≥ 3 neutropenia with grade ≥ 3 infection 
Anemia ≥ grade 4  
Grade > 4 thrombocytopenia or grade ≥ 3 thrombocytopenia and grade ≥ 3 
hemorrhage 
Nonhematologic 
Grade 3 or 4 nonhematologic toxicity with the following exceptions: 
• 
Nausea, vomiting or diarrhea for < 48 hoursa 
• 
Asymptomatic electrolyte abnormalities that are corrected to grade 1 
or better in < 48 hoursb 
• 
Grade 3 hypertension that can be controlled with oral medications and 
does not require treatment delay for > 7 days or dose reduction 
• 
Grade 3 rise in creatinine corrected to Grade 1 or less after 2 liters of 
intravenous fluids within 24 hours. 
• 
Grade 3 elevation in transaminases that is reversible following 
sorafenib dose reduction or interruption. 
• 
Grade 3 rash that decreases to ≤ Grade 2 after 1 week of symptomatic 
treatment. 
• 
Grade 3 hand-foot syndrome 
aPatients with related grade 3 or 4 diarrhea, nausea or vomiting for ≥ 48 hours despite optimal medical therapy will 
require a one-level dose-reduction of TRC105 as outlined in Section 7.7.1. 
bPatients with related grade 3 or 4 electrolyte abnormalities that persist for ≥ 48 hours will require a one-level dose 
reduction of TRC105 as outlined in Section 7.7.1.  
 
Phase 2:  
This is a multicenter, non-randomized, phase 2 study of TRC105 in combination with standard 
dose sorafenib. A maximum of 21 patients will be treated in the phase 2 portion of the study. 
Following completion of the Phase 1 portion of the study and discussions of Phase 1 safety and 
PK data with the study principal investigators, continuous weekly dosing with TRC105 at 10 
mg/kg was selected as the recommended Phase 2 dose.  Patients will receive TRC105 at 10 
mg/kg weekly in combination with 400 mg sorafenib twice daily.  Ongoing patients in the Phase 
1b portion of this study may, at the discretion of the investigator, be treated at the Phase 2 
TRC105 dose of 10 mg/kg weekly.  Each cycle is 28 days in duration.  
Number of patients (planned):  
Approximately 6-12 patients with unresectable hepatocellular carcinoma will be enrolled in the phase 1b 
portion and a maximum of 21 patients will be enrolled in the phase 2 portion. 
Diagnosis and main criteria for inclusion:  


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Inclusion Criteria: 
1. Patients must have confirmed hepatocellular carcinoma (HCC) by either histopathology or 
radiography.  Diagnosis of HCC can be made without a biopsy if radiographic hallmarks of 
arterial hypervascularity and venous/late phase washout are present by either dynamic contrast-
enhanced MRI or helical multidetector CT scan using contrast for a lesion > 2 cm, or by both 
modalities for a lesion 1-2 cm. [2].  
2. Patients must have disease that is not amenable to potentially curative resection or ablative 
techniques or that has recurred following ablative techniques. In addition, disease must not be 
amenable to transhepatic arterial chemoembolization (TACE) or must have progressed on 
TACE. Patients must not be candidates for liver transplantation. 
3. Patient must have a Child-Pugh A or B (7 points) classification 
4. No other prior malignancy is allowed except for the following: adequately treated basal cell or 
squamous cell skin cancer, or adequately treated Stage I or II cancer from which the patient is 
currently in complete remission per investigators' clinical judgment.  
5. Measurable disease by RECIST 1.1 (Phase 2 only) 
6. Age of 18 years or older 
7. ECOG performance status ≤ 1 
8. Resolution of all acute adverse events resulting from prior cancer therapies to NCI CTCAE 
grade ≤ 1 or baseline (except alopecia)   
9. Adequate organ function as defined by the following criteria: 
• 
AST and ALT ≤ 5 x ULN    
• 
Absolute neutrophil count (ANC) ≥ 1500/μL  
• 
Platelets ≥ 60,000/μL without transfusion support within the past 28 days 
• 
Hemoglobin ≥ 9.0 g/dL without transfusion support within the past 14 days (erythropoietin 
or darbepoietin permitted) 
• 
Serum creatinine clearance > 30 mL/min by Cockcroft-Gault formula 
10. Willingness and ability to consent to participate in study   
11. Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests, and 
other study procedures   
12. Men who are sterile (including vasectomy confirmed by post vasectomy semen analysis) OR 
agree to use at least two forms of a reliable and highly effective method of birth control (refer to 
Section 3.5.2.1) and to not donate sperm and for at least 180 days following last dose of TRC105 
or sorafenib. 
13. Woman of non-child bearing potential due to surgical sterilization (at least 6 weeks following 
surgical bilateral oophorectomy with or without hysterectomy or tubal ligation) confirmed by 
medical history or menopause (i.e., no menstrual bleeding for more than 12 months in a women 
aged 45 years or more), OR woman of child bearing potential who test negative for pregnancy at 
time of enrollment based on serum pregnancy test and agree to use at least 2 forms of a reliable 


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and highly effective method of birth control during the study and for at least 180 days after 
stopping TRC105 or sorafenib (refer to Section 3.5.2.1). 
Exclusion Criteria:   
1. Prior anticancer systemic therapy  
2. Current treatment on another therapeutic clinical trial 
3. Prior radiation therapy within 28 days of starting the study treatment, except radiation therapy 
for bone metastases or radiosurgery is permitted up to 14 days of starting treatment 
4. No major surgical procedure or significant traumatic injury within 6 weeks prior to study 
registration, and must have fully recovered from any such procedure; date of surgery (if 
applicable). Note: the following are not considered to be major procedures and are permitted up 
to 7 days before therapy initiation: Thoracentesis, paracentesis, port placement, laparoscopy, 
thorascopy, tube thoracostomy, bronchoscopy, endoscopic ultrasonographic procedures, 
mediastinoscopy, skin biopsies, incisional biopsies, imaging-guided biopsy for diagnostic 
purposes, and routine dental procedures 
5. 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. 
6. Uncontrolled chronic hypertension defined as systolic > 150 or diastolic > 90 on more than one 
measurement despite optimal therapy (initiation or adjustment of BP medication prior to study 
entry is allowed provided that the average of 3 BP readings prior to enrollment is < 150/90 mm 
Hg) 
7. History of brain involvement with cancer, spinal cord compression, or carcinomatous meningitis, 
or new evidence of brain or leptomeningeal disease.  Patients with radiated or resected lesions 
are permitted, provided the lesions are fully treated and inactive, patients are asymptomatic, and 
no steroids have been administered for at least 28 days.   
8. Angina, MI, symptomatic congestive heart failure, cerebrovascular accident, transient ischemic 
attack, arterial embolism, pulmonary embolism, PTCA or CABG within the past 6 months.  
9. Active bleeding or pathologic condition that carries a high risk of bleeding (e.g. hereditary 
hemorrhagic telangiectasia).  No bleeding diathesis. 
10. Thrombolytic use (except to maintain i.v. catheters) within 10 days prior to first day of study 
therapy 
11. History of hemorrhage or hemoptysis (> ½ teaspoon bright red blood) within 3 months of 
starting study treatment 
12. Need for anticoagulation 
13. History of liver transplant 
14. History of bleeding esophageal varices in previous 6 months, which have not been adequately 
managed with banding or sclerotherapy (i.e., following treatment, varices must be ≤ grade 1 with 
no stigmata of recent bleeding). Patients with cirrhosis must have had esophagogastric 
endoscopy within the past 6 months prior to study entry for the assessment of varices, and 
esophageal varices must be ≤ grade 1 with no stigmata of recent bleeding. Those with gastric 


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varices that are deemed as high risk by the endoscopist should be placed on appropriate medical 
therapy as advised by the gastroenterologist. 
15. History of peptic ulcer disease within 3 months of treatment, unless treated for the condition and 
complete resolution has been documented by esophagogastroduodenoscopy (EGD) within 28 
days of starting study treatment 
16. Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS) 
related illness 
17. Patients may not have received a strong CYP3A4 inducer within 12 days prior to registration 
(Table 19) 
18. Patients with known hypersensitivity to Chinese hamster ovary products or other recombinant 
human, chimeric, or humanized antibodies. 
19. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that 
may increase the risk associated with study participation or may interfere with the interpretation 
of study results and, in the judgment of the Investigator, would make the patient inappropriate 
for this study 
20. Ascites or pleural effusion requiring intervention or that required intervention within the 
last month and has recurred 
21. Pericardial effusion (except trace effusion identified by echocardiogram) 
 
TRC105 investigational product dose and mode of administration:  
Phase 1b: 
Dosing will begin at 10 mg/kg weekly in cycle 1 and 15 mg/kg every two weeks beginning with cycle 
2(Dose Level 1); however, a -1 dose level has also been included of 10 mg/kg weekly in cycle 1 and 10 
mg/kg every two weeks beginning with cycle 2 that will be enrolled if Dose Level 1 is found to exceed 
the MTD.  Upon agreement of the study investigators, a given TRC105 dose level may be reenrolled at 
400 mg daily or 400 mg every other day of sorafenib and/or the first dose of TRC105 may be delayed by 
one week (i.e., delayed to cycle 1 day 8).  Following the appropriate premedication regimen, the first 
weekly TRC105 dose will be split into two doses whereby 3 mg/kg is administered on cycle 1 day 1 and 
the balance is administered on cycle 1 day 4. Beginning with cycle 1 day 8 and for the rest of cycle 1, the 
full (e.g., 10 mg/kg) TRC105 dose will be administered i.v. weekly.  Starting on cycle 2 day 1 and 
beyond, TRC105 will be administered at a dose of 15 mg/kg (Dose Level 1) every two weeks on days 1 
and 15 of each 28-day cycle.        
Phase 2:  
 Following completion of the Phase 1 portion of the study and discussions of Phase 1 safety and PK data 
with the study principal investigators, continuous weekly dosing with TRC105 at 10 mg/kg was selected 
as the recommended Phase 2 dose in combination with 400 mg sorafenib twice daily.  Ongoing patients 
in the Phase 1b portion of this study may, at the discretion of the investigator, be treated at the Phase 2 
TRC105 dose of 10 mg/kg weekly.  Following the appropriate premedication regimen, TRC105 is to be 
administered intravenously.   
Sorafenib dose and administration: 
Sorafenib will be dosed at its approved dose of 400 mg p.o. b.i.d. daily. Sorafenib dose modifications are 
allowed starting in cycle 1 in accordance with the package insert and as outlined in Section 7.8.6. 


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Duration of treatment:  
Patients are eligible for treatment until disease progression, unacceptable toxicity or withdrawal of 
consent, or other reasons.  Phase 1b patients may be withdrawn for DLT, but DLT does not mandate 
withdrawal if the DLT resolves and can be treated (i.e., a first dose infusion reaction).  A patient should 
be withdrawn from study treatment if, in the opinion of the Investigator, it is medically necessary, or if it 
is the wish of the patient.  In addition, patients will be withdrawn from treatment in the case of: 
1. RECIST 1.1-defined disease progression. In cases where RECIST cannot be applied, 
progression should be based on unequivocal evidence of progressive disease sufficient to 
require a change in therapy. 
2. A need for anticancer surgery, radiation, or for other anticancer therapy not specified in the 
protocol. 
3. Lost to follow-up or noncompliant. 
4. Any TRC105 dose delay > 2 days in cycle 1 (phase 1b only) unless discussed with sponsor. 
5. Pregnancy.  Pregnant patients should be followed for the duration of the pregnancy and the 
outcome of the pregnancy should be documented. 
6. Arterial thrombosis of any grade (including cerebrovascular ischemia, cardiac 
ischemia/infarction, or peripheral or visceral arterial ischemia), grade 3 or 4 venous 
thrombosis (including pulmonary embolism), grade > 2 intracranial hemorrhage, grade 3 or 
4 non-CNS hemorrhage. Grade 2 non-CNS hemorrhage does not mandate withdrawal if the 
underlying condition is treatable.  Grade 1 intracranial hemorrhage does not mandate 
withdrawal and may be treated with dose interruption if the patient is benefitting from 
treatment.  
7. Missed study drug treatment for > 8 consecutive weeks (i.e., both TRC105 and sorafenib 
dosing held).  Patients who cannot tolerate sorafenib and who demonstrate a response of 
complete response (CR), partial response (PR) or stable disease (SD) and are thought to 
benefit from continued single agent TRC105 therapy may continue on study on TRC105 
alone. 
Parameters to be assessed: 
Safety: 
 
Safety assessments will include physical exams, performance status, laboratory results (complete blood 
counts and serum chemistry) and 12-lead ECG’s, and additional studies as clinically indicated.  Safety 
parameters will be reviewed by a chartered Safety Review Team that reviews data for all TRC105 
studies quarterly. In addition, recurring teleconferences will be held with Investigators at all clinical sites 
(Section 9.4).   
 
Pharmacokinetics: 
Serum TRC105 and sorafenib concentrations will be measured using validated methods at the time 
points specified in the Schedule of Events. 
Immunogenicity: 
Serum will be evaluated using validated methods at time points specified in the Schedule of Events. 
 
 


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Exploratory Biomarkers: 
Concentrations of a panel of angiogenic protein biomarkers in plasma will be measured at baseline and 
during treatment to explore TRC105 pharmacodynamics. Archival tumor specimens will be collected for 
assessment of endoglin expression. 
Efficacy: 
RECIST 1.1 will be applied to measurable disease to assess response and progression.   
Statistical methods: 
Evaluable Study Population: 
Phase 1b: 
The study population for safety and efficacy includes all patients receiving at least a portion of 1 dose of 
TRC105.  
The number of patients to be enrolled in this study will depend upon the observed safety profile, which 
will determine the number of patients per dose level and the number of dose escalations.  It is anticipated 
that a total of approximately 6 patients will be enrolled in the phase 1b portion. 
The probability of escalation to the next higher dose for each underlying true DLT rate is shown in the 
table below.  For example, for a toxicity that occurs in 5% of patients, there is a > 95% probability of 
escalating.  Conversely, for a common toxicity that occurs with a rate of 70%, the probability of 
escalating is < 5%. 
Probability of Escalation to the Next Dose for Each True Underlying DLT Rate at a Dose Level 
True Underlying DLT 
Rate 
5% 
10% 20% 30% 40% 50% 60% 70% 80% 
90% 
Probability of Escalating 
Dose 
0.97 
0.91 
0.71 
0.49 
0.31 
0.17 
0.08 
0.03 
0.01 
0.001 
The probability of failing to observe toxicity in a sample size of 3 or 6 patients given various true 
underlying toxicity rates in shown in the table below.  For example, with 6 patients, the probability of 
failing to observe toxicity occurring at least 40% of the time is < 5%. 
Probability of Failing to Observe True Underlying DLT Rate at a Dose Level 
True Underlying 
DLT Rate 
5% 
10% 20% 30% 40% 
50% 
60% 
70% 
80% 
90% 
Probability of 
Failing to Observe 
Toxicity, N = 3 
0.86 
0.73 
0.51 
0.34 
0.22 
0.13 
0.006 
0.027 
0.008 
0.001 
Probability of 
Failing to Observe 
Toxicity, N = 6 
0.74 
0.53 
0.26 
0.12 
0.05 
0.016 0.004 <0.001 <0.001 <0.001 
The maximum tolerated dose (MTD) will have been exceeded if ≥ 33% of patients experience DLT at a 
given dose level. 
 


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Phase 2: 
Efficacy Analyses 
The primary endpoint of the phase 2 study is objective response (CR or PR) at any time during 
treatment.  The sample size is determined using Simon’s two-stage minimax design.  This design will be 
used to test the null hypothesis that the true objective tumor response rate is < 5% versus the alternative 
hypothesis that the true response rate is > 20%.  
One or more responses by RECIST 1.1 must be observed in the initial 12 patients enrolled to enroll the 
second stage, to a total of 21 patients.  Three or more responses by RECIST of 21 patients will be 
considered sufficiently interesting to warrant further study in later trials.  
 
Phase 2 Sample size justification: 
With an alpha level of 0.1 and 80% power, a maximum of 21 treated patients will be required to evaluate 
the ORR.  Twelve patients will be treated in stage 1.  If < 1 objective response is observed in the first 12 
patients, then the trial will be terminated, and the alternative hypothesis that the true ORR probability is 
> 20 % will be rejected.  However, if one or more responses are observed in the first 12 patients, then the 
study will be expanded to enroll a total of 21 treated patients (9 additional patients to be treated in stage 
2).  At the end of the study, if > 3 objective responses are observed then the null hypothesis that the true 
response rate probability is < 5% will be rejected and further investigation of TRC105 and sorafenib in 
this population is warranted. Under this design, the expected sample size is 21. The probability of early 
termination under the null hypothesis is 50%. 
The study will continue to enroll patients after the 12th patient has been enrolled unless no response is 
observed. If there is no patient achieving response at the time the 12th patient has been enrolled, the 
enrollment will be stopped temporarily. Once one patient is observed to have response, the enrollment 
will be resumed. However, if there is no patient achieving response after the first 12 patients have been 
fully evaluated, the study will be stopped for the futility.   
 


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2. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES  
TABLE OF CONTENTS 
PROCEDURES IN CASE OF EMERGENCY ...............................................................................3 
1. 
SYNOPSIS ...................................................................................................................4 
2. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ...............14 
TABLE OF CONTENTS ...............................................................................................................14 
LIST OF TABLES .........................................................................................................................18 
LIST OF FIGURES .......................................................................................................................19 
3. 
BACKGROUND ........................................................................................................23 
3.1. 
Hepatocellular Carcinoma ..........................................................................................23 
3.1.1. 
Hepatocellular Carcinoma (HCC): sorafenib and angiogenesis .................................23 
3.2. 
CD105 and Angiogenesis ...........................................................................................23 
3.3. 
TRC105 Background ..................................................................................................24 
3.3.1. 
Phase 1 TRC105 Monotherapy Study Design for Solid Cancers ...............................25 
3.3.1.1. 
Phase 1 TRC105 Monotherapy Pharmacokinetics .....................................................25 
3.3.1.2. 
Phase 1 TRC105 Monotherapy Immunogenicity .......................................................26 
3.3.1.3. 
Phase 1 TRC105 Monotherapy Safety .......................................................................27 
3.3.1.4. 
Phase 1 TRC105 Monotherapy Efficacy ....................................................................28 
3.3.2. 
Phase 1b Study of TRC105 with Bevacizumab ..........................................................28 
3.3.2.1. 
Summary of Safety .....................................................................................................28 
3.3.2.2. 
Summary of Efficacy ..................................................................................................29 
3.4. 
Phase 1b Trial of TRC105 and Sorafenib and other VEGFR TKI .............................30 
3.5. 
Study Rationale ...........................................................................................................31 
3.5.1. 
Population to be Studied .............................................................................................32 
3.5.2. 
Potential Risks and Benefits to Human Patients.........................................................32 
3.5.2.1. 
Potential Risks ............................................................................................................32 
3.5.2.2. 
Potential Benefits ........................................................................................................34 
3.5.3. 
Conduct .......................................................................................................................34 
4. 
TRIAL OBJECTIVES AND PURPOSE ....................................................................35 
4.1. 
Purpose .......................................................................................................................35 
4.1.1. 
Phase 1b Trial Objectives ...........................................................................................35 


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4.1.1.1. 
Phase 1b Primary: .......................................................................................................35 
4.1.1.2. 
Phase 1b Secondary ....................................................................................................35 
4.1.2. 
Phase 2 Trial Objectives .............................................................................................35 
4.1.2.1. 
Phase 2 Primary ..........................................................................................................35 
4.1.2.2. 
Phase 2 Secondary: .....................................................................................................35 
5. 
INVESTIGATIONAL PLAN .....................................................................................37 
5.1. 
Overall Study Design and Plan ...................................................................................37 
5.1.1. 
Overview .....................................................................................................................37 
5.1.1.1. 
Phase 1b Overview .....................................................................................................37 
5.1.1.2. 
Phase 2 Overview .......................................................................................................39 
5.1.2. 
Trial Procedures ..........................................................................................................39 
5.1.2.1. 
Screening ....................................................................................................................39 
5.1.2.2. 
Trial Period .................................................................................................................40 
5.1.3. 
End of Study Assessments ..........................................................................................42 
5.1.4. 
Post Treatment Follow-up ..........................................................................................43 
6. 
SELECTION AND WITHDRAWAL OF PATIENTS ..............................................52 
6.1. 
Patient Inclusion Criteria ............................................................................................52 
6.1.1. 
Inclusion Criteria: .......................................................................................................52 
6.1.2. 
Exclusion Criteria: ......................................................................................................53 
6.2. 
Patient Withdrawal Criteria ........................................................................................54 
7. 
TREATMENT OF PATIENTS ..................................................................................56 
7.1. 
Description of TRC105 Study Drug ...........................................................................56 
7.2. 
Composition of TRC105.............................................................................................56 
7.3. 
TRC105 Dose Level ...................................................................................................56 
7.3.1. 
Phase 1b ......................................................................................................................56 
7.3.2. 
Phase 2 ........................................................................................................................56 
7.4. 
TRC105 Packaging and Labeling ...............................................................................57 
7.5. 
TRC105 Storage and Shipping ...................................................................................57 
7.6. 
TRC105 Preparation ...................................................................................................57 
7.7. 
TRC105 Administration .............................................................................................58 
7.7.1. 
TRC105 Dose Reduction/Dose Delays ......................................................................60 
7.7.2. 
Management of TRC105 Infusion Reactions .............................................................62 


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7.7.3. 
TRC105 Study Drug Accountability ..........................................................................63 
7.7.4. 
TRC105 Study Drug Handling and Disposal .............................................................63 
7.8. 
Description of Sorafenib .............................................................................................64 
7.8.1. 
Composition of Sorafenib ...........................................................................................64 
7.8.2. 
Sorafenib Dose Level .................................................................................................64 
7.8.3. 
Sorafenib Packaging and Labeling .............................................................................64 
7.8.4. 
Sorafenib Storage Handling and Disposal ..................................................................64 
7.8.5. 
Sorafenib Dosing ........................................................................................................64 
7.8.6. 
Sorafenib Dose Modification ......................................................................................64 
7.8.7. 
Sorafenib Drug Accountability ...................................................................................68 
7.9. 
Concomitant Medications ...........................................................................................68 
7.10. 
Treatment Compliance ................................................................................................70 
7.10.1. 
TRC105 Treatment Compliance .................................................................................70 
7.10.2. 
Sorafenib Treatment Compliance ...............................................................................70 
7.11. 
Patient Enrollment ......................................................................................................70 
8. 
ASSESSMENT OF EFFICACY ................................................................................71 
8.1. 
Radiological Tumor Assessment ................................................................................71 
8.1.1. 
Measurability of Tumor Lesions ................................................................................71 
8.1.1.1. 
Recording Tumor Measurements ...............................................................................72 
8.1.2. 
Definitions of Tumor Response ..................................................................................72 
8.1.2.1. 
Target Lesions ............................................................................................................72 
8.1.2.2. 
Non-Target Lesions ....................................................................................................72 
8.1.2.3. 
Determination of Overall Response ............................................................................73 
8.1.2.4. 
Determination of Overall Response by the RECIST Criteria .....................................73 
9. 
ASSESSMENT OF SAFETY .....................................................................................75 
9.1. 
Safety Parameters .......................................................................................................75 
9.1.1. 
Laboratory Safety Assessments ..................................................................................75 
9.1.1.1. 
Hematology, Serum Chemistry, Coagulation, Pregnancy Test ..................................75 
9.1.1.2. 
Urinalysis ....................................................................................................................76 
9.1.1.3. 
Physical Examination .................................................................................................76 
9.1.1.4. 
Vital Signs ..................................................................................................................76 
9.1.1.5. 
Performance Status .....................................................................................................76 


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9.1.1.6. 
ECG ............................................................................................................................76 
9.2. 
Adverse Events ...........................................................................................................76 
9.2.1. 
Definition of Adverse Event .......................................................................................76 
9.2.2. 
Serious Adverse Events ..............................................................................................77 
9.2.2.1. 
Hospitalization ............................................................................................................78 
9.3. 
Reporting Adverse Events ..........................................................................................79 
9.3.1. 
Eliciting Adverse Event Information ..........................................................................79 
9.3.2. 
Adverse Event Reporting Period ................................................................................79 
9.3.3. 
Reporting Requirements .............................................................................................79 
9.3.4. 
Recording Adverse Events in the Case Report Forms ................................................81 
9.3.5. 
Grading of Adverse Event Severity ............................................................................81 
9.3.6. 
Relationship to TRC105 Study Drug/Sorafenib .........................................................81 
9.3.7. 
Expectedness ...............................................................................................................82 
9.3.8. 
Exposure in Utero .......................................................................................................82 
9.3.9. 
Follow-up of Unresolved Adverse Events ..................................................................83 
9.4. 
Safety Monitoring .......................................................................................................83 
10. 
OTHER ASSESSMENTS ..........................................................................................84 
10.1. 
Other Laboratory Assessments ...................................................................................84 
10.1.1. 
Pharmacokinetics ........................................................................................................84 
10.1.1.1. 
TRC105 Trough Concentration ..................................................................................84 
10.1.1.2. 
Sorafenib Trough Concentration ................................................................................84 
10.1.2. 
TRC105 Immunogenicity ...........................................................................................84 
10.1.3. 
Protein Biomarkers .....................................................................................................84 
10.1.4. 
Archival Tumor Specimens ........................................................................................85 
11. 
STATISTICS ..............................................................................................................86 
11.1. 
Phase 1b ......................................................................................................................86 
11.1.1. 
Phase 1b Statistical Design/Sample Size ....................................................................86 
11.1.1.1. 
Phase 1b Definition of Analyzed Study Populations ..................................................86 
11.2. 
Phase 2 ........................................................................................................................87 
11.2.1. 
Phase 2 Statistical Design/Sample Size ......................................................................87 
11.2.1.1. 
Phase 2 Definition of Analyzed Study Populations ....................................................87 
11.3. 
Data Analysis ..............................................................................................................88 


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11.4. 
Analysis of Primary and Secondary Objectives .........................................................88 
11.4.1. 
Phase 1b ......................................................................................................................88 
11.4.2. 
Phase 2 ........................................................................................................................88 
11.5. 
Analysis of Pharmacokinetics .....................................................................................89 
11.6. 
Analysis of Protein Biomarkers ..................................................................................89 
11.7. 
Analysis of Immunogenicity .......................................................................................89 
11.8. 
Analysis of Archival Tumor Tissue ............................................................................89 
12. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................90 
13. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................91 
14. 
ETHICS ......................................................................................................................92 
14.1. 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) ..................92 
14.2. 
Ethical Conduct of the Study ......................................................................................92 
14.3. 
Written Informed Consent ..........................................................................................92 
14.4. 
Patient Compensation .................................................................................................93 
15. 
DATA HANDLING AND RECORDKEEPING .......................................................94 
15.1. 
Inspection of Records .................................................................................................94 
15.2. 
Retention of Records ..................................................................................................94 
16. 
DEFINITION OF END OF TRIAL ...........................................................................96 
16.1. 
End of Trial in all Participating Countries ..................................................................96 
16.2. 
End of Trial in a Member State ..................................................................................96 
16.3. 
TRACON Discontinuation Criteria ............................................................................96 
17. 
PUBLICATION OF TRIAL RESULTS ....................................................................97 
18. 
FINANCING AND INSURANCE .............................................................................98 
19. 
INVESTIGATOR PROTOCOL AGREEMENT: 105HCC101 .................................99 
20. 
REFERENCES .........................................................................................................100 
21. 
APPENDICES ..........................................................................................................104 
21.1. 
Appendix 1:  National Cancer Institute (NCI) Common Terminology 
Criteria for Adverse Events (CTCAE) .....................................................................104 
21.2. 
Appendix 2:  ECOG Performance Status .................................................................105 
21.3. 
Appendix 3:  Sorafenib Prescribing Information......................................................106 
 
LIST OF TABLES 


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Table 1: 
Emergency Contact Information ...................................................................................3 
Table 2: 
Abbreviations and Specialist Terms ...........................................................................20 
Table 3: 
Dose Levels ................................................................................................................38 
Table 4: 
Dose Limiting Toxicity Definition and Criteria .........................................................38 
Table 5: 
Schedule of Assessments (Phase 1b) ..........................................................................44 
Table 6: 
Schedule of Assessments (Phase 2) ............................................................................48 
Table 7: 
Ideal TRC105 Dosing Schema for Phase 1b Dose Levels -1 and 1 (10 mg/kg 
weekly C1, 10 or 15 mg/kg every 2 weeks C2+) .......................................................59 
Table 8: 
 Ideal TRC105 Dosing Schema for Phase 2 (10 mg/kg weekly C1+) ........................59 
Table 9: 
Allowable TRC105 Dose Modifications ....................................................................60 
Table 10: TRC105 dosing after Dose Delay (with no split dosing) ...........................................61 
Table 11: TRC105 Dosing after Dose Delay (with split dosing) ................................................62 
Table 12: Management of TRC105 Infusion Reactions .............................................................62 
Table 13: Sorafenib Dose Modification Levels ..........................................................................64 
Table 14: Dose Modification for Hematologic Toxicities ..........................................................65 
Table 15: Dose Modification for Non-hematologic Toxicities...................................................65 
Table 16: Dose Modifications for Hand-Foot-Skin Reaction .....................................................66 
Table 17: Recommended Prevention/Management Strategies for Skin Toxicities 
Consistent With HFSR ...............................................................................................67 
Table 18: Management of Treatment-Emergent Hypertension ..................................................68 
Table 19: Strong CYP3A4 Inducers and Inhibitorsa ...................................................................69 
Table 20: Response Evaluation Criteria in Solid Tumors ..........................................................73 
Table 21: Adverse Event Grading ...............................................................................................81 
Table 22: Probability of Escalation to the Next Dose for Each True Underlying DLT 
Rate at a Dose Level ...................................................................................................86 
Table 23: Probability of Failing to Observe True Underlying DLT Rate at a Dose 
Level ...........................................................................................................................86 
 
LIST OF FIGURES 
Figure 1: 
Single-Dose and Multiple-Dose Pharmacokinetic Data from Study 
105ST101 ....................................................................................................................26 
 


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Table 2: 
Abbreviations and Specialist Terms 
Abbreviation or specialist term 
Explanation 
ADCC 
Antibody-Dependent Cell-mediated Cytotoxicity 
AE 
Adverse Event 
AFP 
Alpha Fetoprotein 
AIDS 
Acquired Immunodeficiency Syndrome 
ALKs 
Activin receptor-Like Kinases 
ALT 
Alanine Aminotransferase 
ANC 
Absolute Neutrophil Count 
APA 
Anti-Product Antibody 
AST 
Aspartate Aminotransferase 
AUC 
Area Under the Curve 
AUClast 
Time of Last Measurable Concentration of Area Under the Curve 
BALB/c mice 
Mouse Strain 
BMP 
Bone Morphogenic Protein 
BUN 
Blood Urea Nitrogen 
CABG 
Coronary Artery Bypass Graft 
CBC 
Complete Blood Count 
CEA 
Carcinoembryonic Antigen 
CL 
Clearance 
Cmax 
Maximum Serum Concentration  
CPA 
Cyclophosphamide 
CR 
Complete Response 
CRF 
Case Report Form 
CT 
Computed Tomography 
CTC 
Common Terminology Criteria 
dL 
Deciliter 
DLT 
Dose Limiting Toxicity 
DVT 
Deep Vein Thrombosis 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
ECM 
Extracellular Matrix 
EGFR 
Epidermal Growth Factor Receptor 
ELISA 
Enzyme-Linked ImmunoSorbent Assay 
EOS 
End of Study 
FDA 
Food and Drug Administration 
FGF 
Fibroblast Growth Factor 
FU 
Fluorouracil 
g 
Gram 
GOG 
Gynecologic Oncology Group 
GCP 
Good Clinical Practice 
HACA 
Human Anti-Chimeric Antibodies 
HAMA 
Human Anti-Murine Antibodies 
Her-2 
Human epidermal growth factor receptor 2 
HHT-1 
Hereditary Hemorrhagic Telangiectasia Type 1 
HIF-1-α 
Hypoxia-Inducible Factor-1-α 


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HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human Immunodeficiency Virus 
HRA 
Health Regulatory Authority 
HUVECs 
Human Umbilical Vein Endothelial Cells 
ICH 
International Conference on Harmonization 
ID 
Identification 
IEC 
Independent Ethics Committee 
IgG 
Immunoglobulin G 
IgM 
Immunoglobulin M 
IL 
Interleukin 
INR 
International Normalized Ratio 
IP 
Intraperitoneal 
IRB 
Institutional Review Board 
i.v. 
Intravenous 
Kd 
Avidity Binding Constant 
kg 
Kilogram 
L 
Liter 
LDH 
Lactate Dehydrogenase 
LOQ 
Limit of Quantification 
μL 
Microliter 
Mg 
Milligram 
mL 
Milliliter 
MACA 
Monkey Anti-Chimeric Antibody 
MAMA 
Monkey Anti-Murine Antibody 
MI 
Myocardial Infarction 
mm 
Millimeter 
MRI 
Magnetic Resonance Imaging 
MTD 
Maximum Tolerated Dose 
NCI 
National Cancer Institute 
NCIC 
National Cancer Institute of Canada 
ng 
Nanogram  
NHP 
Nonhuman Primate 
NOAEL 
No Adverse Effect Level 
PBS 
Phosphate-Buffered Saline 
PD 
Progressive Disease 
PDGF 
Platelet Derived Growth Factor 
PDGFR 
Platelet Derived Growth Factor Receptor 
PlGF 
Placental Growth Factor 
pM 
Picomolar 
PR 
Partial Response 
PSA 
Prostate Specific Antigen 
PT 
Prothrombin Time 
PTCA 
Percutaneous Transluminal Coronary Angioplasty  
PTT 
Partial Thromboplastin Time 
QA 
Quality assurance 
RCC 
Renal cell carcinoma 
RECIST 
Response Evaluation Criteria in Solid Tumors 


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SAE 
Serious Adverse Event 
sCD105 
Soluble CD105/endoglin 
SCID 
Severe Combined Immunodeficient 
SD 
Stable Disease 
SGOT 
Serum Glutamic Oxaloacetic Transaminase 
SGPT 
Serum Glutamic Pyruvic Transaminase 
SN6j 
Murine parent antibody of TRC105 
sVEGFR2  
Soluble VEGF Receptor 2 
TGF-β 
Transforming Growth Factor 
TSH 
Thyroid Stimulating Hormone 
ULN 
Upper Limit of Normal 
US 
United States of America 
VEGF 
Vascular Endothelial Growth Factor 
VEGFR 
Vascular Endothelial Growth Factor Receptor 
VEGFR TKI 
Vascular Endothelial Growth Factor Receptor Tyrosine Kinase 
Inhibitor 


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3. 
BACKGROUND 
3.1. 
Hepatocellular Carcinoma 
Worldwide, hepatocellular carcinoma (HCC) is the fifth most common malignancy with a 
median survival of 6-9 months [3], [4]. The approach to treating HCC has traditionally 
comprised of locoregional strategies; surgery (partial resection or transplantation) and 
interventional radiologic procedures, such as chemoembolization or ablative techniques remain 
the only treatments that are potentially curable. However, the publication of the landmark 
SHARP study established sorafenib as a standard consideration in unresectable disease and set 
the bar for future studies of systemic therapy [5]. 
3.1.1. 
Hepatocellular Carcinoma (HCC): sorafenib and angiogenesis 
Sorafenib is an oral multi-kinase inhibitor of vascular endothelial growth factor (VEGF) receptor 
(VEGFR), the platelet-derived growth factor (PDGF) receptor, and Raf [5, 6], that improved 
overall survival in HCC in a phase III randomized, placebo-controlled study (10.7 months 
overall survival with sorafenib versus 7.9 months with placebo; HR 0.69; 95% CI, 0.55 to 0.87; 
P<0.001) which 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. A second major study conducted in Asia in predominantly Hepatitis B 
patients confirmed the treatment effect of sorafenib [6]. In that study overall survival was 6.5 
months with sorafenib versus 4.2 months with placebo (p=0.014).  The overall response rate in 
these studies was <2% by RECIST.  Despite the survival improvement with sorafenib, patients 
either progress or do not respond at the outset.  Resistance is not the result of receptor mutation, 
but rather appears to result from the development of escape pathways that mediate VEGF 
resistance.  Endoglin (CD105) is a pathway implicated in resistance to VEGF inhibition. 
3.2. 
CD105 and Angiogenesis 
CD105 (endoglin) is a homodimeric cell membrane glycoprotein that was initially identified as a 
human leukemia-associated antigen [7] and later also found on endothelial cells [8, 9].  CD105 is 
a TGF-β coreceptor that is essential for angiogenesis [10, 11] and CD105 is strongly expressed 
on the proliferating vascular endothelium of solid tumors [9, 12], including HCC.  All of these 
properties make CD105 an attractive target for the antiangiogenic therapy of cancer [13].  In 
animal models, CD105 targeted therapy has demonstrated both vascular targeting effects and 
antiangiogenic effects by inducing regression of established tumors as well as by preventing new 
tumor formation and inhibiting expansion of existing tumors [9, 14-17]. Therefore, CD105 offers 
a novel alternative target relative to the VEGF inhibitors currently available for antiangiogenesis 
therapy.   
CD105 acts to modulate signaling of multiple kinase receptor complexes of the TGF-β 
superfamily, including TGF-β receptors, activin receptor-like kinases (ALKs) and activin 
receptors [18] and bone morphogenic protein (BMP).  CD105 expression is required for 
endothelial cell proliferation, and CD105 is upregulated in the setting of hypoxia through the 
induction of hypoxia-inducible factor-1-α (HIF-1-α) [19, 20].  CD105 has also been shown to 
protect hypoxic cells from apoptosis [21].  The expression of CD105 by endothelial cells is 
essential for the development of new vasculature.  Targeted inactivation (knockout) of murine 


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CD105 results in defective vascular development.  Mice lacking CD105 die in utero from 
defective vascular development by gestational day 11 [11].   
CD105 is critical for normal human blood vessel development [22].  CD105 haplotype 
insufficiency causes 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 localized angiodysplasia involving the nasal, buccal, gastrointestinal 
mucosa and skin microvasculature.  Angiodysplasia also occurs in vessels from internal organs 
including the lungs, liver and brain [23].  The genotype is manifested in utero, but the phenotype 
does not become apparent for many years following birth.  Affected patients commonly present 
with epistaxis in the second decade of life.  The phenotype of this disorder is characterized by 
vascular effects, emphasizing the dominant role of CD105 in vascular development [24].  
Notably, HHT-1 is associated with superior overall cancer survival [Duarte]. 
CD105 is highly expressed on the proliferating endothelial cells of tumor vessels including lung, 
breast, colorectal, gastric, hepatocellular, endometrial, renal cell, head and neck, and ovarian 
cancers.  In adults, CD105 expression is limited to endothelial cells, monocytes and 
proerythroblasts, a red blood cell precursor [25].   
CD105 expression is a prognostic factor in solid tumor patients.  High microvessel density of 
CD105-positive vessels has been correlated with poor prognosis in clinical studies of breast 
cancer [26, 27], lung cancer [28], prostate cancer [29, 30], colorectal cancer [31, 32], ovarian 
cancer  [33, 34], gastric cancer [35], endometrial cancer [36], astrocytic brain tumors [37], 
hepatocellular carcinoma [38], esophageal adenocarcinoma [39], and head and neck cancer [40, 
41].   
Importantly, CD105 expression is upregulated in tumor endothelial cells following inhibition of 
the VEGF pathway.  CD105 expression increased more than 2-fold in human pancreatic cancers 
grown in mice treated with an antibody that binds VEGF [42].  As well, 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 vasculature, allowing continued tumor 
growth despite VEGF inhibition [43].  Finally, inadequate expression of CD105, or conditional 
deletion in endothelium, resensitizes resistant tumors to VEGF inhibition [44]. 
3.3. 
TRC105 Background 
 
TRC105 is a genetically engineered human/murine chimeric monoclonal antibody directed 
against human CD105 [45], a proliferation receptor found on the surface of normal and 
proliferating endothelial cells [9, 14, 20].   
The antibody is an IgG1 kappa immunoglobulin containing murine variable region sequences 
and human constant region sequences [45].  TRC105 has an approximate molecular weight of 
148 kDa. TRC105 has a binding avidity for human CD105 of approximately 5 pM. TRC105 is 
formulated as a 20 mM L-Histidine/L-Histidine Monohydrochloride, 240 mM Trehalose, 0.01% 
Polysorbate 20 Formulation (25 mg TRC105/mL) 
SN6j, the murine parent antibody of TRC105, binds to human umbilical vein endothelial cells 
(HUVECs) with nearly identical avidity as TRC105.  SN6j has been shown to bind the tumor 
vasculature of malignant tissues including breast, colon, rectum, kidney and lung cancers and to 


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inhibit the growth of tumor xenografts [15].  Reactivity with tumor tissues is restricted to the 
tumor endothelium, as CD105 is not generally expressed on epithelial tumor cells [14].  TRC105 
induces ADCC on proliferating HUVECs at low conentrations and induces apoptosis and growth 
inhibition at higher concentrations.   
Studies at Duke University explored the in vitro effects of dual angiogenesis inhibition using 
bevacizumab and TRC105 in human umbilical vein endothelial cells (HUVEC) [46]. 
Combination therapy was found to be more potent in decreasing HUVEC proliferation, 
migration, and tubular network formation than bevacizumab or TRC105 treatment alone.    
Furthermore, TRC105 induced apoptosis in HUVEC, while promoting SMAD2/3 
phosphorylation and inhibiting SMAD1/5/8 signaling, confirming its anti-angiogenic properties. 
Finally, antibody to mouse CD105 potentiates the activity of sorafenib, in mouse bearing cancer 
grafts [47]. For these reasons, CD105 blockade using TRC105 in combination with VEGF 
inhibition by sorafenib may provide greater clinical benefit than would be seen with either drug 
alone. 
3.3.1. 
Phase 1 TRC105 Monotherapy Study Design for Solid Cancers  
Several studies with TRC105 are underway or have completed.  An open-label, phase 1, 
multicenter study of TRC105 (Study 105ST101) is complete.  Fifty patients were treated until 
disease progression with TRC105 at 0.01-15 mg/kg/q2wk or 10-15 mg/kg/wk.     
3.3.1.1. 
Phase 1 TRC105 Monotherapy 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). 


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Figure 1: 
Single-Dose and Multiple-Dose Pharmacokinetic Data from Study 105ST101 
 
 
3.3.1.2. 
Phase 1 TRC105 Monotherapy Immunogenicity 
In Study 105ST101, serum samples for evaluation of TRC105 immunogenicity, including 
HAMA and HACA, were collected predose 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 this study. 


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3.3.1.3. 
Phase 1 TRC105 Monotherapy Safety  
A total of 50 patients were treated on 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 or 15 mg/kg every two weeks.  Three of 4 patients at 15 
mg/kg weekly developed grade 3 hypoproliferative anemia (without leucopenia or 
thrombocytopenia) in 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 [25].  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.  A 
glucocorticoids-based premedication regimen and extended infusion time during the initial 
infusion mitigated the frequency and severity of first dose infusion reactions.  At dose levels 
where continuous TRC105 serum levels were achieved (e.g., 10 mg/kg weekly and 15 mg/kg 
every two weeks), 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 
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 


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(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. 
3.3.1.4. 
Phase 1 TRC105 Monotherapy 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 7 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 uterine cancer patient 
remained on TRC105 treatment for 20 months with a minor radiographic response. TRC105 
treatment duration of the patient with carcinosarcoma of the uterus exceeded prior treatment 
duration with all prior therapies including a carboplatin/paclitaxel, anastrozole and ifosfamide.   
3.3.2. 
Phase 1b Study of TRC105 with Bevacizumab 
3.3.2.1. 
Summary of Safety 
A total of 38 patients were dosed on study across six cohorts and four dose levels. Other than 
headaches that were mitigated by adjusting the dosing schedule of TRC105, the combination of 
TRC105 and bevacizumab was well tolerated at the recommended phase 2 doses of the two 
drugs of 10 mg/kg each.  Two patients experienced grade 3 serious adverse suspected events as 
described below. Most adverse events were graded as 1 or 2 and Grade 4 and 5 suspected 
adverse events were not observed. Grade 3 suspected adverse reactions included anemia (the 
dose limiting toxicity of TRC105 established as a single agent; 9 patients), headache (4 patients; 
three of which occurred prior to adjusting the schedule of TRC105), fatigue (2 patients), brain 
abscess (1 patient), infusion reaction (in a patient dosed at 6 mg/kg), and decreased appetite (1 
patient). Headache was the most common suspected adverse event and occurred in 31 patients 
(86.1%); three patients (7.9%) experienced migraine headaches (two of grade 1 and one of grade 
2 severity). Headaches were treated with triptans and NSAIDs. 
Two patients experienced serious adverse suspected events as described below.  One of the grade 
3 headaches (in a patient dosed at 8 mg/kg without splitting the initial TRC105 dose over two 
days) resulted in hospitalization and patient discontinuation.  One patient dosed at 10 mg/kg of 
TRC105 experienced a serious suspected event of grade 3 brain abscess.  Serious adverse events, 
considered unrelated to TRC105 treatment, included: grade 3 pneumonia and subsequent grade 4 
MRSA sepsis that was complicated by a non Q-wave myocardial infarction during a period of 
hemodynamic instability while hospitalized; grade 3 ileus at the time of symptomatic disease 


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progression; grade 5 disease progression; grade 3 left foot cellulitis; grade 3 recurrent 
pneumothorax; grade 3 small bowel obstruction; grade 4 urosepsis. 
At least one sign of the triad of epistaxis, gingival bleeding and telangiectasia, reflecting vascular 
ectasia characteristic of the Osler-Weber-Rendu syndrome of endoglin haplotype insufficiency 
(i.e., an autosomal dominant genetic disorder of heterozygous endoglin expression) was observed 
frequently.  One of these signs or symptoms (of grade 1 or 2 severity) was noted in one of three 
patients treated at 3 mg/kg, four of eight patients treated at 6 mg/kg, four of eight patients treated 
at 8 mg/kg and in all nineteen patients treated at 10 mg/kg of TRC105, generally within the first 
month of dosing.  These signs and symptoms are an expected pharmacologic effects of TRC105 
binding to the endoglin receptor (i.e., they are characteristic of the Osler-Weber-Rendu 
syndrome, that is caused by endoglin haploinsufficiency), and were also observed routinely 
within the first month of dosing of 10 mg/kg weekly in the single agent TRC105 dose escalation 
study.   
Infusion reactions were, as expected, more notable at lower doses, and were rare at the MTD of 
TRC105 of 10 mg/kg, when TRC105 serum concentrations were maintained continuously.  Two 
of nineteen patients (10%) dosed with 10 mg/kg of TRC105 each experienced a single infusion 
reaction of grade 2 severity, both with the initial dose of TRC105, that required a brief 
interruption of the infusion prior to completion of the scheduled dose. 
Clinically significant anemia was not reported in patients dosed with 3 mg/kg or 6 mg/kg of 
TRC105, was reported in three of seven patients (43%; all grade 3) dosed with 8 mg/kg of 
TRC105, and was observed in nine of 19 (47%; three of grade 2 and six of grade 3 severity) of 
patients dosed with 10 mg/kg of TRC105.  Anemia prompted transfusion of packed red blood 
cells in 10 patients and growth factors were used in five patients. 
Other, less frequent, suspected adverse reactions included hypothyroidism, periorbital edema 
(which was generally noted prior to splitting the initial dose of TRC105), gingival pain, nausea, 
oral pain, vomiting, edema, decreased appetite, dyspnea, nasal congestion, rash and flushing. 
Other adverse events characteristic of each individual drug were not increased in frequency or 
severity when the two drugs were administered together.  Of note, the concurrent administration 
of bevacizumab and TRC105 did not potentiate the known toxicities of bevacizumab of 
hypertension, hemorrhage (including tumor-associated hemorrhage, and pulmonary hemorrhage 
or hemoptysis), or proteinuria.  Reversible posterior leukoencephalopathy syndrome (RPLS), 
congestive heart failure, fistulae, gastrointestinal perforation impaired wound healing, and 
arterial thromboembolic events, were not observed. 
Notably, hypertension and proteinuira, known adverse events of bevacizumab, were rarely 
observed when bevacizumab was given with TRC105.  Mild and transient clinically significant 
hypertension or blood pressure increases were observed in five patients (13%; grade 3 in one 
case (prior to dosing with study drugs) and grade 2 in four cases) and mild transient proteinuria 
was observed in two patients (5%; both grade 2). 
3.3.2.2. 
Summary of Efficacy 
The combination of TRC105 and bevacizumab was active in patients with advanced refractory 
cancer who had progressed on prior bevacizumab or other VEGF inhibitor treatment.  Thirty-
three patients had measurable disease (31 patients) or evaluable disease (2 patients) at baseline 


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and received at least one follow up scan and were evaluable for the primary efficacy outcome of 
ORR by RECIST 1.1.  Eighteen patients with measurable disease (58%) had a best response of 
stable disease or partial response.  Two patients (6%), both of whom had been treated with 
bevacizumab and chemotherapy prior to study entry and were then treated at the top dose level of 
TRC105 and bevacizumab, had RECIST 1.1- defined partial responses, including one patient 
with colorectal cancer who continues on treatment for more than 24 months.  A total of 14 
patients (45%) had decreases in overall tumor burden, of whom 10 received prior VEGF 
inhibitor treatment (usually bevacizumab with chemotherapy).  Notably, the duration of 
treatment with TRC105 and bevacizumab of six patients (20% of those with measurable disease) 
exceeded the duration of treatment of the most recent treatment regimen containing a VEGF 
inhibitor (i.e., VEGFR TKI or bevacizumab), received prior to study entry.  These six patients 
had decreases in tumor burden and several were responders by Choi criteria or RECIST.  Time to 
progression ranged from 0 to 437+ days.  Reductions in tumor markers ranging from 5% to 85% 
were observed in 15 of 28 (54%) patients with relevant tumor markers.  Three patients 
demonstrated clinical benefit throughout the study, two of whom continued to receive treatment 
under a continuation protocol for more than 1 year before coming off study. 
3.4. 
Phase 1b Trial of TRC105 and Sorafenib and other VEGFR TKI 
The NCI-sponsored Study 11-C-0102 was an open-label, non-randomized, dose-escalation, 
Phase 1b-2 study of TRC105 in combination with sorafenib 400 mg orally twice daily in patients 
with hepatocellular carcinoma (Childs Pugh A/B7 and ECOG performance status of 0 or 1).  
Standard eligibility criteria used in other TRC105 protocols were modified for the hepatocellular 
cancer population (including the inclusion of patients with thrombocytopenia), reflecting the 
frequent comorbidity of cirrhosis existent in this population.  Twenty patients were enrolled in 
the Phase 1b stage, consisting of 3 patients at 3 mg/kg, 3 at 6 mg/kg, 6 at 10 mg/kg, and 8 at 15 
mg/kg TRC105 every 2 weeks in combination with sorafenib (the MTD).  Of the planned 
enrollment of up to 45 patients in the Phase 2 stage, 7 patients enrolled, at 15 mg/kg TRC105 
every 2 weeks in combination with sorafenib.  A total of 27 patients enrolled, this study is now 
complete.  In general, the combination of TRC105 and sorafenib appears to be well tolerated 
with encouraging signs of activity in this study.   
The only death in this study, myocardial infarction, was assessed as a suspected reaction to 
TRC105.  This was a 60-year-old man with significant coronary artery disease was receiving 
TRC105 10 mg/kg every 2 weeks (last dose 10 days prior to the event) and sorafenib 400 mg p.o. 
daily (last dose 3 days prior to the event).  During his second month of treatment he felt poorly 
and underwent cardiac catheterization, where he was found to “have a 90% heart blockage and 
expired of a myocardial infarction.”  A total of 18 patients contributed a total of 25 SAEs in this 
study, of which 10 were assessed as suspected reactions to TRC105:  Grade 5 Myocardial 
infarction; Grade 3 AST increased and Cerebrovascular accident; Grade 3 Hepatic failure; and 
Grade 2 Epistaxis, Flushing, Haemorrhage intracranial, Hypotension, Infusion-related reaction, 
and Pancreatitis.   
A total of 7 patients were withdrawn from study due to 8 AEs, of which 2 were assessed as 
suspected reactions to TRC105:  Grade 3 Hepatic failure and Grade 1 Epistaxis.  Unrelated AEs 
that led to withdrawal were Grade 4 Sepsis; Grade 3 Blood bilirubin increased, Mucositis oral, 
and Rash maculo-papular; and Grade 1 Abdominal distension and Pain.   


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The majority of AEs were mild (Grade 1) or moderate (Grade 2) in severity.  None of the 4 
Grade 4 AEs were assessed as suspected reactions to TRC105.  The only Grade 3 AEs assessed 
as suspected reactions to TRC105 were 1 event each of Grade 3 AST increased, Cerebrovascular 
accident, and Hepatic failure.   
The most common AEs suspected to be reactions to TRC105 were Headache (63%); AST 
increased (59%); Blood bilirubin increased (55%); Anaemia (52%); Fatigue and Nausea (44%), 
Lymphocyte count decreased (41%); Hypoalbuminaemia and Blood alkaline phosphatase 
increased (37%); Infusion-related reaction (33%); and Platelet count decreased (26%).  All of 
other related AEs occurred at an incidence ≤ 19%.  
The most common AEs regardless of relatedness to TRC105 treatment were Hypophosphataemia 
(81%); Anaemia (78%); Hypoalbuminaemia (74%); AST increased and Pain (67%); Epistaxis, 
Headache, Lymphocyte count decreased, Blood bilirubin increased, Blood alkaline phosphatase 
increased, and Fatigue (each 63%); ALT increased (59%); Rash maculo-papular (52%); 
Hyponatraemia, Nausea, and Diarrhoea (each 48%); and Blood amylase increased and Activated 
partial thromboplastin time prolonged (each 44%).   All other AEs occurred at an incidence 
≤ 37%.   
Five of 15 (33%) evaluable patients in Phase 1b treated at the top dose levels of 10 mg/kg or 
15 mg/kg of TRC105 given every 2 weeks with sorafenib achieved partial responses by RECIST.  
Four additional patients had confirmed stable disease, 1 of whom was treated for 22 months.  
Median time on study was 4 months (range 2 to 22 months).  The NCI concluded that TRC105 
combined with sorafenib was well tolerated at the recommended doses of both drugs and 
demonstrated evidence of activity beyond the expected sorafenib response rate of 2-3% reported 
in its two pivotal Phase 3 studies.   
3.5. 
Study Rationale 
Given the novel mechanism of action and safety profile in early phase clinical studies, TRC105 
is a logical therapy to use with sorafenib in HCC.  This is a phase 2, open label study of TRC105 
plus sorafenib including a lead-in phase 1b dose escalation study of sorafenib in combination 
with TRC105.  The phase 1b portion is a standard “3+3” dose-escalation design of patients with 
unresectable HCC to assess the safety and tolerability of the recommended phase 2 dose (RPTD) 
and schedule of TRC105 given by i.v. infusion.  The purpose of the dose escalation portion is to 
determine the maximum tolerated dose (MTD) of TRC105 with sorafenib and determine dose 
limiting toxicities.   
The starting dose and schedule of TRC105 (10 mg/kg weekly in cycle 1, and 15 mg/kg every two 
weeks in cycle 2+) were selected based on safety, pharmacokinetics and early evidence of 
activity in a phase 1b/2 study of TRC105 in combination with sorafenib in patients with 
hepatocellular carcinoma (NCI Study 11-C-0102), and phase 1b studies of TRC105 with axitinib 
(105RC101) and pazopanib (105SAR101).  NCI Study 11-C-0102 dosed TRC105 at 15 mg/kg 
every two weeks, starting on cycle 1 day1, with sorafenib.  While the dose was tolerable when 
given with sorafenib, patients who did not achieve continuous TRC105 serum concentrations 
developed infusion reactions upon redosing or required chronic steroid premedication to prevent 
infusion reactions (i.e., patients without continuous TRC105 serum levels developed infusion 


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reactions upon repeat dosing when TRC105 bound de novo to its target on the tumor 
endothelium and engaged ADCC).   
Weekly TRC105 dosing at 10 mg/kg is the recommended Phase 2 schedule, and has been 
administered to more than 350 cancer patients including patients enrolling in the Phase 3 pivotal 
study in angiosarcoma that is proceeding following Special Protocol Assessment by the FDA. 
However, TRC105 administration weekly for four weeks followed by every other week 
thereafter has also been studied to improve patient convenience.  This TRC105 administration 
schedule was evaluated in combination with axitinib and pazopanib in separate Phase 1b studies.  
In each case, continuous TRC105 serum levels were achieved in all patients and recurrent 
infusion reactions were not observed when TRC105 was administered every other week. 
TRC105 was also tolerable when given at a dose of 10 mg/kg weekly for four doses in the phase 
1 portion of this study without dose limiting toxicity. However, one patient developed a serious 
adverse event of Grade 3 infusion related reaction when dosed with 15 mg/kg every other week 
starting in cycle 2.  PK analyses indicated that target TRC105 serum concentrations were 
achieved with weekly dosing but were below target concentrations, and were in some cases 
undetectable, following every other week dosing; this observation may reflect increased 
clearance of TRC105 in patients with HCC compared to other tumor types due to the vascular 
nature of the disease.  Therefore, following recommendation of the principal investigators, 
weekly dosing at 10 mg/kg was chosen as the recommended Phase 2 dose for this study.  
Ongoing patients in the Phase 1b portion of this study may, at the discretion of the investigator, 
be treated at the Phase 2 TRC105 dose of 10 mg/kg weekly to achieve optimal target 
concentrations.       
Secondary endpoints will be overall response rate (ORR) and progression free survival (PFS), 
safety, APA, TRC105 and sorafenib PK and correlative studies of plasma angiogenic 
biomarkers.  Following completion of the phase 1b portion, the recommended phase 2 dose was 
determined by principal investigators to be 10 mg/kg TRC105 weekly in combination with 400 
mg sorafenib twice daily. The phase 2 portion is a multicenter, open label, phase 2 study of 
TRC105 in combination with standard dose sorafenib in patients with unresectable HCC. The 
primary endpoint of the phase 2 portion is ORR.  Secondary endpoints will evaluate PFS, safety, 
APA, TRC105 and sorafenib PK and correlative studies of plasma angiogenic biomarkers. 
Achievement of the primary and secondary endpoints of this Phase 1/2 trial will justify the 
initiation of a randomized Phase 3 trial of sorafenib +/- TRC105. 
3.5.1. 
Population to be Studied 
Patients with unresectable histologically confirmed hepatocellular carcinoma (HCC) will be 
enrolled in this trial.   
3.5.2. 
Potential Risks and Benefits to Human Patients 
3.5.2.1. 
Potential Risks 
TRC105 


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Common (≥ ~10%) TRC105 possibly related adverse events across all studies were headache, 
epistaxis, fatigue, anemia, nausea, infusion related reaction, gingival bleeding, flushing, 
vomiting, hypertension, decreased appetite, telangiectasia, and diarrhea. 
Grade 1 and 2 mucocutaneous telangiectasia related to TRC105 occur early in the course of 
therapy and have been the source of gingival bleeding and epistaxis. 
Grade 1 and 2 periodontal disease reported under various terms including gingival pain, gingival 
disorder, gingival swelling and gingival infection was reported in approximately 8% of patients. 
Grade 3 anemia has occurred with TRC105 therapy at the recommended phase 2 dose.  All 
patients treated with TRC105 should be monitored closely for anemia and treated appropriately, 
including the possibility of TRC105 dose interruption and/or reduction.  The anemia related to 
TRC105 is hypoproductive in nature and is reversible with interruption of treatment, transfusion, 
erythropoietin, and other interventions as appropriate. Anemia may also be related to blood loss 
from epistaxis or gingival bleeding that result from mucocutaneous telangiectasia. 
Infusion reactions have been observed following TRC105 administration may include one or 
more of the following signs or symptoms: rigors, flushing, bronchospasm, urticaria, fever, rash, 
dyspnea, nausea, vomiting, change in blood pressure, and change in heart rate.  Infusion 
reactions generally occur with the initial infusion in patients dosed at recommended phase 2 
doses of 10 mg/kg or 15 mg/kg every two weeks, and are typically of grade 1 or 2 severity 
following dosing with premedication that includes glucocorticoids.  All patients treated with 
TRC105 should receive appropriate premedication as defined in this protocol, be monitored 
during the TRC105 infusion, and be treated appropriately for infusion reactions (including 
possible TRC105 dose interruption). Hypersensitivity reactions with infusions are a potential risk 
for sensitized patients, and TRC105 should be avoided or used with caution in patients with 
known hypersensitivity to any component of the drug product.   
Pneumothorax has been observed in trials of TRC105 administered with pazopanib in patients 
with lung metastases. Pneumothorax is an expected adverse event associated with the use of 
pazopanib, particularly in sarcoma patients with lung metastases. However, pneumothorax was 
observed in one patient, also with lung metastases, receiving single-agent TRC105. 
Sorafenib 
The most common adverse reactions (≥ 20%), which were considered to be related to sorafenib, 
in patients with HCC or RCC are fatigue, weight loss, rash/desquamation, hand-foot skin 
reaction, alopecia, diarrhea, anorexia, nausea and abdominal pain.  
Further details are available in the package insert.  
Computed Tomography (CT) Scans 
Patients will be exposed to a small amount of radiation as a result of the CT scans required in 
this study.  This degree of exposure has not been associated with harmful health effects. In 
addition, the frequency of CT scans performed in this study is similar to the standard of care 
frequency. Patients with a medical contraindication to CT scans or known Iodinated contrast 
allergies may undergo MRI.  There is minimal risk of MRI imaging in patients able to undergo 


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this type of exam including very rare reports of gadolinium-induce nephrogenic systemic fibrosis 
in patients with poor renal function  
Venipuncture 
Patients could also experience side effects from venipuncture for tests that will be done as part of 
this study including pain, tenderness or bruising at the site of collection, and rarely infection may 
occur at the spot where the needle is inserted. 
Other Risks 
This study treatment may involve risks to unborn children therefore patients should not become 
pregnant or father a baby while participating in this study.  Patients should not nurse while on 
this study.  Women of childbearing potential must have a negative pregnancy test before taking 
part in this study.  Patients will be asked to practice an effective method of birth control during 
participation in this study and for 180 days after the last treatment.  Women must be of non-child 
bearing potential due to surgical sterilization (at least 6 weeks following surgical bilateral 
oophorectomy with or without hysterectomy or tubal ligation) confirmed by medical history or 
menopause; or must agree to use two methods of effective and highly reliable methods of 
contraception at the same time [i.e., tubal sterilization (tubes tied), partner’s vasectomy, intra-
uterine device (IUD), male latex condom with or without spermicide, diaphragm with 
spermicide, cervical cap with spermicide, vaginal sponge (contains spermicide)] during study 
treatment (including during temporary breaks from treatment), and for at least 180 days after 
stopping TRC105 or sorafenib.  Men must agree to use two effective and highly reliable methods 
of contraception at the same time [i.e., vasectomy, male latex condom with or without 
spermicide, partner’s tubal sterilization (tubes tied), partner’s use of intra-uterine device (IUD), 
partner’s use of diaphragm with spermicide, cervical cap with spermicide, vaginal sponge 
(contains spermicide)] during study treatment (including during temporary breaks from 
treatment), and for at least 180 days after stopping TRC105 or sorafenib. The long term risk of 
infertility is unknown.  Ovarian failure has been observed with other antiangiogenic agents.  
3.5.2.2. 
Potential Benefits 
TRC105 is an investigational product, and its efficacy has not been established.  It is possible 
that the administration of TRC105 may result in clinical benefit (i.e., tumor response or 
prolonged stable disease). 
3.5.3. 
Conduct 
The 105HCC101 clinical trial will be conducted in compliance with the protocol, GCP, and the 
applicable regulatory requirements. 


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4. 
TRIAL OBJECTIVES AND PURPOSE 
4.1. 
Purpose 
The purpose of this study is to evaluate the safety and effectiveness of TRC105 in combination 
with sorafenib. 
4.1.1. 
Phase 1b Trial Objectives 
4.1.1.1. 
Phase 1b Primary: 
• To determine a recommended phase 2 dose for TRC105 by i.v. infusion when given 
with standard dose sorafenib in patients with hepatocellular carcinoma 
4.1.1.2. 
Phase 1b Secondary 
• To determine the frequency and severity of adverse events as assessed by NCI 
CTCAE (Version 4.03) 
• To characterize the pharmacokinetic profile of TRC105 and sorafenib when given 
together 
• To evaluate TRC105 immunogenicity as assessed by Anti-Product Antibody (APA)  
• To assess preliminary evidence of antitumor activity when TRC105 is added to 
sorafenib, by assessing overall response rate (ORR), progression-free survival (PFS) 
and overall survival (OS) 
• To explore changes in circulating angiogenic biomarkers following treatment with 
TRC105 and sorafenib 
4.1.2. 
Phase 2 Trial Objectives 
4.1.2.1. 
Phase 2 Primary 
• To estimate the ORR by RECIST 1.1  
4.1.2.2. 
Phase 2 Secondary: 
• 
To determine duration of response by RECIST 1.1  
• To estimate PFS by RECIST 1.1, and determine overall survival (OS) 
• To determine the frequency and severity of adverse events as assessed by NCI 
CTCAE (Version 4.03) 
• To characterize the pharmacokinetic profile of TRC105 and sorafenib when given 
together 
• To evaluate TRC105 immunogenicity as measured by APA 
• To explore changes in circulating angiogenic biomarkers following treatment with 
TRC105 and sorafenib 


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• 
To prospectively assess IGF-1-modified Child-Pugh score [1] and outcomes in patients with 
HCC treated with sorafenib and TRC105.  


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5. 
INVESTIGATIONAL PLAN 
5.1. 
Overall Study Design and Plan 
5.1.1. 
Overview 
All patients must sign a consent form prior to undertaking any study-related procedures.  
Prospective patients will be screened to determine if they qualify for the study within 28 days of 
enrollment. Toxicities will be graded according to the NCI CTCAE Version 4.03.   
5.1.1.1. 
Phase 1b Overview 
This is a multicenter, open-label, nonrandomized, phase 1b, dose-finding study of TRC105 in 
combination with standard dose sorafenib in patients with unresectable HCC.  Escalating doses 
of i.v. TRC105 will be administered weekly or every two weeks beginning with Dose Level 1 in 
combination with oral sorafenib given as 400 mg p.o. b.i.d. daily.  Sorafenib dose modifications 
are allowed starting in cycle 1 as per the package insert and Section 7.8.6. Intermediate dose 
TRC105 (below the MTD established during the trial) may be explored based upon clinical, PK, 
and/or biomarker data.  
TRC105 dosing will begin at 10 mg/kg weekly in cycle 1 and 15 mg/kg every two weeks 
beginning with cycle 2 (Dose Level 1) however a -1 Dose Level has also been included (10 
mg/kg weekly in cycle 1 and 10 mg/kg every two weeks beginning with Cycle 2) and will be 
enrolled if Dose Level 1 exceeds the MTD. Upon agreement of the study investigators, a given 
TRC105 dose level may be reenrolled at 400 mg daily or 400 mg every other day of sorafenib 
and/or the first dose of TRC105 may be delayed by one week (i.e., delayed to cycle 1 day 8).  
Additional patients may be enrolled at Dose Level 1 or -1 (as long as it does not exceed the 
MTD) to obtain additional safety and PK information. 
The first TRC105 dose will be split into two doses whereby 3 mg/kg is administered on cycle 1 
day 1 and the balance (7 mg/kg) is administered on cycle 1 day 4.  The entire dose of TRC105 
(10 mg/kg) is then given weekly in cycle 1 and 10 mg/kg or 15 mg/kg every two weeks 
thereafter in cycle 2 and beyond (depending on Dose Level) in combination with oral sorafenib 
given as 400 mg p.o. b.i.d. Those who tolerate TRC105 without any infusion reactions may be 
eligible for reduced infusion durations and decreased premedication (see Section 7.7).  Patients 
who demonstrate a complete response (CR), partial response (PR) or stable disease (SD) may 
continue on study until progression. Patients who cannot tolerate sorafenib therapy and are 
thought to benefit from continued TRC105 therapy may continue on study on TRC105 alone. 
Patients who exit the study for reasons other than drug-related dose-limiting toxicity prior to 
completion of the DLT assessment period (first 56-days) will be replaced.  Intrapatient dose 
escalation of TRC105 is not allowed. 
 
 


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Table 3: 
Dose Levels 
Levela 
Number of Evaluable 
Subjects 
Sorafenib mg p.o., 
b.i.d. days 1-28 
TRC105mg/kg IV 
-1 
3-6 
400 
10 (weekly C1), 10 
(every 2 weeks C2+)b 
1 
(starting dose) 
3-6 
400 
10 (weekly C1), 15 
(every 2 weeks C2+)b 
aAdditional intermediate doses (below the MTD established during the trial) may be explored based upon clinical 
PK and/or biomarker data  
bTRC105 will be administered weekly during cycle 1. The first weekly TRC105 dose will be split into two doses 
whereby 3 mg/kg is administered on cycle 1 day 1 and the balance is administered on cycle 1 day 4. Starting on 
cycle 2 day 1 and beyond, TRC105 will be administered every two weeks on days 1 and 15.  
Three patients will be initially enrolled and treated at Dose Level 1. If none of these 3 patients 
experiences a dose-limiting toxicity (DLT) during the 56-day evaluation period (cycle 1 through 
the end of cycle 2) a total of six patients will be treated at this dose level. 
If 1 of 3 patients experiences DLT, the dose level will be expanded to 6 patients.  The maximum 
tolerated dose (MTD) will have been exceeded if ≥ 33% of patients experience DLT at a given 
dose level.  DLT will have occurred when a patient has 1 or more toxicity listed in the table 
below that is at least possibly related to TRC105 during the first 56 days (cycle 1 and 2).  
Patients who exit the study for reasons other than DLT prior to completion of the 56-day DLT 
evaluation period will be replaced to ensure an adequate safety assessment in each cohort.  
Patients who experience DLT and those without DLT who receive less than the prescribed dose 
of sorafenib due to documented toxicity in Cycle 1 or 2 will be considered evaluable for dose 
escalation purposes.  Upon agreement of the study investigators, a given TRC105 dose level may 
be reenrolled at 400 mg daily or 400 mg every other day of sorafenib and/or the first dose of 
TRC105 may be delayed by one week (i.e., delayed to cycle 1 day 8).  
Table 4: 
Dose Limiting Toxicity Definition and Criteria 
Toxicity Category 
Drug-Related Toxicity/Grade 
Hematologic 
Grade 4 neutropenia for ≥ 5 days 
Febrile neutropenia: grade 4 neutropenia with fever > 38.5 ºC both 
sustained over a 24 hour period. 
Neutropenic infection: grade ≥ 3 neutropenia with grade ≥ 3 infection 
Anemia ≥ grade 4  
Grade > 4 thrombocytopenia or grade ≥ 3 thrombocytopenia and grade ≥ 3 
hemorrhage 
Nonhematologic 
Grade 3 or 4 nonhematologic toxicity with the following exceptions: 
• 
Nausea, vomiting or diarrhea for < 48 hoursa 
• 
Asymptomatic electrolyte abnormalities that are corrected to grade 
1 or better in < 48 hoursb 


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Toxicity Category 
Drug-Related Toxicity/Grade 
• 
Grade 3 hypertension that can be controlled with oral medications 
and does not require treatment delay for > 7 days or dose reduction 
• 
Grade 3 rise in creatinine, corrected to Grade 1 or less after 2 liters 
of intravenous fluids within 24 hours. 
• 
Grade 3 elevation in transaminases that is reversible following 
sorafenib dose reduction or interruption. 
• 
Grade 3 rash that decreases to ≤ Grade 2 after 1 week of 
symptomatic treatment. 
• 
Grade 3 hand-foot syndrome 
aPatients with related grade 3 or 4 diarrhea, nausea or vomiting for ≥ 48 hours despite optimal medical 
therapy will require a one-level dose-reduction of TRC105 as outlined in Section 7.7.1. 
bPatients with related grade 3 or 4 electrolyte abnormalities that persist for ≥ 48 hours will require a one-
level dose-reduction of TRC105 as outlined in Section  7.7.1.  
 
The recommended phase 2 dose for the combination determined by the study investigators, 
medical monitor, and TRACON after reviewing the toxicity and pharmacokinetic profile of the 
study combination is 10 mg/kg TRC105 weekly in combination with 400 mg sorafenib twice 
daily.  Ongoing patients in the Phase 1b portion of this study may, at the discretion of the 
investigator, be treated at the Phase 2 TRC105 dose of 10 mg/kg weekly. 
5.1.1.2. 
Phase 2 Overview 
This is a multicenter, open label, phase 2 study of TRC105 in combination with standard dose 
sorafenib in patients with unresectable hepatocellular carcinoma.  All patients will initially 
receive sorafenib 400 mg twice daily in combination with TRC105 at 3 mg/kg on day 1 and the 
remainder (7 mg/kg) on day 4, and weekly thereafter. Dose modifications of sorafenib and 
TRC105 are allowed per patient tolerance. 
5.1.2. 
Trial Procedures 
All on-study procedures are permitted within the time window indicated in the Schedule of 
Assessments (Table 5).  
5.1.2.1. 
Screening 
The following screening procedures must be performed within 28 days prior to the first day of 
study therapy.  Qualifying hematology (including Fe studies), serum chemistry (including TSH 
testing), coagulation, physical examination, ECG, pregnancy and urinalysis collected within 7 
days of cycle 1 day 1 do not need to be repeated. The following will be performed according to 
the Schedule of Assessments (Table 5).  
• Patient signature on current Institutional Review Board (IRB) approved informed consent 
form.  Prior to undergoing any study-specific procedure, patients must read and sign the 
current Institutional Review Board (IRB) approved informed consent form.  Patients may 
sign consent prior to the 28 day screening period. 


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• Medical history, baseline signs and symptoms, prior cancer therapy, prior cancer surgery, 
prior radiation therapy, drug allergies, primary diagnosis and demographics. 
• Physical examination including examination of all major body systems, ECOG 
performance status, and vital signs. 
• Hematology (including serum iron, ferritin and total iron binding capacity), coagulation 
(PT or INR) and serum chemistry (including thyroid stimulating hormone (TSH)) to be 
performed locally. 
• Serum or urine pregnancy test for all females of childbearing potential to be performed 
locally. 
• Urinalysis to be performed locally.  Microscopic analysis and/or urine protein-creatinine 
ratio (UPCR) should be performed as clinically indicated. 
• Imaging: CT or MRI scans of chest, abdomen and pelvis in addition to any other 
applicable sites of disease. Brain MRI or CT with contrast and/or bone scans to be 
performed at screening if clinically indicated.  
 De-identified copies of MRI’s, in DICOM format may be transferred to the 
Sponsor if requested 
• Single tracing 12-Lead ECG (QT, PR and QRS intervals and heart rate will be captured).   
• Assessment of concomitant medications and treatments from 28 days prior to the start of 
study treatment.  
• Archival Tumor Tissue Specimens: Archival specimens (formalin-fixed, paraffin-
embedded) of the primary cancer specimen and/or metastatic cancer specimen for each 
study participant, if they are available. It is preferable that the entire paraffin block be 
submitted, but if this is not feasible, then at least 20 unstained slides are requested for 
immunohistochemical analysis (sections of ~ 5 microns are preferred).  Patients without 
available archival tumor tissue specimens are still eligible to participate in the study. See 
separate laboratory guide for further collection and shipment information 
• Patients with cirrhosis must have had esophagogastric endoscopy within the past 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. 
5.1.2.2. 
Trial Period 
Qualifying hematology (including Fe studies), blood chemistry (including TSH testing), 
coagulation, urinalysis, physical examination, ECG, and pregnancy test do not need to be 
repeated on cycle 1 day 1 if acceptable screening assessments are performed within 7 days prior 
to the start of study therapy. On days of dosing, all assessments should be performed prior to 
dosing with TRC105 unless otherwise indicated in the Schedule of Assessments. Patients who 
demonstrate a response of CR, PR or SD, will be eligible for additional treatment until 
progression.  Each cycle is 4 weeks in duration. The following will be performed according to 
the Schedule of Assessments (Table 5). 


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• Physical examination including examination of all major body systems, ECOG 
performance status, weight and vital signs (heart rate, temperature, blood pressure, 
respiratory rate).  
o Assessment of vital signs during TRC105 infusion: Vital signs are to be 
assessed pre-infusion (i.e., within 30 minutes of starting infusion), every 30 
minutes during the infusion (+/- 15 minutes), and at the end of infusion (i.e., 
within 30 minutes after completing infusion).  Vital signs should be monitored 
more frequently and/or beyond the completion of the infusion if medically 
indicated (e.g. if the patient experiences an infusion reaction that has not yet 
resolved).  
• Hematology, coagulation (PT or INR) and serum chemistry (including TSH) to be 
performed locally. 
• Urinalysis to be performed locally. Microscopic analysis and/or urine protein-creatinine 
ratio (UPCR) should be performed as clinically indicated. 
• Blood sampling for TRC105 and sorafenib pharmacokinetics will include pre-dose trough 
samples to be analyzed by a third party laboratory (see laboratory manual for specific 
instructions regarding collection times, procedures, processing, storage and shipment). 
• Blood sampling for immunogenicity (APA concentrations) to be analyzed by a third party 
laboratory (see laboratory manual for specific instructions regarding collection, 
processing, storage and shipment). 
• Blood sampling for protein biomarker analysis by a third party laboratory (see laboratory 
manual for specific instructions regarding collection processing, storage and shipment) 
• Blood sampling for tumor markers (i.e. AFP) 
• Imaging: CT or MRI scans of chest, abdomen and pelvis in addition to any other 
applicable sites of disease. Scan of the chest, abdomen, and pelvis to be performed on-
study as outlined in the assessment table.  Known areas of disease should be consistently 
followed throughout the study.    Bone scans to be performed throughout the study at the 
time of CT assessments if screening scans are positive and/or if bone metastases are 
identified that cannot be followed by CT.  Brain scans to be performed if metastasis is 
suspected during study conduct.  Scans will be performed on day 22 of even cycles (C2, 
C4, C6, etc.). Assessments should be performed whenever disease progression is 
suspected.  Allowable window for tumor imaging studies is +/- 7 days. 
 De-identified copies of CTs or MRI’s, in DICOM format, may be transferred to 
the Sponsor if requested 
• Administration of TRC105.  TRC105 diluted in normal saline will be administered as a 1 
to 4 hour infusion (+/- 15 minutes) following premedication (see Section 7.7) according 
to the schedule of assessments (Table 5). 
  (Dose Level -1): The first weekly TRC105 dose (cycle 1 day 1) will split into 
two doses whereby 3 mg/kg is administered on cycle 1 day 1 and the balance (7 
mg/kg) is administered on cycle 1 day 4.  The entire weekly dose of TRC105 (10 


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mg/kg) is then given on cycle 1 day 8, day 15 and day 22.  The full 10 mg/kg dose 
will then be administered beginning on cycle 2 day 1 and every two weeks 
thereafter for the remainder of the trial period.  Note this dose level will only be 
enrolled if the TRC105 MTD is exceeded in Dose Level 1.   
 Dose Level 1: The first TRC105 dose (cycle 1 day 1) will split into two doses 
whereby 3 mg/kg is administered on cycle 1 day 1 and the balance (7 mg/kg) is 
administered on cycle 1 day 4 (7 mg/kg).  The entire weekly dose of TRC105 (10 
mg/kg) is then given on cycle 1 day 8, day 15 and day 22.  The full 15 mg/kg dose 
will then be administered beginning on cycle 2 day 1 and every two weeks 
thereafter for the remainder of the trial period  
 Phase 2 Dosing: The first TRC105 dose (cycle 1 day 1) will split into two doses 
whereby 3 mg/kg is administered on cycle 1 day 1 and the balance (7 mg/kg) is 
administered on cycle 1 day 4.  The entire weekly dose of TRC105 (10 mg/kg) is 
then given on cycle 1 day 8, day 15 and day 22 and weekly thereafter for the 
remainder of the trial period (see Section 7.7) 
TRC105 will be administered intravenously utilizing an infusion pump.  TRC105 has 
been demonstrated to be compatible with polyethylene lined, non-di(2-ethyl-
hexyl)phthalate (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.   
• Sorafenib dosing. The oral dose of sorafenib is 400 mg twice daily of each 28 day cycle.  
Sorafenib tablets should be taken without food (at least 1 hour before or 2 hours after a 
meal). Patients are to swallow the tablets whole with approximately 250 ml (8 oz) of 
water, each morning and evening (i.e., approximately 12 hours apart). Sorafenib dose 
reductions are allowed starting on cycle 1 based on patient tolerability as per the package 
insert and Section 7.8.6.  
• Assessment of adverse events. 
• Assessment of concomitant medications and concomitant treatments. 
5.1.3. 
End of Study Assessments  
Assessments other than TRC105 pharmacokinetics, immunogenicity, and protein biomarkers 
only need to be completed if they were not completed during the previous 2 weeks on study 
(during the last 8 weeks on study for radiologic tumor assessments unless progression is 
suspected).  The following will be performed according to the Schedule of Assessments 
(Table 5). 
• Physical examination including examination of all major body systems, ECOG 
performance status, and vital signs. 
• Single tracing 12-Lead ECG (QT, PR and QRS intervals and heart rate will be captured). 
• Hematology and serum chemistry (including TSH) to be performed locally. 


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• Urinalysis to be performed locally.  Microscopic analysis and/or urine protein-creatinine 
ratio (UPCR) should be performed as clinically indicated. 
• Blood sampling for TRC105 and sorafenib pharmacokinetics to be analyzed by a third 
party laboratory (see laboratory manual for specific instructions regarding collection 
times, procedures, processing, storage and shipment). 
• Blood sampling for immunogenicity (APA concentrations) to be analyzed by a third party 
laboratory (see laboratory manual for specific instructions regarding collection, 
processing, storage and shipment). 
• Blood sampling for protein biomarker analysis by a third party laboratory (see laboratory 
manual for specific instructions regarding collection processing, storage and shipment) 
• Blood sampling for tumor markers (i.e. AFP) 
• Imaging: CT or MRI scans of chest, abdomen and pelvis in addition to any other 
applicable sites of disease. Bone scans to be performed throughout the study at the time 
of CT assessments if screening scans are positive and/or if bone metastases are identified 
that cannot be followed by CT. Brain scans to be performed if metastasis is suspected. 
 De-identified copies of CTs or MRI’s, in DICOM format, may be transferred to 
the Sponsor if requested 
• Assessment of adverse events. 
• Assessment of concomitant medications and concomitant treatments. 
5.1.4. 
Post Treatment Follow-up 
The following will be performed according to the Schedule of Assessments (Table 5). Samples 
should be collected and assessments performed even if new anti-cancer therapy commences 
during the follow-up period.  
• Assessment of adverse events. The Investigator should continue to report any related 
adverse events that occur beyond the adverse event reporting period.  
• Serum or urine pregnancy test for all females of childbearing potential to be performed 
locally. 
• Blood sampling for TRC105 and sorafenib pharmacokinetics to be analyzed by a third 
party laboratory (see laboratory manual for specific instructions regarding collection 
times, procedures, processing, storage and shipment). 
• Blood sampling for immunogenicity (APA concentrations) to be analyzed by a third party 
laboratory (see laboratory manual for specific instructions regarding collection, 
processing, storage and shipment). 
• Assessment of concomitant medications and concomitant treatments.


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Table 5: 
Schedule of Assessments (Phase 1b)  
Protocol Activities 
Screening 
Cycle 1 
 (10 mg/kg Weekly) [23] 
Cycle 2 + 
 (10 mg/kg or 15 mg/kg every two weeks) 
[23] 
End 
of 
Study 
[3] 
28 Day 
Follow-up 
[23] 
 
 
 
Long Term  
Follow Up 
(bimonthly)  
Day -28 
 
 
Day 1 
[1] [2] 
 
 
Day 4 
 [1] 
Day 
8 
[1] 
Day 
15 
[1] 
Day 
22 
[1] 
Day 1  
[1] 
Day 15 
[1] 
Baseline Documentation 
  
 
 
  
  
  
  
  
  
  
 
Informed Consent [4] 
X 
 
 
  
  
  
  
  
  
  
 
Medical/Oncology History [5] 
X 
 
 
  
  
  
  
  
  
  
 
Baseline Signs and Symptoms  
X 
 
 
 
 
 
 
 
  
 
 
Physical Examination [6] 
X 
X 
 
 
  
  
X 
  
X 
  
 
Vital Signs [7] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
 
Laboratory Studies 
  
 
 
  
  
  
  
  
 
  
 
Hematology [8] 
X+Fe 
X+Fe 
 
  
X 
  
X  
 X 
 X 
  
 
Coagulation [8] 
X 
X 
 
  
  
  
 
  
X 
  
 
Blood Chemistry [8] 
X+TSH 
X+TSH 
 
  
X 
  
X+TSH  
X  
X + TSH 
  
 
Pregnancy Test [9] 
Day -7 
 
 
  
  
  
X 
  
 
 X 
 
Urinalysis [10] 
X 
X 
 
  
  
  
X  
  
X  
  
 
Treatment w/ Study Drug 
  
 
 
  
  
  
  
  
 
  
 
TRC105 Dosing [11] 
  
X Split  
X 
Split  
X 
X  
X 
X  
X  
  
  
 
Sorafenib [12] 
 
Daily (28 days) 
Daily (28 days) 
  
 
 
Tumor Assessments 
  
 
 
  
  
  
  
  
 
  
 
CT or MRI Scans [13] 
X 
 
 
  
  
  
  
X  
Day 22* 
 
 X 
  
 
Other Clinical Assessments 
  
 
 
  
  
  
  
  
 
  
 
12-Lead ECG [14] 
X 
 
 
  
  
  
  
  
 X 
  
 
Concomitant Medications/Treatments 
[15] 
X 
X 
X 
X 
X 
X 
X  
X 
X  
X 
 
Adverse Events [16] 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Overall Survival [17] 
 
 
 
 
 
 
 
 
 
 
X 
Special Laboratory Assessments 
  
 
 
X 
  
  
  
  
X 
  
 
Pre Dose PK [18] 
  
X 
 
 X 
X 
 X 
X (Even Cycles) 
 X (C2 Only) 
 X 
X 
 
Anti-product antibodies [19] 
 
X 
 
X 
X 
X 
X (Even Cycles) 
X (C2 Only) 
 X 
X 
 
Protein Biomarkers [20] 
 
 
X 
 
 
 
 
X (Even Cycles) 
 
X 
 
 
Tumor Markers [21] 
 
X 
 
 
 
 
X 
 
X 
 
 
Archival Tumor Tissue [21] 
X 
 
 
 
 
 
 
 
 
 
 
   


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Schedule of Assessments Footnotes 
1. Days of Treatment with TRC105: All assessments should be performed prior to the TRC105 infusion unless otherwise indicated.  Each cycle 
is 28 days in duration.  
2. Cycle 1 day 1: Hematology (including iron studies), blood chemistry (including TSH testing), urinalysis, physical examination, ECG and 
pregnancy test not required if acceptable screening assessment is performed within 7 days prior to the start of treatment on cycle 1 day 1.  
3. End of Study: The end of study visit should generally occur within 14 days (+/- 1 day) of the last dose of TRC105. Assessments other than 
pharmacokinetics, immunogenicity and protein biomarkers do not need to be repeated if performed within the previous 2 weeks (previous 8 
weeks for radiologic tumor assessments). Follow-up visits should occur 28 days following the last dose of TRC105 study drug as outlined in 
the Schedule of Assessments.  
4. Informed Consent: Must be obtained prior to undergoing any study specific procedure and may occur prior to the 28-day screening period. 
5. Medical and Oncologic History, Demographics and Baseline Signs and Symptoms: All information related to prior anticancer treatment 
should be recorded. Significant medical history and baseline signs and symptoms should be captured from the date of informed consent.  
6. Physical Examination: Examination of major body systems and ECOG performance status.  
7. Vital Signs: Heart rate, temperature, blood pressure, respiratory rate, weight. Assessment of vital signs during TRC105 Infusions: Vital signs 
are to be assessed pre-infusion (i.e., within 30 minutes of starting the infusion) every 30 minutes during the infusion (+/- 15 minutes) and at the 
end of the infusion (i.e. within 30 minutes after completing the infusion). Vital signs should be monitored more frequently and/or beyond the 
completion of the infusion if medically indicated (e.g. if the patient experiences an infusion reaction that has not yet resolved).   
8. Hematology, Chemistry & Coagulation:  Testing to be performed locally.  Thyroid stimulating hormone to be tested at screening, day 1 of 
each cycle and at the end of study visit.  Cycle 1 day 1 assessments only need to be performed if screening assessments were performed more 
than 7 days prior to cycle 1 day 1.  Iron studies (FE) to be performed according to the schedule of assessments and as clinically indicated 
during the study.  Thyroid stimulating hormone (TSH) to be performed according to the schedule of assessments and as clinically indicated 
during the study.  Lab assessments may be performed within 3 days prior to TRC105 dosing. In addition to the assessments scheduled for the 
clinical trial, patients should undergo assessment as appropriate to ensure safe treatment. See Section 8.1.1.1 for specific panel collection 
requirements.  
9. Pregnancy Test: Testing to be performed locally. All female patients of childbearing potential must have a negative serum or urine pregnancy 
test within 7 days of cycle 1 day 1, day 1 of every cycle starting with cycle 2, and 28 days following the last dose of TRC105. 
10. Urinalysis: To be performed locally. Cycle 1 day 1 urinalysis only needs to be performed if screening urinalysis was performed more than 7 
days prior to cycle 1 day 1.  Microscopic analysis and/or urine protein creatinine ratio or 24-hour urine protein collection should be performed 
as clinically indicated. 
11. TRC105 Administration: Intravenous TRC105 diluted in normal saline will be administered every 7 days during Cycle 1.  The first weekly 
TRC105 dose will be given on cycle 1 day 1and split into two doses whereby 3 mg/kg is administered on cycle 1 day 1 and the balance is 
administered on cycle 1 day 4.  The entire dose of TRC105 (10 mg/kg) is then given on cycle 1 day 8, cycle 1 day 15 and cycle 1 day 22. 
Starting on cycle 2 day 1 and beyond, TRC105 will be administered every two weeks on days 1 and 15. See Section 7.7 for specific TRC105 
administration guidelines. 


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12. Sorafenib Dosing: Oral sorafenib will be dosed twice daily on days 1-28 of each 28 day cycle according to the sorafenib package insert. See 
Section 7.8 for specific dosing guidelines..    
13. *Imaging: CT or MRI Images of the chest, abdomen, and pelvis to be performed at screening, and on-study as outlined in the assessment 
table.  A brain MRI or CT with contrast and bone scans to be performed at screening and on study if metastases are suspected.  Known areas 
of disease should be consistently followed throughout the study.  Assessments should be performed whenever disease progression is suspected.  
Allowable window for tumor imaging study is +/- 7 days.  Scans will be performed every 2 cycles (day 22 of cycle 2, 4, 6, 8, 10, etc.).  De-
identified copies of CT/MRI’s, in DICOM format, may be transferred to the Sponsor if requested.  Patients are eligible for treatment until 
progression.  
14. 12-Lead ECG: Single tracing 12-lead ECG will be performed at screening and at the time-points indicated in the Schedule of Assessments 
(pre-dose). If the patient develops an arrhythmia, the ECG should be repeated on day 1 of each subsequent cycle. For a QTc >500 ms, a repeat 
ECG for confirmation and evaluation of the ECG by a cardiologist is recommended.   Additional ECGs may be performed on study as 
clinically indicated.  
15. Concomitant Medications and Treatments: Concomitant medications and treatments will be recorded from 28 days prior to the start of 
study treatment and up to 28 days following the last dose of study treatment. Required TRC105 premedications should be recorded on 
TRC105 premedications CRF. 
16. Adverse Events: Patients must be followed for adverse events from the first day of treatment with sorafenib or TRC105 until at least 28 days 
after the last dose of study treatment, or until all serious or TRC105 related toxicities have resolved or are determined to be “chronic” or 
“stable”, whichever is later. Baseline signs and symptoms will be recorded on corresponding case report forms. Any serious AE that is 
possibly related to TRC105 occurring from the time of first dose or at any point after the reporting period must be promptly reported to 
TRACON. 
17. Overall Survival: Phone call to patient every two months to determine overall survival.     
18. TRC105 and Sorafenib Pharmacokinetics Pre-Dose (Trough) Concentration: One 5 mL blood sample and one 4 mL sample to be 
collected at the time-points indicated in the Schedule of Assessments, prior to dosing with sorafenib and prior to starting the TRC105 infusion. 
Samples will be stored at approximately -70°C.  Samples will be batch shipped as indicated in the laboratory manual to a third-party 
laboratory.  See separate laboratory guide for further collection and shipment information.  Additional PK samples may also be collected at the 
time of unexpected clinical events.   
  
19.  Anti-product antibodies: 5 mL blood sample will be collected to assess anti-product antibodies at the time-points indicated in the schedule of      
assessments and stored at approximately -70°C to be analysed by a central laboratory. Samples will be batch shipped as indicated in the 
laboratory manual to a third-party laboratory. See separate laboratory guide for further collection and shipment information. Additional anti-
product antibody samples may also be collected at the time of unexpected clinical events. 
20. Protein Biomarkers: One 10 mL purple top (K3EDTA) tube will be collected at the time-points indicated in the schedule of assessments and 
stored at approximately -70°C to be analysed by a central laboratory. See separate laboratory guide for further collection and shipment 
information. 


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21. Tumor Marker: Blood sampling for tumor markers (i.e. AFP) will be collected and analyszed locally as indicated in the schedule of 
assessments.   
22. Archival Tumor Tissue: Archival specimens (formalin-fixed, paraffin-embedded) are required of the primary cancer and/or metastatic cancer 
specimen for each study participant. It is preferable that the entire paraffin block be submitted, but if this is not feasible, then at least 20 
unstained slides are requested for immunohistochemical analysis (sections of 5 microns are preferred).  See separate laboratory guide for 
further collection and shipment information. 
23. 28-Day Follow-up:  The follow-up visit should occur 28 days following the last dose of TRC105. The allowable visit window is +/- 7 days.  
24. Allowable window for each visit within the cycle is +/- 2 days unless otherwise stated. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 6: 
Schedule of Assessments (Phase 2)  
Protocol Activities 
Screening 
Cycle 1 
 (10 mg/kg Weekly) [23] 
Cycle 2 + 
 (10 mg/kg Weekly) [23] 
End 
of 
Study 
[3] 
28 Day 
Follow-up 
[23] 
 
 
 
Long Term  
Follow Up 
(bimonthly)  
Day -28 
 
 
 
Day 1 
[1] [2] 
 
 
 
Day 4 
[1] 
Day 8 
[1] 
Day 15 
[1] 
Day 22 
[1] 
 
 
 
Day 1  
[1] 
 
 
 
Day 8 
[1] 
 
 
 
Day 15 
[1] 
 
 
 
Day 22 
[1] 
Baseline Documentation 
  
 
 
  
  
  
  
  
  
  
 
Informed Consent [4] 
X 
 
 
  
  
  
 
 
  
  
  
  
 
Medical/Oncology History [5] 
X 
 
 
  
  
  
 
 
  
  
  
  
 
Baseline Signs and Symptoms  
X 
 
 
 
 
 
 
 
 
 
  
 
 
Physical Examination [6] 
X 
X 
 
 
  
  
X 
 
 
  
X 
  
 
Vital Signs [7] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
 
Laboratory Studies 
  
 
 
  
  
  
 
 
  
  
 
  
 
Hematology [8] 
X+Fe 
X+Fe 
 
  
X 
  
X 
 
X  
 
 X 
  
 
Coagulation [8] 
X 
X 
 
  
  
  
X 
 
  
  
X 
  
 
Blood Chemistry [8] 
X+TSH 
X+TSH 
 
  
X 
  
X+TSH 
 
X  
 
X + TSH 
  
 
Pregnancy Test [9] 
Day -7 
 
 
  
  
  
 
 
  
  
 
 X 
 
Urinalysis [10] 
X 
X 
 
  
  
  
X 
 
  
  
X  
  
 
Treatment w/ Study Drug 
  
 
 
  
  
  
 
 
  
  
 
  
 
TRC105 Dosing [11] 
  
X Split  
X Split  
X 
X  
X 
X  
X  
X 
X  
  
  
 
Sorafenib [12] 
 
Daily (28 days) 
Daily (28 days) 
  
 
 
Tumor Assessments 
  
 
 
  
  
  
 
 
  
  
 
  
 
CT or MRI Scans [13] 
X 
 
 
  
  
  
 
 
  
X 
 
 X 
  
 
Other Clinical Assessments 
  
 
 
  
  
  
 
 
  
  
 
  
 
12-Lead ECG [14] 
X 
 
 
  
  
  
 
 
  
  
 X 
  
 
Concomitant 
Medications/Treatments [15] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 X  
X 
 
Adverse Events [16] 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Overall Survival [17] 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Special Laboratory 
Assessments 
  
 
 
X 
  
  
 
 
X 
  
X 
  
 
Pre Dose PK [18] 
  
X 
 
 X 
X 
 X 
X (Even 
Cycles) 
 
 X (C2 Only) 
 
 X 
X 
 
Anti-product antibodies [19] 
 
X 
 
X 
X 
X 
X (Even 
Cycles) 
 
X (C2 Only) 
 
 X 
X 
 
Protein Biomarkers [20] 
 
 
X 
 
 
 
 
X (Even 
Cycles) 
 
 
 
X 
 
 
Tumor Markers [21] 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
Archival Tumor Tissue [21] 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Schedule of Assessments Footnotes 
1. Days of Treatment with TRC105: All assessments should be performed prior to the TRC105 infusion unless otherwise indicated.  Each cycle 
is 28 days in duration.  
2. Cycle 1 day 1: Hematology (including iron studies), blood chemistry (including TSH testing), urinalysis, physical examination, ECG and 
pregnancy test not required if acceptable screening assessment is performed within 7 days prior to the start of treatment on cycle 1 day 1.  
3. End of Study: The end of study visit should generally occur within 14 days (+/- 1 day) of the last dose of TRC105. Assessments other than 
pharmacokinetics, immunogenicity and protein biomarkers do not need to be repeated if performed within the previous 2 weeks (previous 8 
weeks for radiologic tumor assessments). Follow-up visits should occur 28 days following the last dose of TRC105 study drug as outlined in 
the Schedule of Assessments.  
4. Informed Consent: Must be obtained prior to undergoing any study specific procedure and may occur prior to the 28-day screening period. 
5. Medical and Oncologic History, Demographics and Baseline Signs and Symptoms: All information related to prior anticancer treatment 
should be recorded. Significant medical history and baseline signs and symptoms should be captured from the date of informed consent.  
6. Physical Examination: Examination of major body systems and ECOG performance status.  
7. Vital Signs: Heart rate, temperature, blood pressure, respiratory rate, weight. Assessment of vital signs during TRC105 Infusions: Vital signs 
are to be assessed pre-infusion (i.e., within 30 minutes of starting the infusion) every 30 minutes during the infusion (+/- 15 minutes) and at the 
end of the infusion (i.e. within 30 minutes after completing the infusion). Vital signs should be monitored more frequently and/or beyond the 
completion of the infusion if medically indicated (e.g. if the patient experiences an infusion reaction that has not yet resolved).   
8. Hematology, Chemistry & Coagulation:  Testing to be performed locally.  Thyroid stimulating hormone to be tested at screening, day 1 of 
each cycle and at the end of study visit.  Cycle 1 day 1 assessments only need to be performed if screening assessments were performed more 
than 7 days prior to cycle 1 day 1.  Iron studies (FE) to be performed according to the schedule of assessments and as clinically indicated 
during the study.  Thyroid stimulating hormone (TSH) to be performed according to the schedule of assessments and as clinically indicated 
during the study.  Lab assessments may be performed within 3 days prior to TRC105 dosing. In addition to the assessments scheduled for the 
clinical trial, patients should undergo assessment as appropriate to ensure safe treatment. See Section 8.1.1.1 for specific panel collection 
requirements.  
9. Pregnancy Test: Testing to be performed locally. All female patients of childbearing potential must have a negative serum or urine pregnancy 
test within 7 days of cycle 1 day 1, day 1 of every cycle starting with cycle 2, and 28 days following the last dose of TRC105. 
10. Urinalysis: To be performed locally. Cycle 1 day 1 urinalysis only needs to be performed if screening urinalysis was performed more than 7 
days prior to cycle 1 day 1.  Microscopic analysis and/or urine protein creatinine ratio or 24-hour urine protein collection should be performed 
as clinically indicated. 
11. TRC105 Administration: Intravenous TRC105 diluted in normal saline will be administered every 7 days.  The first weekly TRC105 dose 
will be given on cycle 1 day 1and split into two doses whereby 3 mg/kg is administered on cycle 1 day 1 and the balance is administered on 
cycle 1 day 4.  The entire dose of TRC105 (10 mg/kg) is then given on cycle 1 day 8, cycle 1 day 15, cycle 1 day 22 and weekly thereafter. 
See Section 7.7 for specific TRC105 administration guidelines. 
12. Sorafenib Dosing: Oral sorafenib will be dosed twice daily on days 1-28 of each 28 day cycle according to the sorafenib package insert. See 
Section 7.8 for specific dosing guidelines. 


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13. Imaging: CT or MRI Images of the chest, abdomen, and pelvis to be performed at screening, and on-study as outlined in the assessment table.  
A brain MRI or CT with contrast and bone scans to be performed at screening and on study if metastases are suspected.  Known areas of 
disease should be consistently followed throughout the study.  Assessments should be performed whenever disease progression is suspected.  
Allowable window for tumor imaging study is +/- 7 days.  Scans will be performed every 2 cycles (day 22 of cycle 2, 4, 6, 8, 10, etc.).  De-
identified copies of CT/MRI’s, in DICOM format, may be transferred to the Sponsor if requested.  Patients are eligible for treatment until 
progression.  
14. 12-Lead ECG: Single tracing 12-lead ECG will be performed at screening and at the time-points indicated in the Schedule of Assessments 
(pre-dose). If the patient develops an arrhythmia, the ECG should be repeated on day 1 of each subsequent cycle. For a QTc >500 ms, a repeat 
ECG for confirmation and evaluation of the ECG by a cardiologist is recommended.   Additional ECGs may be performed on study as 
clinically indicated.  
15. Concomitant Medications and Treatments: Concomitant medications and treatments will be recorded from 28 days prior to the start of 
study treatment and up to 28 days following the last dose of study treatment. Required TRC105 premedications should be recorded on 
TRC105 premedications CRF. 
16. Adverse Events: Patients must be followed for adverse events from the first day of treatment with sorafenib or TRC105 until at least 28 days 
after the last dose of study treatment, or until all serious or TRC105 related toxicities have resolved or are determined to be “chronic” or 
“stable”, whichever is later. Baseline signs and symptoms will be recorded on corresponding case report forms. Any serious AE that is 
possibly related to TRC105 occurring from the time of first dose or at any point after the reporting period must be promptly reported to 
TRACON. 
17. Overall Survival: Phone call to patient every two months to determine overall survival.     
18. TRC105 and Sorafenib Pharmacokinetics Pre-Dose (Trough) Concentration: One 5 mL blood sample and one 4 mL sample to be 
collected at the time-points indicated in the Schedule of Assessments, prior to dosing with sorafenib and prior to starting the TRC105 infusion. 
Samples will be stored at approximately -70°C.  Samples will be batch shipped as indicated in the laboratory manual to a third-party 
laboratory.  See separate laboratory guide for further collection and shipment information.  Additional PK samples may also be collected at the 
time of unexpected clinical events.  
19.  Anti-product antibodies: 5 mL blood sample will be collected to assess anti-product antibodies at the time-points indicated in the schedule of      
assessments and stored at approximately -70°C to be analysed by a central laboratory. Samples will be batch shipped as indicated in the 
laboratory manual to a third-party laboratory. See separate laboratory guide for further collection and shipment information. Additional anti-
product antibody samples may also be collected at the time of unexpected clinical events. 
20. Protein Biomarkers: One 10 mL purple top (K3EDTA) tube will be collected at the time-points indicated in the schedule of assessments and 
stored at approximately -70°C to be analysed by a central laboratory. See separate laboratory guide for further collection and shipment 
information. 
21. Tumor Marker: Blood sampling for tumor markers (i.e. AFP) will be collected and analyszed locally as indicated in the schedule of 
assessments.   


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22. Archival Tumor Tissue: Archival specimens (formalin-fixed, paraffin-embedded) are required of the primary cancer and/or metastatic cancer 
specimen for each study participant. It is preferable that the entire paraffin block be submitted, but if this is not feasible, then at least 20 
unstained slides are requested for immunohistochemical analysis (sections of 5 microns are preferred).  See separate laboratory guide for 
further collection and shipment information. 
23. 28-Day Follow-up:  The follow-up visit should occur 28 days following the last dose of TRC105. The allowable visit window is +/- 7 days.  
24. Allowable window for each visit within the cycle is +/- 2 days unless otherwise stated. 
 
 
 
 
 
 
 
 
 
 
 
 


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6. 
SELECTION AND WITHDRAWAL OF PATIENTS 
6.1. 
Patient Inclusion Criteria 
6.1.1. 
Inclusion Criteria: 
1. Patients must have confirmed hepatocellular carcinoma (HCC) by either histopathology or 
radiography.  Diagnosis of HCC can be made without a biopsy if radiographic hallmarks of 
arterial hypervascularity and venous/late phase washout are present by either dynamic contrast-
enhanced MRI or helical multidetector CT scan using contrast for a lesion > 2 cm, or by both 
modalities for a lesion 1-2 cm. [2]. 
2. Patients must have disease that is not amenable to potentially curative resection or 
ablative techniques or that has recurred following ablative techniques. In addition, 
disease must not be amenable to transhepatic arterial chemoembolization (TACE) or must 
have progressed TACE. Patients must not be candidates for liver transplantation. 
3. Patient must have a Child-Pugh A or B (7 points) classification 
4. No other prior malignancy is allowed except for the following: adequately treated basal 
cell or squamous cell skin cancer, or adequately treated Stage I or II cancer from which 
the patient is currently in complete remission per investigators' clinical judgment.  
5. Measurable disease by RECIST 1.1 (Phase 2 only) 
6. Age of 18 years or older 
7. ECOG performance status ≤ 1 
8. Resolution of all acute adverse events resulting from prior cancer therapies to NCI 
CTCAE grade ≤ 1 or baseline (except alopecia)   
9. Adequate organ function as defined by the following criteria: 
• AST and ALT ≤ 5 x ULN    
• Absolute neutrophil count (ANC) ≥ 1500/μL  
• Platelets ≥ 60,000/μL without transfusion support within the past 28 days 
• Hemoglobin ≥ 9.0 g/dL without transfusion support within the past 14 days 
(erythropoietin or darbepoietin permitted) 
• Serum creatinine clearance > 30 mL/min by Cockcroft-Gault formula 
10. Willingness and ability to consent to participate in study   
11. Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests, 
and other study procedures. 
12. Men who are sterile (including vasectomy confirmed by post vasectomy semen analysis) 
OR agree to use at least two forms of a reliable and highly effective method of birth 


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control (refer to Section 3.5.2.1) and to not donate sperm and for at least 180 days 
following last dose of TRC105 or sorafenib. 
13. Woman of non-child bearing potential due to surgical sterilization (at least 6 weeks 
following surgical bilateral oophorectomy with or without hysterectomy or tubal ligation) 
confirmed by medical history or menopause (i.e., no menstrual bleeding for more than 12 
months in a women aged 45 years or more), OR woman of child bearing potential who test 
negative for pregnancy at time of enrollment based on serum pregnancy test and agree to 
use at least 2 forms of a reliable and highly effective method of birth control during the 
study and for at least 180 days after stopping TRC105 or sorafenib (refer to 
Section 3.5.2.1)   
6.1.2. 
Exclusion Criteria:   
1. Prior anticancer systemic therapy  
2. Current treatment on another therapeutic clinical trial 
3. Prior radiation therapy within 28 days of starting the study treatment, except radiation 
therapy for bone metastases or radiosurgery is permitted up to 14 days of starting 
treatment 
4. No major surgical procedure or significant traumatic injury within 6 weeks prior to study 
registration, and must have fully recovered from any such procedure; date of surgery (if 
applicable). Note: the following are not considered to be major procedures and are 
permitted up to 7 days before therapy initiation: Thoracentesis, paracentesis, port 
placement, laparoscopy, thorascopy, tube thoracostomy, bronchoscopy, endoscopic 
ultrasonographic procedures, mediastinoscopy, skin biopsies, incisional biopsies, 
imaging-guided biopsy for diagnostic purposes, and routine dental procedures 
5. 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. 
6. Uncontrolled chronic hypertension defined as systolic > 150 or diastolic > 90 on more 
than one measurement despite optimal therapy (initiation or adjustment of BP medication 
prior to study entry is allowed provided that the average of 3 BP readings prior to 
enrollment is < 150/90 mm Hg) 
7. History of brain involvement with cancer, spinal cord compression, or carcinomatous 
meningitis, or new evidence of brain or leptomeningeal disease.  Patients with radiated or 
resected lesions are permitted, provided the lesions are fully treated and inactive, patients 
are asymptomatic, and no steroids have been administered for at least 28 days.   
8. Angina, MI, symptomatic congestive heart failure, cerebrovascular accident, transient 
ischemic attack, arterial embolism, pulmonary embolism, PTCA or CABG within the 
past 6 months.  
9. Active bleeding or pathologic condition that carries a high risk of bleeding (e.g. 
hereditary hemorrhagic telangiectasia).  No bleeding diathesis. 


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10. Thrombolytic use (except to maintain i.v. catheters) within 10 days prior to first day of 
study therapy 
11. History of hemorrhage or hemoptysis (> ½ teaspoon bright red blood) within 3 months of 
starting study treatment 
12. Need for anticoagulation 
13. History of liver transplant 
14. History of bleeding esophageal varices in previous 6 months, which have not been adequately 
managed with banding or sclerotherapy (i.e., following treatment, varices must be ≤ grade 1 with 
no stigmata of recent bleeding).   Patients with cirrhosis must have had esophagogastric 
endoscopy within the past 6 months prior to study entry for the assessment of varices, and 
esophageal varices must be ≤ grade 1 with no stigmata of recent bleeding. Those with gastric 
varices that are deemed as high risk by the endoscopist should be placed on appropriate 
medical therapy as advised by the gastroenterologist. 
15. History of peptic ulcer disease within 3 months of treatment, unless treated for the 
condition and complete resolution has been documented by esophagogastroduodenoscopy 
(EGD) within 28 days of starting study treatment 
16. Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome 
(AIDS) related illness 
17. Patients may not have received a strong CYP3A4 inducer within 12 days prior to 
registration (Table 19) 
18. Patients with known hypersensitivity to Chinese hamster ovary products or other 
recombinant human, chimeric, or humanized antibodies. 
19. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality 
that may increase the risk associated with study participation or may interfere with the 
interpretation of study results and, in the judgment of the Investigator, would make the 
patient inappropriate for this study 
20. Ascites or pleural effusion requiring intervention or that required intervention within the 
last month and has recurred 
21. Pericardial effusion (except trace effusion identified by echocardiogram)  
6.2. 
Patient Withdrawal Criteria 
A patient should be withdrawn from study treatment if, in the opinion of the Investigator, it is 
medically necessary, or if it is the wish of the patient.  If a patient does not return for a scheduled 
visit, every effort should be made to contact the patient.  In any circumstance, every effort should 
be made to document patient outcome.  Data to be collected at the end of study visit are 
described in the Schedule of Assessments (Table 5).  Patients will be followed for at least 28 
days after the last dose of TRC105 study drug for adverse events.  If the patient withdraws 
consent, no further evaluations should be performed, and no attempts should be made to collect 
additional data.  Patients may be withdrawn for DLT, but DLT does not mandate withdrawal if 


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the DLT resolves and can be treated (i.e., a first dose infusion reaction).  Patients will be 
withdrawn from treatment in the case of: 
1. RECIST 1.1-defined disease progression. In cases where RECIST cannot be applied, 
progression should be based on unequivocal evidence of progressive disease 
sufficient to require a change in therapy. 
2. A need for anticancer surgery, radiation, or for other anticancer therapy not specified 
in the protocol. 
3. Lost to follow-up or noncompliant. 
4. Any TRC105 dose delay > 2 days in cycle 1 (phase 1b only) unless discussed with 
sponsor.  
5. Pregnancy.  Pregnant patients should be followed for the duration of the pregnancy 
and the outcome of the pregnancy should be documented. 
6. Arterial thrombosis of any grade (including cerebrovascular ischemia, cardiac 
ischemia/infarction, or peripheral or visceral arterial ischemia), grade 3 or 4 venous 
thrombosis (including pulmonary embolism), grade > 2 intracranial hemorrhage, 
grade 3 or 4 non-CNS hemorrhage. Grade 2 non-CNS hemorrhage does not mandate 
withdrawal if the underlying condition is treatable.  Grade 1 intracranial hemorrhage 
does not mandate withdrawal and may be treated with dose interruption if the patient 
is benefitting from treatment.  
7. Missed study drug treatment for > 8 consecutive weeks (i.e., both TRC105 and 
sorafenib dosing held concurrently).  Patients who cannot tolerate sorafenib and who 
demonstrate a response of complete response (CR), partial response (PR) or stable 
disease (SD) and are thought to benefit from continued single agent TRC105 therapy 
may continue on study on TRC105 alone. 


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7. 
TREATMENT OF PATIENTS 
7.1. 
Description of TRC105 Study Drug 
TRC105 is a genetically engineered human/murine chimeric monoclonal antibody directed 
against human CD105 found on the surface of proliferating endothelial cells.   
7.2. 
Composition of TRC105 
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.  
7.3. 
TRC105 Dose Level 
7.3.1. 
Phase 1b 
Each patient will be dosed with 10 mg/kg weekly during cycle 1 then, 10 mg/kg (Dose Level -1) 
or 15 mg/kg (Dose Level 1) every two weeks thereafter of each 28 day cycle beginning with 
cycle 2 in the phase 1b portion and 10 mg/kg weekly in Phase 2. The maximum weight that 
should be used for purpose of dose calculation is 85 kg for women and 100 kg for men.  Thus, 
the maximum dose that should be given to a woman at the 10 mg/kg dose is 850 mg and at the 
15 mg/kg dose is 1275 mg.  The maximum dose that should be given to a man at the 10 mg/kg 
dose is 1000 mg and the 15 mg/kg dose is 1,500 mg.  TRC105 is distributed according to lean 
body mass rather than overall body weight.  Patients who are overweight would be at risk for 
high serum levels of TRC105 if the doses were not capped.  85 kg for women and 100 kg for 
men represent accepted maximum lean body masses for the two genders. The calculated dose of 
TRC105 can be rounded up or down to the nearest 1.0 mg; in the case of an increment of 0.5 mg 
the dose should be rounded up.  The first TRC105 dose (cycle 1 day 1) will be split into two 
doses whereby 3 mg/kg is administered on cycle 1 day 1 and the balance is administered on 
cycle 1 day 4 (i.e., 7 mg/kg), in both Phase 1b and 2.   Patients enrolled into the Phase 1b Dose 
Level -1 or Dose Level 1 will receive the entire dose of TRC105 (i.e. 10 or 15 mg/kg 
respectively) starting on cycle 2 day 1 and every two weeks thereafter of each subsequent 28 day 
cycle.  
As outlined in Section 3.5 10 mg/kg of TRC105 weekly is the recommended phase 2 dose.  
Ongoing patients in the Phase 1b portion of this study may, at the discretion of the investigator, 
be treated at the Phase 2 TRC105 dose of 10 mg/kg weekly. 
7.3.2. 
Phase 2 
 Patients enrolled in the Phase 2 portion of the trial will receive 10 mg/kg weekly (see 
Section 3.5 for dose selection rational).   


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7.4. 
TRC105 Packaging and Labeling 
TRC105 will be supplied at 25 mg/mL in 20 mM L-Histidine/L-Histidine Monohydrochloride, 
240 mM Trehalose, 0.01% Polysorbate 20 Formulation in one or more of the following 
presentations. 
200 mg TRC105/8 mL single-use vial 
400 mg TRC105/16 mL single-use vial  
7.5. 
TRC105 Storage and Shipping 
TRC105 must be stored between 2 °C and 8 °C (36 °F to 46 °F) and protected from light 
7.6. 
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 0.6 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. 
TRC105 should be diluted in ≤ 250 mL of normal saline in patients weighing less than 70 kg 
(this will prevent the administration of intravenous fluid in excess of 10% of blood volume 
during an infusion). 


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7.7. 
TRC105 Administration 
Patients should be encouraged to drink abundant fluid (e.g., two eight-ounce glasses of water or 
juice) prior to the first treatment.  IV hydration prior to and during therapy is left to the discretion 
of the Investigator, but should be considered for patients that may be volume depleted. 
The following TRC105 premedications should be administered and completed 2 hours to 30 
minutes prior to the start of each infusion as described below:  
Phase 1b Dose Levels -1, 1 (10 mg/kg weekly C1, and 10 or 15 mg/kg every 2 weeks C2+) 
and Phase 2 (10 mg/kg weekly) 
• Acetaminophen 650 mg p.o. x 1 
• Famotidine 20 mg i.v. or p.o. (or similar H2 blocker) x 1.  Famotidine or similar H2 
bloacker may be discontinued begining with cycle 2 in the absence of an infusion 
reaftion with the previous dose 
• Cetirizine 10 mg i.v. or p.o. x 1 (or similar oral or intravenous antihistamine).  
Ceterizine or similar antihistamine may be discontinued begining with cycle 2 in the 
absence of an infusion reaftion with the previous dose. 
• Methylprednisolone 100 mg i.v. will be given prior to the Cycle 1 Day 1, and Cycle 1 
Day 4 infusions. In addition, methylprednisolone will be given in the case of a delay 
of > 10 days between any weekly doses or > 17 days between any two TRC105 doses 
or if the patient develops an infusion reaction > grade 2 during the immediate prior 
infusion.   
• Anti-emetic treatment, while not required, may be given prior to the initial dose and 
subsequent doses to reduce the frequency of nausea and vomiting that may be 
observed during TRC105 infusions. 
TRC105 premedication, including the methylprednisolone infusion, should be completed 2 
hours to 30 minutes prior to initiating TRC105 infusions.   
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.   
Three mg/kg of TRC105 will be administered on cycle 1 day 1 and administered over 4 hours 
(+/- 15 minutes). Do not increase the infusion rate above 25 mg/min during the Cycle 1 Day 1 
dose. The remainder of the cycle 1 dose will be administered on cycle 1 day 4 (e.g., 7 mg/kg) 
and infused over a period of 2 hours (+/- 15 minutes). The full cycle 1 dose (i.e., 10 mg/kg) will 
be administered on cycle 1 day 8 and infused over 1 hour (+/- 15 minutes) and every week 
thereafter for the remainder of cycle 1 (and cycle 2 in the phase 2 portion). The full every two 
week TRC105 dose for patients in phase 1b Dose Level -1 and 1 (10 mg/kg or 15 mg/kg) and 
weekly dosing for patients in phase 2 will be administered on cycle 2 day 1 and infused over 1 


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hour (+/- 15 minutes) in the absence of infusion reaction with the prior dose patients must 
complete at least one 4 hour infusion without the development of any infusion reactions, in order 
to reduce the subsequent TRC105 infusion to 2 hours (+/- 15 minutes) and complete a 2 hour 
infusion without the development of any infusion reactions in order to reduce subsequent 
TRC105 infusions to 1 hour (+/- 15 minutes). Starting on cycle 2 day 1, TRC105 will be 
administered at 10 mg/kg or 15 mg/kg over 1 hour (+/- 15 minutes). Patients with infusion 
reactions of any kind should be managed appropriately (see Section 7.7.2) and are not permitted 
to reduce the duration of the next planned infusion. In the event a dose cannot be completed on a 
given day, the balance of the planned dose may be administered the following day at the rate of 
infusion planned for the prior day 
The minimum infusion duration for Dose Level 1 is 1 hour (60 minutes +/- 15 minutes).  
Table 7: 
Ideal TRC105 Dosing Schema for Phase 1b Dose Levels -1 and 1 (10 mg/kg 
weekly C1, 10 or 15 mg/kg every 2 weeks C2+)   
 
C1D1 
C1D4 
C1D8 
C1D15 
C1D22 
C2D1 
C2D15 
C3D1+ 
TRC105 Dose level -1: 10mg/kg weekly 
C1 and 15 mg/kg every 2 weeks C2+ 
3  
7  
10  
10 
10  
10  
10  
10  
Infusion Duration (hours) 
4 
2 
1 
1 
1 
1 
1 
1 
TRC105 Dose level 1: 10mg/kg weekly 
C1 and 15 mg/kg every 2 weeks C2+ 
3 
7 
10 
10 
10 
15 
15 
15 
Infusion Duration (hours) 
4 
2 
1 
1 
1 
1 
1 
1 
Premedication 
Methylprednisolone (mg) 
100 
100 
0 
0 
0 
0 
0 
0 
Famotidine (mg) 
20 
20 
20 
20 
20 
0 
0 
0 
Cetirizine (mg) 
10 
10 
10 
10 
10 
0 
0 
0 
Acetaminophen (mg) 
500 - 
1000 
500 - 
1000 
500 - 
1000 
500 - 
1000 
500 - 
1000 
500 - 
1000 
500 - 
1000 
500 - 
1000 
Table 8: 
 
Ideal TRC105 Dosing Schema for Phase 2 (10 mg/kg weekly C1+) 
 
C1D1 
C1D4 
C1D8 
C1D15 
C1D22 
C2D1 
C2D8 
C2D15 
C2D2
2 
TRC105 Dose level -1: 10mg/kg 
weekly  
3  
7  
10  
10 
10  
10  
10 
10  
10 


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Infusion Duration (hours) 
4 
2 
1 
1 
1 
1 
1 
1 
1 
Methylprednisolone (mg) 
100 
100 
0 
0 
0 
0 
0 
0 
0 
Famotidine (mg) 
20 
20 
20 
20 
20 
0 
0 
0 
0 
Cetirizine (mg) 
10 
10 
10 
10 
10 
0 
0 
0 
0 
Acetaminophen (mg) 
500 - 
1000 
500 - 
1000 
500 - 
1000 
500 - 
1000 
500 - 
1000 
500 - 
1000 
500-
1000 
500 - 
1000 
500-
1000 
7.7.1. 
TRC105 Dose Reduction/Dose Delays 
TRC105 dose reductions and interruptions should be avoided in cycle 1 and 2.  In cycle 3 and 
beyond, TRC105 dose reductions are allowed for grade 3 or 4 related adverse events that resolve 
to ≤ grade 2 or baseline (including anemia).  Dose reductions for other toxicities are allowed at 
the discretion of the investigator.  Treatment dose delays cannot exceed 8 weeks (i.e., both 
TRC105 and sorafenib dosing cannot both be held at the same time for > 8 consecutive weeks). 
However, patients who cannot tolerate sorafenib and who demonstrate a response of complete 
response (CR), partial response (PR) or stable disease (SD) with the combination and are thought 
to benefit from continued single agent therapy may continue on study on TRC105 alone per 
Section 6.2 of the protocol.  
Table 9: 
Allowable TRC105 Dose Modifications 
Toxicity Attributed to 
TRC105 
Dose Adjustment for Next Dose of TRC105  
Dose Schedule/Level 
10 mg/kg weekly or biweekly 
15 mg/kg every 2 weeks 
Grade 1 or 2 
Maintain Dose Level 
Maintain Dose Level 
Grade 3 or 4 
 
 
• 
1st appearance 
8 mg/kg weekly 
12 mg/kg every 2 weeks 
• 
2nd appearance 
6 mg/kg weekly 
10 mg/kg every 2 weeks 
• 
3rd appearance 
4 mg/kg weekly 
8 mg/kg every 2 weeks 
• 
4th appearance 
Discontinue TRC105 
treatment permanently 
Discontinue TRC105 treatment 
permanentlya 
aAfter discussion with and agreement of the Sponsor, patients receiving TRC105 every two weeks have the 
option to return to weekly dosing at the lowest level (i.e., 4 mg/kg weekly), if 8 mg/kg every 2 weeks is not 
tolerable (i.e., 4th appearance of a Grade 3 or 4 toxicity attributable to TRC105 occurs) and the investigator 
believes that the patient is receiving benefit from the treatment. 
Patients with arterial thrombosis or grade 3 or 4 venous thrombosis should be removed from 
study.  Patients with grade 1 or 2 venous thrombosis who require anticoagulation will have their 
TRC105 therapy interrupted.  TRC105 therapy may resume once the following criteria are met:   


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• The patient is on a stable dose of heparin or low molecular weight heparin.  
• The patient has a platelet count > 60,000. 
• The patient has not had a hemorrhagic event of grade 2 or higher while on study. 
• The patient does not have a pathological condition that carries a high risk of bleeding 
(e.g., tumor involving major vessels). 
• The patient is benefiting from TRC105 therapy (no evidence of disease progression). 
TRC105 and sorafenib should be held for two weeks prior and for two weeks following surgical 
procedures. However, resumption of study treatment can be shorter (but no less than 7 days) or 
longer than two weeks based on clinical judgement of adequate wound healing and recovery 
from the procedure. For minor procedures (e.g., port placement), TRC105 (and sorafenib) 
should be held for at least 1 week prior and for at least 1 week after (or until adequate healing). 
TRC105 DOSING DELAY:  If a patient misses a scheduled weekly TRC105 dose and dosing 
is resumed ≥ 10 days after the last dose or if a patient misses a scheduled every-2-week dose and 
dosing is resumed ≥ 17 days after the last dose, premedication (including methylprednisolone) 
and TRC105 are to be administered as described in Table 10. Split dosing is not required. 
However, it is recommended that if the patient experienced a severe headache with a previous 
infusion, the first TRC105 dose upon resumption should be administered over two days as was 
done for the initial dose, see Table 11.  
 
Table 10: 
TRC105 dosing after Dose Delay (with no split dosing) 
 
CxDy 
CxDy 
CxDy 
CxDy 
CxDy+ 
TRC105 Dose (mg/kg) 
10 or 15  
10 or 15  
10 or 15  
10 or 15  
10 or 15  
Infusion Duration (hours) 
4 
2 
1  
1  
1  
Premedication 
Methylprednisolone (mg) 
100 
0 
0 
0 
0 
Famotidine (mg) 
20 
20 
20 
20 
0 
Cetirizine (mg) 
10 
10 
10 
10 
0 
Acetaminophen (mg) 
650 
650 
650 
650 
650 
Note that acetaminophen should NOT be discontinued.  


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Table 11: TRC105 Dosing after Dose Delay (with split dosing)  
 
Day 1 
resumin
g 
TRC105 
 3 days 
later 
Weekly or 
every 2 
weeks from 
Day 1 
Weekly 
or every 2 
weeks  
CxDy+ 
TRC105 Dose (mg/kg) 
3   
7 or 12  
10 or 15  
10 or 15  
10 or 15  
Infusion Duration 
(hours) 
4 
2 
1  
1  
1  
Premedication 
Methylprednisolone 
(mg) 
100 
100 
0 
0 
0 
Famotidine (mg) 
20 
20 
20 
20 
0 
Cetirizine (mg) 
10 
10 
10 
10 
0 
Acetaminophen (mg) 
650 
650 
650 
650 
650 
Note that acetaminophen should NOT be discontinued.  
The schedule of assessment should be followed with regards to visits, labs, and any other 
required assessments even if TRC105 dosing is held. 
7.7.2. 
Management of TRC105 Infusion Reactions 
If a patient experiences a grade 2 or higher adverse reaction during infusion, the infusion should 
be interrupted and the patient treated accordingly.  Antipyretic, antihistamine, antiemetic, anti-
inflammatory, or other symptomatic medications including epinephrine may be administered as 
indicated.  For grade 2 and certain grade 3 infusion reactions, the infusion may be restarted at 
half of the previous rate if and when the infusion reaction has resolved, and then increased per 
patient tolerance to a maximum of 25 mg/min.  For grade 4 infusion reactions, the infusion 
should not be restarted and the patient should be discontinued from study treatment.  Infusion 
reactions will be recorded as AEs in the case report form.  Interventions should be documented 
as concomitant medications or concomitant treatments as appropriate.   
Table 12: 
Management of TRC105 Infusion Reactions 
Infusion Reaction 
Severity 
Recommended Management 
Grade 1 (mild) 
1. No intervention 
2. Continue infusion unless symptoms worsen 


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Infusion Reaction 
Severity 
Recommended Management 
Grade 2 (moderate) 
1. Interrupt infusion 
2. Treat with symptomatic medicationsa 
3. Resume infusion at half the previous rate when infusion-related 
symptoms improve to grade 1 or less. 
Grade 3 (severe) 
1. Interrupt infusion 
2. Treat with symptomatic medicationsa 
3. Monitor patient until infusion-related symptoms resolve, including 
hospitalization if necessary 
4. Discontinue TRC105 unless other factors that contributed to the 
infusion reaction are identified and corrected 
Grade 4 (life-
threatening) 
1. Discontinue infusion 
2. Treat with symptomatic medicationsa 
3. Hospitalize patient 
4. Permanently discontinue TRC105 
aSymptomatic medications may include but are not limited to diphenhydramine 50 mg i.v. and/or hydrocortisone 
100 mg i.v. (for fever, rash, hypoxia, or other hypersensitivity reactions), meperidine 50-100 mg i.v. (for shaking 
chills/rigors), oxygen by mask or nasal cannula (for hypoxia), epinephrine 0.5 mg i.m. (for hypotension or 
bronchospasm), albuterol inhaler or nebulizer (for bronchospasm), i.v. fluids (for hypotension), and ondansetron 
0.15 mg/kg i.v. (for nausea). 
7.7.3. 
TRC105 Study 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 lot number of the TRC105 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. 
7.7.4. 
TRC105 Study Drug Handling and Disposal 
TRC105 must be stored upright between 2 °C and 8 °C (36 °F to 46 °F). The Investigator should 
not return clinical study materials to TRACON unless specifically instructed to do so by 
TRACON.  Used vials do not need to be maintained.  All expired vials of TRC105 should be 
retained until destruction is authorized by a TRACON representative.  The Site Pharmacist will 
be responsible for documenting the destruction (according to institutional requirements) of used 
or expired vials. 


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7.8. 
Description of Sorafenib 
See sorafenib package insert. 
7.8.1. 
Composition of Sorafenib 
See sorafenib package insert.  
7.8.2. 
Sorafenib Dose Level 
Each patient will be dosed initially with 400 mg of sorafenib twice per day for each day of a 28 
day cycle. Dose de-escalation is permitted per the package insert starting in cycle 1.   
7.8.3. 
Sorafenib Packaging and Labeling 
See sorafenib package insert. 
7.8.4. 
Sorafenib Storage Handling and Disposal 
See sorafenib package insert. 
7.8.5. 
Sorafenib Dosing 
The oral dose of sorafenib is 400 mg (2 tablets) twice daily of each 28 day cycle (for a total of 4 
tablets each day).  Sorafenib tablets should be taken without food (at least 1 hour before or 2 
hours after a meal). Patients are to swallow the tablets whole with approximately 250 ml (8 oz) 
of water, each morning and evening (i.e., approximately 12 hours apart). 
7.8.6. 
Sorafenib Dose Modification 
Management of suspected adverse drug reactions may require temporary interruption and/or dose 
reduction of sorafenib therapy. Dose reduction is allowed based on individual safety and 
tolerability starting in cycle 1 as outlined below and in accordance with sorafenib package insert.  
Doses will be delayed or reduced for clinically significant hematologic and non-hematologic 
toxicities that are related to sorafenib according to the guidelines that follow.   
Dose modifications will follow predefined dose levels in Table 13.  Dose adjustments for 
hematologic toxicity are based on blood counts obtained in preparation for the day of treatment. 
 
 
Table 13: 
Sorafenib Dose Modification Levels 
Dose 
Sorafenib 


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Starting Dose 
400 mg twice daily 
-1 
400 mg once daily 
-2 
400 mg every other day 
Table 14: 
Dose Modification for Hematologic Toxicities 
Recommended Dose Modification for Hematologic Toxicities  
 
Toxicity 
ANC/AGC 
(x 109/L) 
Hemoglobin 
(g/dL) 
Platelets 
(x 109/L) 
Sorafenib 
Grade 1 
> 1.5 
< LLN – 10.0 
> 75 
Treat on time 
No change 
Grade 2 
> 1.0 to < 1.5 
< 10.0 – 8.0 
> 50 to < 75 
Treat on time 
No change 
Grade 3 
> 0.5 to < 1.0 
< 8.0 – 6.5 
> 25 to < 50 
Treat on time 
Reduce by one dose level 
Grade 4 
< 0.5 
Life-threatening 
consequence; 
urgent 
intervention 
indicated 
<25 
Delay sorafenib until toxicity 
resolves to Grade 2 or less then 
Reduce by two dose levels 
Febrile 
Neutropenia 
 
 
 
Sorafenib held until toxicity has 
resolved to Grade 2 or less; 
when sorafenib is restarted, 
reduce by one dose level 
ANC - absolute neutrophil count; AGC - absolute granulocyte count 
  aIf no recovery after 28 day delay, treatment should be permanently discontinued unless treating physician 
determines subject is deriving clinical benefit. 
Table 15: 
Dose Modification for Non-hematologic Toxicities 
Recommended dose modification for non-hematologic toxicity  
(excluding hypertension and hand foot skin reaction, diarrhea and fatigue)  
Grade 
Dose Interruption 
Dose Modification 
Grade 0-2 
Treat on time 
No Change 
Grade 3 
Interrupt until ≤Grade 2 
Reduce one dose level 
Grade 4 
OFF protocol therapy  
OFF protocol therapy 
aIf no recovery after 28 day delay, treatment will be discontinued unless subject is deriving clinical 
benefit. 
Prevention/management strategies for diarrhea and fatigue 
Diarrhea and fatigue are common side effects of sorafenib.  The same dose-modification 
algorithm used for skin toxicities can be used to address these toxicities.  However, the 
preventive/management strategies for diarrhea and fatigue should be consistent with local 
standards (e.g., anti-diarrheals and optimized hydration status for diarrhea). 


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Table 16: 
Dose Modifications for Hand-Foot-Skin Reaction 
Recommended dose modification for hand foot skin reaction 
Toxicity Grade 
Suggested dose modification 
Grade 1 
Any occurrence 
Maintain dose level and consider topical therapy for 
symptomatic relief 
Grade 2 
1st occurrence 
Maintain dose level and consider topical therapy for 
symptomatic relief 
If no improvement within 7 days, see below 
 
No improvement 
within 7 days or 2nd 
occurrence  
Interrupt until resolved to Grade 0-1 
When resuming treatment, reduce dose by one dose 
level 
 
3rd occurrence  
Interrupt until resolved to Grade 0-1 
When resuming treatment, reduce dose by two dose 
levels 
 
4th occurrence 
Discontinue treatment permanently 
Grade 3 
1st occurrence 
Interrupt until resolved to Grade 0-1 
When resuming treatment, reduce dose by one dose 
level 
 
2nd occurrence 
Interrupt until resolved to Grade 0-1 
When resuming treatment, reduce dose by two dose 
levels 
 
3rd occurrence 
Discontinue treatment permanently 
At first occurrence of HFSR, independent of grade, prompt institution of supportive measures 
such as topical emollients, low potency steroids, or urea-containing creams should be 
administered. 


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Table 17: 
Recommended Prevention/Management Strategies for Skin Toxicities 
Consistent With HFSR  
Toxicity Grade 
Practical Prevention / Management Strategies for HFSR  
Grade 0 (Preventive 
strategies) 
• Maintain frequent contact with trial physician to ensure 
early diagnosis of HFSR. 
• Practical prevention strategies 
o Pedicurea for subjects with pre-existing hyperkeratosis. 
o Subjects should avoid hot water, and clothing or 
activities that can cause friction on the skin. 
o Moisturizing cream should be applied sparingly. 
• Padded gloves and open shoes with padded soles should 
be worn to relieve pressure points. 
Grade 1  
Any occurrence 
• Continue preventive strategies and in addition: 
o Soak hands in cool water. 
o Apply petroleum jelly to moist skin. 
• In the case of hyperkeratotic lesions, exfoliate the hands 
or feet and apply moisturizing cream immediately 
afterwards. 
Grade 2 Any occurrence or 
Grade 3 Any occurrence 
• Continue supportive/management measures and add 
analgesic(s) for pain. 
aPedicure should be done by a podiatrist. 
Treatment-emergent hypertension 
Hypertension is a known and potentially serious adverse event associated with sorafenib 
treatment. Subjects will check blood pressure at home, on a weekly basis through the first 4 
weeks of therapy.  Thereafter, blood pressure will be monitored at each clinic visit. Subjects with 
pre-existing hypertension will monitor blood pressure at home daily basis. 
Blood pressure measurements that are out of the normal range must be reported by the treating 
physician.  Blood pressure measurements considered out of the normal range are diastolic 
pressure > 90 mm Hg and/or systolic pressure > 140 mm Hg, or a 20 mm Hg increase in diastolic 
pressure if the previous measurement was within normal limits. 
The dose-modification schedule to be followed in the event of treatment-emergent hypertension 
is outlined below.  The choice of anti-hypertensive medication to be used in cases of treatment-
emergent hypertension will be at the investigator's discretion and based on site-specific treatment 
guidelines as applicable.  All anti-hypertensive medications used for the management of 
treatment-emergent hypertension should be recorded in the subject’s records and pertinent CRFs. 
Once a dose-reduction modification has been made for treatment-emergent hypertension, NO 
dose re-escalation will be allowed. 


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Table 18: 
Management of Treatment-Emergent Hypertension 
Grade of Event (NCI-CTCAE v4.0) 
Management/ Next Dose 
Grade 1 
Consider increasing blood pressure 
monitoring.  Continue sorafenib dosing as 
scheduled. 
Grade 2 asymptomatic and diastolic 
pressure 90-99 mm Hg  
Begin anti-hypertensive therapy.  Continue 
sorafenib dosing as scheduled. 
Grade 2 (symptomatic/persistent) 
OR 
Grade 2 symptomatic increase by > 
20 mm Hg (diastolic) or to > 140/90 
mm Hg if previously within normal 
limits 
OR  
Grade 3 
Sorafenib should be helda until symptoms resolve 
and diastolic blood pressure < 90 mm Hg; also treat 
subject with anti-hypertensives and when sorafenib 
is restarted, reduce by 1 dose levelb 
If diastolic blood pressure is not controlled (< 90 
mm Hg) on anti-hypertensive therapy, reduce 
another dose levelb 
Grade 4 
Discontinue sorafenib 
aSubjects requiring a delay of > 28 days should discontinue sorafenib unless, in the opinion of the treating 
physician, the subject may benefit from continued treatment. 
bSubjects requiring dose reductions beyond 400 mg once daily, every other day, should discontinue sorafenib. 
Sorafenib should be held for two weeks prior and for two weeks following surgical procedures. 
Patients who cannot tolerate sorafenib therapy and who demonstrate a response of complete 
response (CR), partial response (PR) or stable disease (SD) with the combination and are thought 
to benefit from continued TRC105 therapy may continue on study on TRC105 alone.  
7.8.7. 
Sorafenib Drug Accountability 
Patients will be asked to bring their sorafenib prescription bottle to the clinic at the beginning of 
each cycle for proper drug accountability and destruction in accordance with institution 
guidelines.  A new prescription will be dispensed at the beginning of each new cycle.  
7.9. 
Concomitant Medications 
No other approved or investigational anticancer treatment will be permitted during the study 
period.  No other investigational drug may be used during treatment on this protocol, and 
concurrent participation in another clinical trial is not allowed. 
Patients who receive NSAIDs on study for more than three consecutive days should also receive 
peptic ulcer disease (PUD) prophylaxis with an H2 or proton pump blocker. 
Narcotic analgesics, nonsteroidal anti-inflammatory drugs, and triptans (e.g. sumatriptan) may be 
offered as needed for relief of pain or headaches.  Triptans are recommended for patients who 
experience a migraine headache following dosing, and may be taken prior to the occurrence of 


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headache, as a prophylactic medication.  Antihistamines and decongestants may be offered for 
the treatment of sinus congestion. 
Packed red blood cell, colony stimulating factors, and platelet transfusions should be 
administered as clinically indicated.  
The concomitant use of strong CYP3A4/5 inducers is strongly discouraged and should be 
avoided (Table 19) as they may decrease sorafenib plasma concentrations. Patients may not have 
received a strong CYP3A4 inducer within 12 days prior to registration (see eligibility.  
 Table 19: 
Strong CYP3A4 Inducers and Inhibitorsa 
Inducers: 
 
aInhibitors: 
dexamethasone 
 
Boceprevir 
Conivaptan 
phenytoin 
 
Indinavir 
Itraconazole 
carbamazepine 
 
Nelfinavir 
Ketoconazole 
rifampin 
 
Lopinavir/ritonavir Mibefradil 
rifabutin 
 
Saquinavir 
Nefazodone 
rifapentin 
 
Telaprevir 
Posaconazole 
phenobarbital 
 
Ritonavir 
Voriconazole 
St. John’s Wort 
 
Clarithromycin 
Telithromycin 
aBecause the lists of these agents are constantly changing, it is important to regularly consult a comprehensive list 
such as the one located at http://medicine.iupui.edu/clinpharm/ddis/ 
Furthermore, patients taking narrow therapeutic index medications, (e.g. quinidine or digoxin) 
should be monitored proactively.  
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.  
Patients with arterial thrombosis or grade 3 or 4 venous thrombosis should be removed from 
study.  Patients with grade 1 or 2 venous thrombosis who require anticoagulation will have their 
TRC105 therapy interrupted.  TRC105 therapy may resume once the following criteria are met:   
• The patient is on a stable dose of heparin or low molecular weight heparin or Factor 
X inhibitor.  
• The patient has a platelet count > 60,000. 
• The patient has not had a hemorrhagic event of grade 2 or higher while on study. 
• The patient does not have a pathological condition that carries a high risk of bleeding 
(e.g., tumor involving major vessels). 
• The patient is benefiting from TRC105 therapy (no evidence of disease progression).   


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7.10. 
Treatment Compliance 
7.10.1. 
TRC105 Treatment Compliance 
All TRC105 infusions will occur at the trial site under the direct supervision of the treating 
physician or his or her designee.  
7.10.2. 
Sorafenib Treatment Compliance 
Patients will be asked to record the day and time of sorafenib home dosing on a TRACON 
supplied log to be reviewed by site personnel prior to initiation of each new cycle.  
7.11. 
Patient Enrollment 
Patients will be manually enrolled by TRACON Pharmaceuticals and assigned an eight-digit 
patient number. This eight-digit number will be used to identify patients throughout their 
participation in the trial. A regulatory binder will be provided and will include detailed 
instructions for the manual enrollment process.  


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8. 
ASSESSMENT OF EFFICACY 
8.1. 
Radiological Tumor Assessment 
The primary efficacy assessment for phase 1b is best overall response and progression free 
survival (defined as time from screening to either first disease progression or death from any 
cause, patients alive at the time of analysis will be censored at the date of last disease 
assessment) by RECIST 1.1. The primary efficacy assessment for phase 2 will be best overall 
response, including duration of response by RECIST 1.1 in as defined in Section 8.1.2.  The 
determination of antitumor efficacy will be based on objective tumor assessments made by the 
Investigator according to RECIST version 1.1 [48].  Investigators will make treatment decisions 
based on these assessments.  All lesions will be classified as target or non-target lesions at the 
Screening visit.  Each lesion designation will be maintained through the course of the study.  
The same method and technique should be used to characterize each identified and reported 
lesion at Screening, during the study treatment period, and at the End of Study visit. Imaging-
based evaluation over clinical examination is the required technique when both could be used to 
assess the antitumor effect of the treatment.  Clinical Oncology review of all tumor 
measurements is desired. 
Whenever possible, clinical evaluation of superficial lesions should not be used as the sole form 
of measurement.  However, when necessary, color photograph with metric caliper is acceptable.  
Tumor evaluation by positron emission tomography (PET) scan or by ultrasound may not 
substitute for CT or MRI scans.  
Radiological tumor assessments will be performed at screening, as outlined in the Schedule of 
Assessments (Table 5), and whenever disease progression is suspected.  Another tumor 
assessment will be performed at the End of Study Visit if an assessment has not been performed 
within the prior 8 weeks.  All patient files and radiological images must be available for CRF 
source verification. De-identified copies of MRI’s, in DICOM format, may be transferred to the 
Sponsor if requested 
8.1.1. 
Measurability of Tumor Lesions 
At Screening, individual tumor lesions will be categorized by the Investigator as either target or 
non-target according to RECIST 1.1 as described below. 
• Measurable:  Lesions that can be accurately measured in at least one dimension 
(longest diameter to be recorded) as ≥ 10 mm with spiral CT scan. Lytic bone lesions, 
with an identifiable soft tissue component, evaluated by CT or MRI, can be 
considered as measurable lesions if the soft tissue component otherwise meets the 
definition of measurability previously described. Blastic bone lesions are non-
measurable.  Lesions in previously irradiated areas (or areas treated with local 
therapy) should not be selected as target lesions, unless there has been demonstrated 
progression in the lesion.  Clinical lesions will only be considered measurable when 
they are superficial (e.g. skin nodules, palpable lymph nodes) and ≥ 10 mm.  Clinical 
lesions must be measured with calipers. 


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• Non-Measurable:  All other lesions, including small lesions and bone lesions other 
than lytic bone lesions, leptomeningeal disease, ascites, pleural or pericardial 
effusions, lymphangitis of the skin or lung, abdominal masses that are not confirmed 
and followed by imaging techniques, previously irradiated lesions (unless there has 
been demonstrated progression in the lesion), and disease documented by indirect 
evidence only (e.g. by laboratory tests such as alkaline phosphatase).  
8.1.1.1. 
Recording Tumor Measurements 
Measurable lesions up to a maximum of 5 lesions representative of all involved organs (with a 
maximum of 2 lesions per organ) should be identified as target lesions and measured and 
recorded at Screening and at the stipulated intervals during treatment.  Target lesions should be 
selected on the basis of their size (lesion with the longest diameters) and their suitability for 
accurate repetitive measurements (either by imaging techniques or clinically).  Target lesions 
may include lymph nodes with a short axis > 15 mm.  
The longest diameter will be recorded for each target lesion (with the exception of lymph nodes, 
where the short axis will be used). The sum of the diameter for all target lesions at Screening will 
be calculated and recorded as the baseline sum diameter to be used as reference to further 
characterize the objective tumor response of the measurable dimension of the disease during 
treatment.  All measurements should be performed using a caliper or ruler and should be 
recorded in metric notation in millimeters. 
All other lesions (or sites of disease) should be identified as non-target lesions and should also be 
recorded at baseline.  Measurements are not required and these lesions should be followed as 
“present”, “complete response”, “non-CR/non-PD” or “progressive disease”. 
8.1.2. 
Definitions of Tumor Response 
8.1.2.1. 
Target Lesions 
• Complete response (CR) is defined as the disappearance of all target lesions. 
• Partial response (PR) is defined as a ≥ 30% decrease in the sum of the dimensions of 
the target lesions taking as a reference the baseline sum dimensions. 
• Progressive disease (PD) is defined as a ≥ 20% relative increase and ≥ 5 mm absolute 
increase in the sum of the dimensions of the target lesions taking as a reference the 
smallest sum of the dimensions recorded since the treatment started, or the appearance of 
one or more new lesions. 
• Stable disease (SD) is defined as neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD taking as a reference the smallest sum of the 
dimensions since the treatment started.  
8.1.2.2. 
Non-Target Lesions 
• Complete response (CR) is defined as the disappearance of all non-target lesions. 
• non-CR/non-PD is defined as a persistence of ≥ 1 non-target lesions. 


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• Progressive disease (PD) is defined as unequivocal progression of existing non-target 
lesions, or the appearance of ≥ 1 new lesions. 
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment when the measurable tumor has met criteria for response or stable disease is 
mandatory to differentiate between response or stable disease and progressive disease. 
8.1.2.3. 
Determination of Overall Response  
8.1.2.4. 
Determination of Overall Response by the RECIST Criteria 
When both target and non-target lesions are present, individual assessments will be recorded 
separately.  The overall assessment of response will involve all parameters as depicted in Table 
20 below. Per RECIST 1.1, as this is a non-randomized trial with response is a primary endpoint, 
confirmation of PR or CR is required.  Per RECIST 1.1, a modest increase in the size of one or 
more non-target lesions is usually not sufficient to qualify for unequivocal progression status.  
Table 20: 
Response Evaluation Criteria in Solid Tumors 
Target Lesionsa 
Non-target Lesionsb 
New Lesionsc 
Overall Response 
CR 
CR 
No 
CR 
CR 
non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all 
evaluated 
No 
PR 
SD 
Non-PD or not all 
evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No  
Not Evaluable 
PD 
Any Response 
Yes or No 
PD 
Any Response 
PD 
Yes or No 
PD 
Any Response 
Any Response 
Yes 
PD 
aMeasurable lesions only. 
bMay include measurable lesions not followed as target lesions or non-measurable lesions. 
cMeasurable or nonmeasurable lesions.  
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. 
NOTE:  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 
“Need for additional anti-cancer therapy/surgery”.  Every effort should be made to document the 
objective progression even after discontinuation of treatment.   


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In some circumstances, it may be difficult to distinguish residual disease from normal tissue.  
When the evaluation of complete response depends upon this determination, it is recommended 
that the residual lesion be investigated by fine needle aspirate or biopsy before confirming the 
complete response status. 


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9. 
ASSESSMENT OF SAFETY 
9.1. 
Safety Parameters 
Safety will be characterized in terms of the incidence, timing, severity (graded by the National 
Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE], Version 
4.03), seriousness, and relatedness of adverse events and laboratory abnormalities.  In addition, 
physical examination, vital signs, and ECOG performance status will be serially monitored.  
Laboratory safety analyses will be based on the local laboratory data, and will include 
hematology, serum chemistry (including liver and kidney function), urinalysis, serum or urine 
pregnancy testing, and coagulation profile. Serum will also be assessed for immunogenicity to 
TRC105 (APA titers).  In addition, ECG will be performed at the time-points indicated in the 
Schedule of Assessments (Table 5) and as clinically indicated throughout the study. 
9.1.1. 
Laboratory Safety Assessments 
Abnormal and clinically significant laboratory tests should be recorded as adverse events.  To 
meet the definition of clinically significant, the test result generally requires a change in medical 
management (e.g. new medication, unplanned treatment, additional tests, etc.). 
9.1.1.1. 
Hematology, Serum Chemistry, Coagulation, Pregnancy Test  
Assessments will be performed at the time points indicated in the Schedule of Assessments 
(Table 5) and analyzed at local laboratories.  Investigators may have additional blood tests 
performed for the purpose of planning treatment administration, or for following adverse events 
as clinically indicated.  
• Hematology: CBC with differential and platelet count. Iron studies (serum iron, ferritin 
and total iron binding capacity). 
• Coagulation: International Normalized Ratio (INR) will be assessed 
• Serum Chemistry: Total bilirubin, alanine transaminase (ALT), aspartate transaminase 
(AST), alkaline phosphatase, lipase, amylase, total protein, albumin, sodium, potassium, 
bicarbonate, chloride, calcium, phosphorus, blood urea nitrogen, creatinine, thyroid 
stimulating hormone and glucose 
• Pregnancy Test: Serum or urine pregnancy tests will be performed locally on all female 
patients of childbearing potential. Patients must be surgically sterile (i.e., hysterectomy) 
or be postmenopausal, or must agree to use two methods of effective and highly reliable 
contraception at the same time [i.e., tubal sterilization (tubes tied), partner’s vasectomy, 
intra-uterine device (IUD), male latex condom with or without spermicide, diaphragm 
with spermicide, cervical cap with spermicide, vaginal sponge (contains spermicide)] 
during study treatment (including during temporary breaks from treatment), and for at 
least 180 days after stopping TRC105. 


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9.1.1.2. 
Urinalysis  
Urinalysis (without microscopic analysis, unless indicated) will be performed at time points 
indicated in the Schedule of Assessments (Table 5) and analyzed by local laboratories. 
Microscopic analysis and/or urine protein-creatinine ratio (UPCR) should be performed as 
clinically indicated. 
9.1.1.3. 
Physical Examination  
A physical examination including, but not limited to, general appearance, head, eyes, ears, nose, 
throat, neck, heart, chest, abdomen, musculoskeletal, extremities, skin, lymph nodes, 
neurological genitourinary (as appropriate), and rectal (as appropriate) will be assessed at time 
points indicated within the Schedule of Assessments (Table 5).  The physical examination will 
include examination of known and suspected sites of disease.   
9.1.1.4. 
Vital Signs  
Heart rate, temperature, blood pressure, respiratory rate and weight will be assessed at time 
points indicated within the Schedule of Assessments (Table 5). Heart rate, temperature, blood 
pressure, and respiratory rate will also be assessed during TRC105 infusions as described in 
Section 5.1.2.2 and the footnotes of the Table 5.  
9.1.1.5. 
Performance Status  
The ECOG scale will be used to assess performance status at Screening.  
9.1.1.6. 
ECG  
A single 12-lead (with a 10–second rhythm strip) tracing will be used for all ECGs.  It is 
preferable that the machine used has a capacity to calculate standard intervals automatically. 
ECG will be performed at the time-points indicated in the Schedule of Assessments (Table 5) 
and as clinically indicated throughout the study 
9.2. 
Adverse Events 
All observed or volunteered AEs regardless of suspected causal relationship to study drug will be 
reported as described below.  Medications administered and all other actions taken to treat the 
event, the outcome, and any recurrence upon re-challenge will be captured. 
9.2.1. 
Definition of Adverse Event  
An adverse event is any untoward medical occurrence in a trial patient who is administered a 
drug or biologic (medicinal product); the event may or may not have a causal relationship with 
the medicinal product.  Examples of AEs include, but are not limited to the following: 
• Clinically significant symptoms and signs including:  
o Signs and symptoms resulting from drug overdose, abuse, misuse, withdrawal, 
sensitivity, dependency, interaction or toxicity.   


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o All possibly related and unrelated illnesses, including the worsening of a 
preexisting illness.  
o Injury or accidents.  Note that if a medical condition is known to have caused the 
injury or accident (hip fracture from a fall secondary to dizziness), the medical 
condition (dizziness) and the outcome of the accident (hip fracture from a fall) 
should be reported as 2 separate adverse events.   
o Symptoms or signs resulting from exposure in utero. 
• Abnormalities in physiological testing or physical examination findings that require 
clinical intervention or further investigation (beyond ordering a repeat confirmatory test). 
• Laboratory abnormalities that meet any of the following (Note: merely repeating an 
abnormal test, in the absence of any of the below conditions, does not constitute an AE.  
Any abnormal test result that is determined to be an error does not require reporting as an 
AE.): 
o Test result that is associated with accompanying symptoms 
o Test result that requires additional diagnostic testing or medical/surgical 
intervention 
o Test result that leads to a change in study drug dosing outside of protocol-
stipulated dose adjustments or discontinuation from the trial, significant additional 
concomitant drug treatment, or other therapy 
o Test result that is considered to be an AE by the Investigator or TRACON 
9.2.2. 
Serious Adverse Events 
An AE that meets one or more of the following criteria/outcomes is classified as serious: 
• Results in death 
• Is life-threatening (i.e., at immediate risk of death) 
• Requires in patient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability/incapacity  
• Results in congenital anomaly/birth defect 
• Other important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the patient or may require medical or surgical intervention 
to prevent one of the outcomes listed above.  Examples of such events are intensive 
treatment in an emergency room for allergic bronchospasm; blood dyscrasias or 
convulsions that do not result in hospitalization; or the development of drug dependence 
or drug abuse.  
• Cases of potential drug-induced liver injury as assessed by laboratory test values 
(“Hy’s Law Cases”) are also reportable as an SAE.  If a Study subject develops 


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abnormal values (3 x ULN) in aspartate transaminase (AST) or alanine transaminase 
or both, concurrent with abnormal elevations (2 x ULN) in total bilirubin and no other 
known cause of liver injury, that event would be classified as a Hy’s Law Case and an 
SAE.  
Serious also includes any other event that the Investigator or sponsor judges to be serious, or 
which is defined as serious by the human rights act in the country in which the event occurred.   
Progression of the malignancy under study (including signs and symptoms of progression) 
should not be reported as SAEs unless the outcome is fatal during the trial or within the safety 
reporting period.  Hospitalizations due to signs and symptoms of disease progression should not 
be reported as SAEs.  If the malignancy has a fatal outcome during the trial or within the safety 
reporting period, then the event leading to death must be recorded as an SAE with NCI CTC 
grade 5.  
The onset date of an SAE is defined as the date on which the event initially met serious criteria 
(e.g., the date of admission to a hospital).  The end date is the date on which the event no longer 
met serious criteria (e.g., the date the patient was discharged from a hospital).  
9.2.2.1. 
Hospitalization 
AEs associated with in-patient hospitalization, or prolongation of an existing hospitalization, are 
considered serious.  Any initial admission, even if the duration is less than 24 hours is considered 
serious.  In addition, any transfer within the hospital to an acute/intensive care unit is considered 
serious (e.g., transfer from the psychiatric wing to a medical floor or transfer from a medical 
floor to a coronary care unit). However, the following situations should not be considered on 
their own to constitute a serious AE:  
• Rehabilitation facility admission 
• Hospice facility admission 
• Respite care 
• Skilled nursing facility admission 
• Nursing home admission 
• Emergency room visit 
• Outpatient same day surgery/procedure 
• Hospitalization or prolongation of hospitalization in the absence of precipitating clinical 
adverse events as follows: 
o Admission for treatment of preexisting condition not associated with the 
development of a new adverse event or with a worsening of the preexisting 
condition  
o Social admission 
o Administrative admission (e.g. for yearly physical exam) 


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o Protocol-specified admission during a clinical trial 
o Optional admission not associated with a precipitating clinical adverse event (e.g. 
for elective cosmetic surgery) 
o Preplanned treatments or surgical procedures that are not related to an SAE 
o Hospitalization for observation without an AE 
• Diagnostic and therapeutic noninvasive and invasive procedures, such as surgery, should 
not be reported as adverse events.  The medical condition for which the procedure was 
performed should be reported if it meets the definition of an adverse event (e.g. acute 
appendicitis that begins during the adverse event reporting period should be reported as 
an adverse event and the appendectomy should be recorded as a concomitant procedure). 
9.3. 
Reporting Adverse Events 
9.3.1. 
Eliciting Adverse Event Information 
The Investigator is to report all directly observed AEs and all AEs spontaneously reported by the 
trial patient using concise medical terminology.  In addition, each trial patient will be questioned 
about AEs at each clinic visit following initiation of treatment.  The question asked will be, 
“Since your last clinic visit have you had any health problems?” 
9.3.2. 
Adverse Event Reporting Period 
Safety information for each patient will be collected from the date of informed consent.  AEs 
occurring prior to the initiation of the study treatment will be considered "baseline-signs and 
symptoms” and will be recorded on corresponding case report forms (CRFs) and will not be 
retained for patients who fail screening. The AE reporting period for this trial begins when the 
patient has taken the first dose of sorafenib or TRC105 study drug and ends 28 days after the last 
dose of sorafenib or TRC105 study drug is administered.  
All AEs that occur in trial patients during the AE reporting period specified in the protocol must 
be reported to TRACON, whether or not the event is considered study treatment-related.  In 
addition, any known untoward event that occurs beyond the AE reporting period that the 
Investigator assesses as possibly related to the investigational medication/product should also be 
reported as an AE. 
9.3.3. 
Reporting Requirements 
Each AE is to be classified by the Investigator as SERIOUS or NONSERIOUS (Section 9.2.2 for 
SAE definition).  This classification of the event determines the reporting procedures to be 
followed.  If an SAE occurs, reporting will follow local and international regulations, as 
appropriate. 
The Investigator must notify the Sponsor of any AE that meets one of the criteria for an SAE 
immediately upon learning of the event.  Any subsequent revisions that are made to information 
pertaining to SAEs (e.g., change in seriousness criteria, relationship to study drug, etc.) should be 
communicated to TRACON immediately.  This notification should be made to: 


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Primary Medical Monitor 
Charles Theuer, MD, PhD 
TRACON Pharmaceuticals, Inc. 
4350 La Jolla Village Drive, Suite 800 
San Diego, California 92122 
Office Phone:  1.858.550.0780 x233 
Cell Phone:  1.858.344.9400 
Email: ctheuer@traconpharma.com  
 
Secondary Medical Monitor  
James Freddo, MD 
TRACON Pharmaceuticals, Inc. 
4350 La Jolla Village Drive, Suite 800 
San Diego, California 92122 
Cell Phone:  1.858.472.2330 
Email: jfreddo@traconpharma.com  
 
 
Following notification, the Investigator will report the SAE via the AE CRF via the data 
management system.  The initial AE CRF is to be updated with followed more detailed AE 
information within 5 calendar days of the event. 
In the rare event that the Investigator is not immediately aware of an SAE (for example, if the 
study subject seeks urgent medical attention elsewhere), the Investigator is to notify the Sponsor 
immediately upon learning of it and document his/her first awareness. 
Each SAE should be followed until resolution, or until such time as the Investigator determines 
its cause or determines that it has become stable.  Information pertaining to follow-up of SAEs 
should also be sent to the TRACON Pharmaceuticals Inc. 
SAEs that are unexpected and associated with use of the study medication will be reported to the 
US Food and Drug Administration (FDA) and all participating clinical sites by TRACON via 
MedWatch or CIOMS forms.  For AEs that are fatal or life-threatening, unexpected, and 
associated with use of the investigational product, a 7-Day Alert Report will be submitted to the 
FDA within 7 calendar days of receipt of the SAE information.  For all other AEs that are 
serious, unexpected, and associated with use of the investigational product, a written report will 


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be made no more than 15 calendar days from the date TRACON learns of the event. 
Participating clinical sites will be notified of these events in parallel. 
All AEs, including SAEs, are to be reported on the AE CRFs.  
9.3.4. 
Recording Adverse Events in the Case Report Forms 
The Investigator is to report all directly observed AEs and all AEs spontaneously reported by the 
trial patient.  In addition, each trial patient will be questioned about AEs.  All AEs that meet the 
criteria specified in Section 9.2.1 are to be recorded on patient source documents and on the 
CRFs. AEs should be reported using concise medical terminology on the CRFs.  
9.3.5. 
Grading of Adverse Event Severity 
To report AEs on the CRFs, the Investigator will use the severity grading as described in NCI 
CTCAE (Version 4.03).   
Every effort should be made by the Investigator to assess the AE according to CTCAE criteria. If 
the Investigator is unable to assess severity because the term is not described in NCI CTCAE 
(Version 4.03), severity of MILD, MODERATE, SEVERE, LIFE-THREATENING, or FATAL 
may be used to describe the maximum intensity of the AE. For purposes of consistency, these 
intensity grades are defined as follows:  
Table 21: 
Adverse Event Grading 
Grade 
Non-CTCAE Severity 
Definition 
1 
Mild  
Does not interfere with patient’s usual function 
2 
Moderate 
Interferes to some extent with patient’s usual function 
3 
Severe 
Interferes significantly with patient’s usual function 
4 
Life-Threatening 
Results in immediate risk of patient’s death 
5 
Fatal 
Results in patient’s death 
Note the distinction between the severity and the seriousness of an AE.  A severe AE is not 
necessarily a serious AE.  For example, a headache may be severe (interferes significantly with 
patient’s usual function) but would not be classified as serious unless it met one of the criteria for 
serious events.     
9.3.6. 
Relationship to TRC105 Study Drug/Sorafenib 
In this study, TRC105 study drug is given in combination with sorafenib.  The relationship of an 
adverse event to TRC105 study drug and sorafenib should be classified by the Investigator using 
the following guidelines: 
• Suspected Adverse Reaction: There is a reasonable possibility that TRC105 caused the 
AE (i.e.: there is evidence to suggest a causal relationship between TRC105 and AE). 
• Not Related: There is no reasonable possibility that the AE is associated with TRC105 
study drug.  


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AE’s related to TRC105 study drug or sorafenib are considered Adverse Drug Reactions (ADR). 
9.3.7. 
Expectedness  
All TRC105 AEs and adverse drug reactions are considered “unexpected” if it’s not listed in the 
investigator brochure or not listed at the specificity or severity that has been observed.  For 
example, under this definition, hepatic necrosis would be unexpected (by virtue of greater 
severity) if the investigator brochure referred only to elevated hepatic enzymes or hepatitis.  
Similarly, cerebral thromboembolism and cerebral vasculitis would be unexpected (by virtue of 
greater specificity) if the investigator brochure listed only cerebral vascular accidents.  
"Unexpected," as used in this definition, also refers to AEs 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. 
All sorafenib AEs and adverse drug reactions are considered “unexpected” if it’s not listed in the 
package insert or not listed at the specificity or severity that has been observed. "Unexpected," as 
used in this definition, also refers to AEs or suspected adverse reactions that are mentioned in the 
package insert 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 sorafenib.  
9.3.8. 
Exposure in Utero 
An exposure in utero (EIU) occurs if: 
• A female becomes, or is found to be, pregnant either while receiving or having been 
directly exposed to (e.g., environmental exposure) the investigational product, or the 
female becomes, or is found to be, pregnant after discontinuing and/or being directly 
exposed to the investigational product (maternal exposure) 
• A male has been exposed, either due to treatment or environmental, to the investigational 
product prior to or around the time of conception and/or is exposed during the partner’s 
pregnancy (paternal exposure)  
A pregnant patient will be withdrawn from the study.  If any trial patient becomes or is found to 
be pregnant during the study or within 28 days of discontinuing the investigational 
medication/product, the Investigator must report the information to TRACON, or designee via 
the Pregnancy Notification Report Form.  This must be done irrespective of whether an adverse 
event has occurred and within 24 hours of awareness of the pregnancy.  The information 
submitted should include the anticipated date of delivery.   
The Investigator will follow the patient until completion of the pregnancy or until pregnancy 
termination (i.e., induced abortion) and then notify TRACON, or its designee, of the outcome 
within 5 days or as specified below.  The Investigator will provide this information as a follow-
up to the initial report.  The reason(s) for an induced abortion must be specified. 
For pregnancies of partners of male participating in the study: all partners who become pregnant 
and provide appropriate consent to TRACON will be monitored to the completion or termination 
of the pregnancy as described above.  


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The Investigator should follow procedures for reporting an SAE if pregnancy outcome meets 
criteria for an SAE (i.e., spontaneous abortion, stillbirth, neonatal death, or congenital anomaly 
[including that in an aborted fetus]). 
In the case of a live birth, the “normality” of the newborn can be assessed at the time of birth and 
the Pregnancy Outcome Report Form should be completed (i.e., no minimum follow-up period 
of a presumably normal infant must pass before a Pregnancy Outcome Report Form can be 
completed).  The “normality” of an aborted fetus can be assessed by gross visual inspection 
unless pre-abortion laboratory findings are suggestive of a congenital anomaly. 
Additional information about pregnancy outcomes that are classified as SAEs follows:  
• “Spontaneous abortion” includes miscarriage and missed abortion. 
• All neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs.  In addition, any infant death after 1 month that the Investigator 
assesses as possibly related to the in utero exposure to the investigational medication 
should also be reported. 
9.3.9. 
Follow-up of Unresolved Adverse Events  
All AEs should be followed until they are resolved or the Investigator assesses them as chronic 
or stable; every effort should be made to make this determination by the 28 day follow-up 
visit.  Any increase or decrease in AE grade should be recorded as a new AE.  
All serious and those non-serious AEs assessed by the Investigator as possibly related to the 
investigational medication/product should continue to be followed even after the patient’s 
participation in the trial is over.  Such events should be followed until they resolve or until the 
Investigator assesses them as chronic or stable; every effort should be made to make this 
determination by the 28 day follow-up visit.   
9.4. 
Safety Monitoring 
The TRACON Clinical Team will monitor safety throughout the study via the following 
activities:  
• Surveillance for SAEs according to regulatory guidelines 
• Routine monitoring of non-serious AEs as they are recorded in the case report forms and 
the source documents at study sites 
• A formally chartered TRACON in-house Safety Review Team that includes, among other 
staff, two physicians 
• Periodic teleconferences with the Principal Investigators to share experiences and ensure 
communication 
• Toxicity information that may affect the treatment of patients on this study will be 
promptly communicated in writing to all participating clinical sites and institutions 
participating in this clinical trial.      


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10. 
OTHER ASSESSMENTS 
10.1. 
Other Laboratory Assessments  
10.1.1. 
Pharmacokinetics  
Samples will be sent to Fisher BioServices (Franklin, MA 02038). See separate laboratory 
manual for specific collection, storage and shipping information.  
10.1.1.1. TRC105 Trough Concentration  
A 5 mL blood sample will be collected prior to dosing with TRC105 on the days indicated within 
the Schedule of Assessments (Table 5).  Samples will be separated and stored at approximately -
70 °C for shipment to third party laboratory. See separate laboratory guide for further collection 
and shipment information.  The serum concentration data set from this study will be pooled with 
data sets from additional TRC105 Phase 2 studies in other oncology populations.  Population PK 
analyses will involve mixed effects modelling performed using appropriate software. 
10.1.1.2. Sorafenib Trough Concentration  
A 4 mL blood sample will be collected prior to dosing with sorafenib on the days indicated 
within the Schedule of Assessments (Table 5).  Samples will be separated and stored at 
approximately -70 °C for shipment to third party laboratory. See separate laboratory guide for 
further collection and shipment information.   
10.1.2. 
TRC105 Immunogenicity 
Samples will be sent to Fisher BioServices (Franklin, MA 02038) for storage.  See separate 
laboratory manual for specific collection, storage and shipping information. 
Anti-Product Antibody (APA) concentrations will be measured using validated ELISA methods 
at the time points specified in the Schedule of Assessments (Table 5) in all patients.  APA 
concentrations will be evaluated in the context of pharmacokinetic parameters and AE profiles. 
Samples will be separated and stored at approximately -70 °C for shipment to Fisher 
BioServices.  See separate laboratory guide for further collection and shipment information.  
10.1.3. 
Protein Biomarkers 
One 10 mL purple top (K2EDTA) tube of blood will be collected on the days indicated within the 
Schedule of Assessments (Table 5).  Samples will be stored at approximately -70 °C and shipped 
to Fisher BioServices Inc. (10 Forge Park, Franklin, MA 02038) for storage until the time of 
analysis. Duke University Medical Center will analyze plasma for several biomarkers including 
but not limited to VEGF, VEGF-R2, PIGF and sCD105 (Phase 1 Biomarker Laboratory, Duke 
University Medical Center, 309 MSRB, Research Dr., Durham, NC 27710).  Please see the 
separate laboratory guide for further collection and shipment information.  


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10.1.4. 
Archival Tumor Specimens 
Archival specimens (formalin-fixed, paraffin-embedded) of the primary cancer and/or metastatic 
cancer specimen for each study participant will be obtained, if they are available. It is preferable 
that the entire paraffin block be submitted, but if this is not feasible, then at least 20 unstained 
slides are requested for immunohistochemical analysis (sections of ~ 5 microns are preferred).  
Samples will be stored at room temperature and shipped to Fisher BioServices Inc. (10 Forge 
Park, Franklin, MA 02038) for storage until the time of analysis.  See separate laboratory guide 
for further collection and shipment information. 


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11. 
STATISTICS 
11.1. 
Phase 1b 
11.1.1. 
Phase 1b Statistical Design/Sample Size 
The number of patients to be enrolled in this study will depend upon the observed safety profile, 
which will determine the number of patients per dose level and the number of dose escalations.  
It is anticipated that up to 6 patients will be treated in the phase 1b portion of the study.  
The probability of escalation to the next higher dose for each underlying true DLT rate is shown 
in Table 22.  For example, at a dose level with a true DLT rate of 5%, there is a greater than 95% 
probability of escalating.  Conversely, for a dose level with a true DLT rate of 70%, the 
probability of escalating is < 5%. 
The maximum tolerated dose (MTD) will have been exceeded if ≥ 33% of patients experience 
DLT at a given dose level in which at least 6 patients have been evaluated. 
Table 22: 
Probability of Escalation to the Next Dose for Each True Underlying DLT 
Rate at a Dose Level 
True Underlying DLT Rate 
5% 
10% 20% 30% 40% 50% 60% 70% 80% 
90% 
Probability of Escalating Dose 0.97 
0.91 
0.71 
0.49 
0.31 
0.17 
0.08 
0.03 
0.01 
0.001 
The probability of failing to observe DLT in a sample size of 3 patients given various true 
underlying DLT rates is shown in Table 23.  For example, with 3 patients, the probability of 
failing to observe DLT occurring at least 50% of the time is less than 15%. 
Table 23: 
Probability of Failing to Observe True Underlying DLT Rate at a Dose Level 
True Underlying 
DLT Rate 
5% 
10% 20% 30% 
40% 
50% 
60% 
70% 
80% 
90% 
Probability of Failing 
to Observe Toxicity if 
N = 3 
0.86 
0.73 
0.51 
0.34 
0.22 
0.13 
.0064 
0.027 
0.008 
0.001 
11.1.1.1. Phase 1b Definition of Analyzed Study Populations 
The following study populations will be considered when reporting study results: 
• The study population for safety includes all patients receiving at least a portion of 1 
dose of TRC105.   
• The study population for PK includes also subjects with adequate data for PK 
modeling of TRC105 and sorafenib.   
• The study population for efficacy will include all safety population patients who have 
baseline and follow-up tumor measurements as required for assessment by RECIST 
1.1. 


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Patients who experience DLT who receive less than the prescribed dose of TRC105 or sorafenib 
due to documented toxicity in cycle 1 will be considered evaluable for dose escalation purposes. 
Only those patients who are deemed ineligible or who receive no therapy (i.e. no TRC105 or 
sorafenib) will be eliminated from the analysis.  Ineligible patients who receive therapy will not 
be included in the assessment of efficacy endpoints, but their data will be included in the 
assessment of all adverse event reporting.  
11.2. 
Phase 2 
11.2.1. 
Phase 2 Statistical Design/Sample Size 
Efficacy Analysis 
The primary endpoint of the phase 2 study is objective response (CR or PR) at any time during 
treatment.  The sample size is determined using Simon’s two-stage minimax design.  This design 
will be used to test the null hypothesis that the true objective tumor response rate is < 5% versus 
the alternative hypothesis that the true response rate is > 20%.  
One or more responses by RECIST 1.1 must be observed in the initial 12 patients enrolled to 
enroll the second stage, to a total of 21 patients.  Three or more responses by RECIST of 21 
patients will be considered sufficiently interesting to warrant further study in later trials.  
Sample size justification 
With an alpha level of 0.1 and 80% power, a maximum of 21 treated patients will be required to 
evaluate the ORR.  Twelve patients will be treated in stage 1.  If < 1 objective response is 
observed in the first 12 patients, then the trial will be terminated, and the alternative hypothesis 
that the true ORR probability is > 20 % will be rejected.  However, if one or more responses are 
observed in the first 12 patients, then the study will be expanded to enroll a total of 21 treated 
patients (9 additional patients to be treated in stage 2).  At the end of the study, if > 3 objective 
responses are observed then the null hypothesis that the true response rate probability is < 5% 
will be rejected and further investigation of TRC105 and sorafenib in this population is 
warranted. Under this design, the expected sample size is 21. The probability of early 
termination under the null hypothesis is 50%. 
The study will continue to enroll patients when the 12th patient has been enrolled unless no 
response is observed. If there is no patient achieving response at the time the 12th patient has 
been enrolled, the enrollment will be stopped temporarily. Once one patient is observed to have 
response, the enrollment will be resumed. However, if there is no patient achieving response 
after the first 12 patients have been fully evaluated, the study will be stopped for the futility.   
11.2.1.1. Phase 2 Definition of Analyzed Study Populations 
The following study populations will be considered when reporting study results for the phase 2 
portion: 
• The study population for safety includes all patients receiving at least a portion of 1 
dose of TRC105.   


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• The study population for efficacy will include all safety population patients who have 
baseline and follow-up tumor measurements as required for assessment by RECIST 
1.1. 
Only those patients who are deemed ineligible or who receive no therapy (i.e., no TRC105 or 
sorafenib) will be eliminated from the analysis.  Ineligible patients who receive therapy will not 
be included in the assessment of efficacy endpoints, but their data will be included in the 
assessment of all adverse event reporting.  
11.3. 
Data Analysis 
Descriptive statistics (such as means, medians, standard deviations and ranges for continuous 
data and percentages for categorical data) will be used to summarize patient characteristics, 
treatment administration/compliance, immunogenicity (APA), efficacy, pharmacokinetic 
parameters protein biomarkers, and archival tumor tissue.  Data will also be displayed 
graphically, where appropriate. Overall survival and progression-free survival will be presented as 
Kaplan-Meier plots and estimates of the median time until death or the earlier of documented 
progression or death, respectively.  
11.4. 
Analysis of Primary and Secondary Objectives  
11.4.1. 
Phase 1b 
For each cohort, DLTs will be summarized by category (hematologic and non-hematologic) and 
by MedDRA preferred term.    
All AEs with an onset after initiation of treatment will be considered as treatment-emergent AEs.  
A preexisting condition that worsens during the treatment period will also be considered as a 
treatment emergent AE.  All AEs will be coded by system organ class (SOC) and preferred term 
using NCI CTCAE (MedDRA) version 4.0.  
The number and percentage of patients with the following types of treatment-emergent AEs will 
be summarized: common and serious AEs, AEs related to study medication, AEs resulting in 
study discontinuation, and clinically significant laboratory abnormalities. Non-treatment-
emergent serious AEs will be described separately.  Deaths will be reported with demographic 
information. 
11.4.2. 
Phase 2 
The primary endpoint of the phase 2 study is objective response (CR or PR) at any time during 
treatment.  The sample size is determined using Simon’s two-stage minimax design.  This design 
will be used to test the null hypothesis that the true objective tumor response rate is < 5% versus 
the alternative hypothesis that the true response rate is > 20%.  
One or more responses by RECIST 1.1 must be observed in the initial 12 patients enrolled to 
enroll the second stage, to a total of 21 patients.  Three or more responses by RECIST of 21 
patients will be considered sufficiently interesting to warrant further study in later trials.  


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11.5. 
Analysis of Pharmacokinetics  
Serum TRC105 and plasma sorafenib concentrations will be measured using validated methods 
and assessed for potential correlations with response, PFS, survival, adverse events, baseline 
characteristics and immunogenicity using descriptive statistics and models as appropriate. 
11.6. 
Analysis of Protein Biomarkers 
Angiogenic protein biomarker data for each patient who received at least one dose of TRC105 
study drug will be listed. 
11.7. 
Analysis of Immunogenicity 
Anti-Product Antibody (APA) concentrations will be measured using validated ELISA methods 
at the time points specified in the Schedule of Assessments (Table 5).  APA concentrations will 
be evaluated in the context of pharmacokinetic parameters and AE profiles. 
11.8. 
Analysis of Archival Tumor Tissue 
CD105 expression within the tumor vasculature will be quantified for each patient who received 
at least one dose of study drug and will be listed by cohort.  Expression will be determined by 
IHC and/or by PCR.  Other markers that may relate to efficacy or toxicity of TRC105 will also 
be explored. 


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12. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
All data entered on CRFs/eCRFs must be verifiable within the patients’ source documents 
(written or electronic record).  The Investigator/institution guarantees TRACON representatives 
and appropriate regulatory authorities direct access to the original source records for the duration 
of the agreed study record retention period.  Printouts of source records that are electronically 
obtained and stored will not be acceptable for audit/inspection unless provided as certified exact 
copies and the data remains as meaningful and useful as in its original electronic state.     
Legally protected subject identification and other personal health information must be securely 
stored with limited access by the participating institutions. Unless secure provisions are 
established by the institution to allow TRACON (or designee) to perform remote monitoring of 
electronic source records, TRACON (or designee) will review source records/data on site and 
will not remove any such protected health information.   


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13. 
QUALITY CONTROL AND QUALITY ASSURANCE 
Monitoring visits to clinical investigator sites will be made by TRACON or its representatives 
periodically during the trial to ensure that GCPs and all aspects of the protocol are being 
followed.   
The trial site will also be subject to possible inspection by the institutional review board (IRB) or 
independent ethics committee (IEC) or other appropriate regulatory authority. The trial site is 
also subject to quality assurance (QA) audits performed by TRACON or its representatives. 
It is important that the Investigator(s) and their relevant personnel are available during the 
monitoring visits, audits, and inspections and that sufficient attention, time, and support is 
devoted to the process.  
TRACON and its representatives will be governed by applicable regulations, good clinical 
practice standards, and internal SOPs for the conduct of monitoring visits and QA audits.    


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14. 
ETHICS 
14.1. 
Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) 
It is the responsibility of the Investigator to have approval of the trial protocol, protocol 
amendments, informed consent forms, and advertisements from the IRB/IEC before potential 
patients are consented for participation on the trial. All correspondence and other evidence of 
appropriate and timely communications with the IRB/IEC should be retained in the 
Investigator/site files. Copies of all IRB/IEC approvals should also be forwarded to TRACON. 
The only circumstance in which an amendment may be initiated prior to IRB/IEC approval is 
where the change is necessary to eliminate apparent immediate hazards to the patients.  In that 
event, the Investigator must notify the IRB/IEC and TRACON in writing within 5 business days 
after the implementation. 
14.2. 
Ethical Conduct of the Study 
The trial will be performed in accordance with the protocol, applicable local regulatory 
requirements and laws, and the International Conference on Harmonization Guideline on Good 
Clinical Practice, which supports the application of ethical principles that have their origin in the 
Declaration of Helsinki (see ICH E6, §2.1).  
14.3. 
Written Informed Consent 
The informed consent form language must be agreed upon by TRACON and the IRB/IEC and 
must be in compliance with ICH GCP, local regulatory requirements, and legal requirements. 
The informed consent information must not be changed without prior approval by TRACON and 
the IRB/IEC. The informed consent form used in this trial, and any changes made during the 
course of the trial, must be approved by both the IRB/IEC and TRACON, or designee, before 
use.  
It is the responsibility of the Investigator to give each patient full and adequate verbal and written 
information regarding the objective and procedures of the trial and the possible risks involved.  
This information must be provided to the patient prior to undertaking any trial-related procedure.  
Patients must be informed about their right to withdraw from the trial at any time.  Furthermore, 
it is the responsibility of the Investigator to ensure all subjects are appropriately informed before 
obtaining their signed and dated consent. Signatures from the investigator conducting the 
informed consent discussion should also be obtained prior to undertaking any trial-related 
procedure. Consent by a legally authorized representative is not permitted. Should an impartial 
witness be needed, ICHE6 requirements for impartial witnesses will apply.  
The Investigator will retain the original of each patient’s signed consent form in the 
Investigator/site files. 


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14.4. 
Patient Compensation 
Patients will not be compensated for participation in this trial; this will be outlined in the patient 
informed consent form. 


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15. 
DATA HANDLING AND RECORDKEEPING 
15.1. 
Inspection of Records 
CRF’s are required and should be completed for each patient who receives treatment with 
TRC105.  Screen failure CRF’s will not be collected.  Nevertheless, records of potential patients 
identified and screened shall be retained on site screening logs. The completed original CRFs are 
the sole property of TRACON and should not be made available in any form to third parties 
without written permission from TRACON (except for authorized representatives of the HRA 
and in accordance with HIPAA regulations). 
It is the Investigator’s responsibility to ensure completion and to review and approve all CRF 
data. The investigator will sign off on his/her data per patient.  These signatures serve to attest 
that the investigator has reviewed and approved the information contained on the case report 
forms and that the information is complete, accurate, and true.   At all times, the Investigator has 
final personal responsibility for the accuracy and authenticity of all clinical and laboratory data 
entered on the CRFs.   
The use of electronic CRFs (eCRFs) to capture study data using automated computerized data 
capture systems does not change the principles and requirements for collecting study data.  The 
investigator still retains final personal responsibility for eCRF data and any associated data 
pertaining to it (e.g. metadata including any record of change to the originally recorded data).  
The investigator’s signed approval of the eCRF data serves to attest that the electronic data and 
all of its associated metadata (including changes) has been reviewed and accepted as complete, 
accurate, and true for each patient in the study. 
All CRF/eCRF data must be verifiable in the patient’s source records by TRACON or its 
designee.  TRACON will review CRF data as compared to source records in an attempt to 
identify missing and spurious data and notify the investigator of findings so that proper 
corrections can be made.  TRACON representatives (monitors and auditors), and regulatory 
inspectors shall have direct access to the original source records in its original recorded format: 
electronic or hardcopy.   
TRACON (or its designee) will perform all data management functions associated with the 
study.  Data will be captured electronically.  Automated data verification (“edit checks”) will be 
used to ensure that the data are logical and consistent. Any inconsistencies will be queried for 
clarification or correction as appropriate by the clinical site.   
15.2. 
Retention of Records 
To allow for appropriate evaluations and/or audits by regulatory authorities or TRACON, the 
Investigator agrees to keep records, including the identity of all participating patients (sufficient 
information to link records, CRFs and hospital records), all original signed informed consent 
forms, copies of all CRFs, source documents, and detailed records of treatment disposition.  The 
Investigator should retain these records according to local regulations or as specified in the 
Clinical Trial Agreement, whichever is longer.   


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If the Investigator relocates, retires, or for any reason withdraws from the study, then TRACON 
should be prospectively notified.  The study records must be transferred to an acceptable 
designee, such as another Investigator, another institution, or to TRACON.  The Investigator 
must inform TRACON of any such transfer of responsibilities and properly identify the person or 
institution assuming the responsibility.  The responsible investigator/institution must obtain 
TRACON’s written permission before disposing of any records.  
 


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16. 
DEFINITION OF END OF TRIAL 
16.1. 
End of Trial in all Participating Countries 
End of trial in all participating countries is defined as the time at which all patients enrolled in 
the study have completed treatment on study. 
16.2. 
End of Trial in a Member State 
End of trial in a Member State of the European Union is defined as the time at which it is 
deemed that sufficient patients have been recruited and completed the trial as stated in the 
regulatory application (e.g. the Clinical Trials Agreement (CTA)) and ethics application in the 
Member State.  Poor recruitment is not a reason for premature termination but is considered a 
normal conclusion to the trial in that Member State.  
16.3. 
TRACON Discontinuation Criteria 
Premature termination of this trial may occur because of a regulatory authority decision, change 
in opinion of the IRB/IEC, drug safety problems, or at the discretion of TRACON.  In addition, 
TRACON retains the right to discontinue development of TRC105 at any time.  
TRACON reserves the right to discontinue the trial prior to inclusion of the intended number of 
patients, but intends only to exercise this right for valid scientific or administrative reasons. If a 
trial is prematurely terminated or discontinued, TRACON will promptly notify the Investigator.  
After notification, the Investigator must contact all participating patients within a 28 day time 
period.  As directed by TRACON, all trial materials must be collected and all CRF data must be 
completed to the greatest extent possible.  


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17. 
PUBLICATION OF TRIAL RESULTS 
Publication of trial results is discussed in the Clinical Trial Agreement.  


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18. 
FINANCING AND INSURANCE 
Financing and Insurance are discussed in the Clinical Trial Agreement.  


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19. 
INVESTIGATOR PROTOCOL AGREEMENT: 105HCC101 
I understand that all information concerning this study supplied to me by TRACON 
Pharmaceuticals, Inc. is confidential information.  I have read this protocol and agree to conduct 
the study according to all applicable regulations, Good Clinical Practice Guidelines and in 
accordance with the Clinical Trial Agreement. 
I understand that this protocol and all amendments must be submitted to the appropriate 
IRB/IEC. 
 
 
Investigator Name (PLEASE PRINT):  ______________________________________________ 
 
 
 
Signature: _________________________________________________Date: _______________ 
 
 
Please sign and return this agreement to: 
TRACON Pharmaceuticals, Inc.  
Attn: Clinical Operations  
4350 La Jolla Village Drive, Suite 800 
San Diego, CA  92122 
 
Please keep a copy for your records. 
 


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20. 
REFERENCES 
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Claudius; Curley, Steven A.; Vierling, John M.; Jalal, Prasun; Raghav, Kanwal; Wallace, 
Michael; Rashid, Asif, Abbruzzese, James L.; Wolff, Robert A.; Morris, Jeffrey S., 
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14. 
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Svatek, R.S., et al., Preoperative plasma endoglin levels predict biochemical progression 
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31. 
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antibody and elevated plasma levels of CD105 in colorectal cancer patients correlate 
with poor prognosis. Br J Cancer, 2003. 88(9): p. 1424-31. 
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Romani, A.A., et al., The risk of developing metastatic disease in colorectal cancer is 
related to CD105-positive vessel count. J Surg Oncol, 2006. 93(6): p. 446-55. 
33. 
Rubatt, J.M., et al., Independent prognostic relevance of microvessel density in advanced 
epithelial ovarian cancer and associations between CD31, CD105, p53 status, and 
angiogenic marker expression: A Gynecologic Oncology Group study. Gynecol Oncol, 
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Taskiran, C., et al., The prognostic value of endoglin (CD105) expression in ovarian 
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prognostic markers in esophageal adenocarcinoma. Hum Pathol, 2005. 36(9): p. 955-61. 
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head and neck squamous cell carcinoma. Virchows Arch, 2006. 448(6): p. 768-75. 
41. 
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oral and oropharyngeal carcinoma. Acta Otolaryngol, 2006. 126(6): p. 633-9. 
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Shiozaki, K., et al., Antiangiogenic chimeric anti-endoglin (CD105) antibody: 
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the combination of TRC105 and bevacizumab on endothelial cell biology. Invest New 
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Greten, T.F., Duffy, A.G.,  et al. A phase I/II study of TRC105 in combination with 
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Choi, H.C., Chuslip;  Faria, Silvana C.; Macapinlac, Homer A.;  Burgess, Michael A.; 
and S.R.C. Patel, Lei L.;  Podoloff, Donald A. and Benjamin, Robert S. , Correlation of 
Computed Tomography and Positron Emission Tomography in Patients With Metastatic 


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Gastrointestinal Stromal Tumor Treated at a Single Institution With Imatinib Mesylate: 
Proposal of New Computed Tomography Response Criteria. Journal of Clinical 
Oncology, 2007. 25(13). 
 
 


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21. 
APPENDICES 
21.1. 
Appendix 1:  National Cancer Institute (NCI) Common Terminology 
Criteria for Adverse Events (CTCAE) 
The NCI CTCAE (Version 4.03) should be used to assess Adverse Events and may be reviewed 
on-line at the following NCI website: 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf  
 
 
 


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5.3.3.2 Clinical Protocol                                                                                      15February2018 
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21.2. 
Appendix 2:  ECOG Performance Status 
 
Grade 
Performance 
0 
Fully active, able to carry on all pre-disease performance without restriction. 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light 
or sedentary nature, e.g., light house work, office work. 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and 
about more than 50% of waking hours. 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours. 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. 
5 
Dead. 
 
 


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5.3.3.2 Clinical Protocol                                                                                      15February2018 
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21.3. 
Appendix 3:  Sorafenib Prescribing Information 
 
 
 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021923s008s009lbl.pdf