A Randomized Phase 3 Trial of TRC105 and Pazopanib Versus Pazopanib Alone in Patients With Advanced Angiosarcoma (TAPPAS)
Phase: PHASE3
Conditions: Advanced Angiosarcoma
Sponsor: Tracon Pharmaceuticals Inc.



Combining TRC105 with Pazopanib (TAPPAS) 
 
TRACON Pharmaceuticals, Inc. 
Clinical Study Protocol: 105SAR301 
 
Amendment #4: 23Jul2018 
Confidential 
 
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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: 1.858.251.3490 
Mobile Phone: 1.858.344.9400 
Email: ctheuer@traconpharma.com 
Secondary Medical Monitor 
James Freddo MD  
4350 La Jolla Village Drive, Suite 800 
San Diego, CA 92122 
Mobile Phone: 1.858. 472.2330 
Email: jfreddo@traconpharma.com  

Combining TRC105 with Pazopanib (TAPPAS) 
 
TRACON Pharmaceuticals, Inc. 
Clinical Study Protocol: 105SAR301 
 
Amendment #4: 23Jul2018 
Confidential 
 
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1. 
SYNOPSIS 
Name of Sponsor/Company: TRACON Pharmaceuticals, Inc.  
Name of Investigational Product: TRC105 
Name of Active Ingredient: TRC105 (carotuximab) 
Title of Study:  
A RANDOMIZED PHASE 3 TRIAL OF TRC105 AND PAZOPANIB VERSUS PAZOPANIB 
ALONE IN PATIENTS WITH ADVANCED ANGIOSARCOMA (TAPPAS) 
Investigators and Study center(s):  Approximately 40 centers in North America and Europe 
Studied period (years):  
Date first patient enrolled: December 2016 
Estimated date last patient enrolled: March 2020 
Estimated date phase 3 endpoint obtained: September 2020 
Phase of development: 3 
 
Rationale:  
Angiosarcoma, a subtype of soft tissue sarcoma, is a rare and aggressive vascular malignancy 
associated with poor prognosis. About half of these patients present with primary cutaneous lesions 
(tumor arising from the skin, often consisting of multiple lesions and located in critical areas like 
head and neck). Risk factors for this presentation include prior radiation exposure as well as 
inflammatory damage in chronically sun exposed skin. Non-cutaneous angiosarcoma may also occur 
in the setting of prior radiation exposure.  Angiosarcoma has also been associated with prolonged 
lymphedema from any cause or prolonged immune-suppression. Although complete resection with 
curative intent, followed by adjuvant radiotherapy, is the treatment of choice for localized disease 
amenable to surgery, approximately 50% of these patients will develop metastases and die from the 
disease. Furthermore, metastases are frequently present at the time of diagnosis. Current treatment 
options are limited and of modest benefit. Median overall survival is approximately 8 to 11 months 
for patients with metastatic disease. Aside from pazopanib, standard regimens for advanced 
angiosarcoma include taxanes, anthracyclines, and gemcitabine. Tumor control with these therapies is 
short-lived with median progression-free survival (PFS) ranging from 3.9 to 6.6 months. The short 
time to progression following current treatment emphasizes that angiosarcoma is a disease in need of 
more effective and well tolerated treatment options. 
Pazopanib is an oral inhibitor of multiple receptor tyrosine kinases, including vascular endothelial 
growth factor receptor (VEGFR)-1, VEGFR-2, and VEGFR-3 at therapeutic plasma concentrations. 
These receptors are implicated in pathologic angiogenesis, tumor growth, and cancer progression. 
Pazopanib is approved based on improved PFS in the United States for the treatment of patients with 
advanced soft tissue sarcoma who have received prior chemotherapy and approved in Europe for 
adult patients with selective subtypes of advanced soft tissue sarcoma who have received prior 
chemotherapy for metastatic disease or who have progressed within 12 months after (neo) adjuvant 
therapy. However, activity in angiosarcoma is limited; no complete responses were observed in the 
largest series of angiosarcoma patients treated with single agent pazopanib reported to date (n=30). 
TRC105 (carotuximab) is a monoclonal antibody to endoglin (CD105), an essential angiogenic target 
highly expressed on tumor vessels that is distinct from VEGFR. Endoglin is also expressed directly 
on tumor cells in angiosarcoma and is upregulated following VEGF inhibition. TRC105 inhibits 
angiogenesis, tumor growth and metastases in preclinical models and complements the activity of 

Combining TRC105 with Pazopanib (TAPPAS) 
 
TRACON Pharmaceuticals, Inc. 
Clinical Study Protocol: 105SAR301 
 
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bevacizumab and multi-kinase inhibitors that target the VEGFR. In a phase 1 study of advanced solid 
tumors, single agent TRC105 therapy reduced tumor burden at doses that were well-tolerated.   
By targeting a non-VEGF pathway that is upregulated following VEGF inhibition, TRC105 has the 
potential to complement VEGFR tyrosine kinase inhibitors (TKIs) and could represent a major 
advance in the treatment of angiosarcoma. Together, the use of TRC105 with pazopanib may result in 
more effective angiogenesis inhibition and improved clinical efficacy over that seen with pazopanib 
alone.  
In a phase 1b/2 study of TRC105 and pazopanib in advanced soft tissue sarcoma, TRC105, at its 
recommended phase 2 dose of 10 mg/kg given by weekly intravenous infusion, was combined safely 
with pazopanib given at 800 mg p.o. once daily. Interim efficacy data from the Phase 1b/2 study 
indicated tumor reductions in all 5 of the first patients with angiosarcoma, of whom 2 had progressed 
following prior pazopanib treatment; notably, median PFS was greater than 12.9 months in these 5 
patients and 2 of the 3 patients with cutaneous angiosarcoma achieved durable complete responses by 
Response Evaluation Criteria in Solid Tumor version 1.1 (RECIST 1.1). Data available from the 
patients in the expansion cohorts enrolling angiosarcoma patients continues to demonstrate activity 
and tolerability of TRC105 in combination with pazopanib. 
Objectives:  
Primary: 
 
To compare PFS of TRC105 and pazopanib vs single agent pazopanib in patients with 
unresectable angiosarcoma 
Secondary: 
 
To compare the objective response rate (ORR) of TRC105 and pazopanib vs single agent 
pazopanib in patients with unresectable angiosarcoma 
 
To compare overall survival (OS) of TRC105 and pazopanib vs single agent pazopanib in 
patients with unresectable angiosarcoma 
 
To assess the overall safety and tolerability of TRC105 and pazopanib vs single agent 
pazopanib in patients with unresectable angiosarcoma 
 
To characterize patient reported outcomes between the two arms of the study    
 
To characterize the pharmacokinetic (PK) profile of TRC105 and pazopanib between the two 
arms of the study 
 
To assess PFS and ORR by Investigator assessment between the two arms of the study  
 
To characterize the immunogenicity of TRC105 
Exploratory: 
 
To correlate efficacy endpoints (e.g., PFS, ORR and OS) with endoglin expression on 
angiosarcoma tumor samples 
 
To correlate efficacy endpoints (e.g., PFS, ORR and OS) with circulating angiogenic protein 
biomarkers  
 
To correlate efficacy endpoints (e.g., PFS, ORR and OS) with numbers of endoglin 
expressing circulating tumor cells (CTCs)   
Endpoints: 
Primary: 

Combining TRC105 with Pazopanib (TAPPAS) 
 
TRACON Pharmaceuticals, Inc. 
Clinical Study Protocol: 105SAR301 
 
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 
PFS is defined as time from randomization to either first disease progression (per independent 
radiology review of images by RECIST 1.1) or death from any cause.  For the purpose of 
analysis for patients who are alive at the time of analysis and have not had disease 
progression, the following rules will apply:  (1) The patient will be censored on the date of 
the last tumor assessment documenting absence of progressive disease; (2) if the patient was 
given antitumor treatment other than study drug treatment, the patient will be censored as of 
the date of the last tumor assessment prior to initiating that antitumor therapy; (3) if the 
patient was removed from study for toxicity or other reason, the patient will be censored as of 
the date of the last tumor assessment on study. With regard to missed tumor assessments, in 
the event of one missed tumor assessment followed by a subsequent assessment of 
progressive disease (PD), the subsequent PD assessment qualifies as objective tumor 
progression. In the event of more than one consecutive missing tumor assessment followed by 
a subsequent assessment of PD, the patient will be censored at the last adequate tumor 
assessment. 
Secondary: 
 
Objective response rate (ORR) is defined as the number of patients with a best response of 
complete response (CR) or partial response (PR) divided by the number of randomized 
patients. ORR is defined as the best response designation recorded between the date of 
randomization and the date of documented progression, as determined by Central 
Radiographic Review according to RECIST 1.1, or date of subsequent therapy, whichever 
occurs first. For patients without documented progression or subsequent therapy, all available 
response designations will contribute to the ORR determination. A designation of CR or PR 
in this study requires confirmation at a subsequent consecutive assessment at least 4 weeks 
following the initial designation of CR or PR, respectively. Duration of response (DR) will 
be reported in patients who achieve ORR, but without a formal statistical comparison 
between arms. 
 
Overall Survival (OS) is defined as the time between the date of randomization and the date 
of death from any cause.  Overall survival will be calculated in days as: Date of Death – Date 
of Randomization +1.  Subjects alive or lost to follow-up at the time of analysis will be 
censored at the date when they were last known to be alive. 
 
Type, incidence, severity (graded by National Cancer Institute [NCI] Common Terminology 
Criteria for Adverse Events [CTCAE] Version 4.03), timing, seriousness, and relatedness of 
AEs and laboratory abnormalities. 
 
Patient reported outcomes as measured by the EuroQol five dimensions questionnaire (EQ-
5D-5L) and the EORTC QLQ-C30 questionnaire. 
 
TRC105 and pazopanib pharmacokinetic (PK) concentrations will be measured using 
validated methods from peak and trough samples. 
 
Anti-TRC105 antibodies will be measured using validated methods and anti-drug antibody 
(ADA) titers will be correlated with PK parameters and AEs. 
 

Combining TRC105 with Pazopanib (TAPPAS) 
 
TRACON Pharmaceuticals, Inc. 
Clinical Study Protocol: 105SAR301 
 
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Study Design:  
This is a multinational, multicenter, randomized, open label, parallel group, phase 3 study of TRC105 
in combination with standard dose pazopanib compared to single agent pazopanib in patients with 
angiosarcoma not amenable to curative intent surgery (e.g., metastatic or bulky disease, and disease 
for which surgical resection would carry an unacceptable risk to the patient) who have not received 
pazopanib or TRC105 previously.  
Adult patients will be randomized in a 1:1 ratio to TRC105 in combination with standard dose 
pazopanib (Arm B) vs standard dose single agent pazopanib (Arm A). Patients will be stratified by 
angiosarcoma subtype (cutaneous vs non-cutaneous) and the number of lines of prior systemic 
therapy for angiosarcoma (0 versus 1 or 2). For the purposes of this study, cutaneous angiosarcoma 
will include primary skin/scalp angiosarcoma; all other angiosarcoma including primary 
subcutaneous angiosarcoma will be categorized as non-cutaneous (e.g., visceral, bone, soft tissue).  
Due to possible differences in treatment effect in the cutaneous and non-cutaneous angiosarcoma 
subgroups, an adaptive enrichment design will be employed. An interim analysis is planned after 40 
events or 30 days after the enrollment of 120 patients from Cohort 1 and will result in one of the 
following decisions: (1) no change to the study design and sample size, (2) no change to the study 
design but an increase in the sample size, or (3) termination of enrollment of the non-cutaneous 
subtype and adjustment of the sample size of the cutaneous subtype.  Cohort 1 is defined as the adult 
patients enrolled prior to the interim analysis. 
Enrollment at a given site will be limited to a maximum of 15% of total patients. Additionally, 
enrollment of Cohort 1 will be monitored to ensure that no more than 50% of the total adult patients 
enrolled will have the non-cutaneous subtype. 
Treatment in the assigned arm must start within 3 calendar days of randomization.  
Trial Design Schema: 
 
 
 
Number of patients (planned):  
At least 190 patients will be enrolled. The number of patients enrolled may increase to a maximum of 
approximately 340 after the planned, prospectively specified interim analysis. 
 
 
 

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TRACON Pharmaceuticals, Inc. 
Clinical Study Protocol: 105SAR301 
 
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Patient Selection:  
Inclusion Criteria: 
1. Histologically-confirmed angiosarcoma that is not amenable to curative intent surgery 
(e.g., metastatic or bulky disease and disease for which surgical resection would carry an 
unacceptable risk to the patient). Pathology report will be reviewed by sponsor prior to 
randomization.  
2. Documented progression on or following most recent systemic chemotherapy regimen (not 
required for chemotherapy-naïve patients), within 4 months prior to screening 
3. Measurable disease by RECIST v1.1 
4. Age of 18 years or older; in addition, patients age 12 to 17 years may enroll beginning in 
Cohort 2 if weight ≥ 40 kg 
5. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1 
6. Resolution of all acute AEs resulting from prior cancer therapies to National Cancer Institute 
Common Terminology Criteria for Adverse Events version 4.03 (NCI CTCAE v4.03) grade ≤ 
1 or to that patient’s pre-study baseline (except alopecia or neuropathy)  
7. Adequate organ function as defined by the following criteria: 
 
Serum aspartate transaminase (AST; serum glutamic oxaloacetic transaminase [SGOT]) 
and serum alanine transaminase (ALT; serum glutamic pyruvic transaminase [SGPT]) 
≤ 2.5 x upper limit of normal (ULN) or ≤ 5 x ULN in cases of liver metastases 
 
Total serum bilirubin ≤ 1.5 x ULN 
 
Absolute neutrophil count (ANC) ≥ 1500/μL  
 
Platelets ≥ 100,000/μL (without transfusion support within 28 days prior to 
randomization) 
 
Hemoglobin ≥ 9.0 g/dL (without transfusion support within 14 days prior to 
randomization; erythropoietin or darbepoetin permitted) 
 
Serum creatinine ≤ 1.5 times the upper limit of normal or creatinine clearance 
> 30 mL/min by Cockcroft-Gault formula 
 
International normalized ratio (INR) ≤ 1.2 unless the patient is receiving a direct Factor 
Xa inhibitor 
8. Willingness and ability to consent (and assent if under age 18) for self to participate in study 
9. Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests, and 
other study procedures   
10. Angiosarcoma tumor specimen, if available 
11. Men who are sterile (including vasectomy confirmed by post vasectomy semen analysis) OR 
agree to use a condom with spermicide (refer to Section 2.6.1.3) and to not donate sperm 
during the study and for at least 180 days following last dose of TRC105 or pazopanib 
12. 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 

Combining TRC105 with Pazopanib (TAPPAS) 
 
TRACON Pharmaceuticals, Inc. 
Clinical Study Protocol: 105SAR301 
 
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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 
acceptable methods of birth control, one of which must be highly effective, during the study 
and for at least 180 days after stopping TRC105 or pazopanib (refer to Section 2.6.1.3).   
Exclusion Criteria:   
1. Prior treatment with TRC105 
2. Prior treatment with any VEGF inhibitor  
3. More than two prior lines (may be combination regimens) of chemotherapy for angiosarcoma 
(neoadjuvant/adjuvant treatment does not count as a line of treatment) 
4. Current treatment or participation on another therapeutic clinical trial 
5. Women who are pregnant or breastfeeding 
6. Receipt of systemic anticancer therapy, including investigational agents, within 5 times the 
agent’s elimination half-life or 14 days of starting study treatment, whichever is shorter 
7. Major surgical procedure or significant traumatic injury within 4 weeks prior to 
randomization and must have fully recovered from any such procedure or injury; planned 
surgery (if applicable) or the anticipated need for a major surgical procedure within the next 
six months. Note: the following are not considered to be major procedures and are permitted 
up to 7 days before randomization: Thoracentesis, paracentesis, laparoscopy, thoracoscopy, 
tube thoracostomy, bronchoscopy, endoscopic ultrasonographic procedures, 
mediastinoscopy, skin biopsies, and imaging-guided biopsy for diagnostic purposes 
8. Patients who have received wide field radiotherapy ≤ 28 days (defined as > 50% of volume 
of pelvic bones or equivalent) or limited field radiation for palliation < 14 days prior to 
randomization  
9. Uncontrolled hypertension defined as systolic > 150 or diastolic > 100 mm Hg on the average 
of the 3 most recent BP readings. Anti-hypertensives may be started prior to randomization.  
10. Ascites or pleural effusion requiring intervention or that required intervention or recurred 
within three months prior to randomization 
11. Pericardial effusion (except trace effusion identified by echocardiogram) within three months 
prior to randomization 
12. 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 prior to 
randomization 
13. Angina, myocardial infarction, symptomatic congestive heart failure, cerebrovascular 
accident, transient ischemic attack, arterial embolism , pulmonary embolism, percutaneous 
transluminal coronary angioplasty (PTCA) or coronary artery bypass graft (CABG) within 6 
months prior to randomization. Deep venous thrombosis within 3 months prior to 
randomization unrelated to a central venous catheter, unless the patient is anti-coagulated 
without the use of warfarin for at least 2 weeks prior to randomization. In this situation, low 
molecular weight heparin or a direct Factor Xa inhibitor is preferred 

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14. Active bleeding or pathologic condition that carries a high risk of bleeding (e.g., hereditary 
hemorrhagic telangiectasia).  Patients with bleeding cutaneous lesions not actively requiring 
transfusions are eligible. Patients who have been uneventfully anti-coagulated with a direct 
Factor Xa inhibitor or low molecular weight heparin are eligible 
15. Hemoptysis (> ½ teaspoon [2.5 mL] of bright red blood) within 6 months  prior to 
randomization 
16. Thrombolytic use (except to maintain i.v. catheters) within 10 days prior to randomization 
17. Known active viral or nonviral hepatitis or cirrhosis 
18. Peptic ulcer within the past 3 months prior to randomization, unless treated for the condition 
and complete resolution has been documented by esophagogastroduodenoscopy (EGD)  
19. Presence of tumor(s) invading into the heart or great vessels (including carotid artery) or 
another location where bleeding is associated with high morbidity including patients with 
primary cardiac or great vessel angiosarcoma  
20. Gastrointestinal perforation or fistula in the 6 months prior to randomization unless 
underlying risk has been resolved (e.g., through surgical resection or repair) 
21. Presence of a malabsorption syndrome, gastrointestinal disorder, or gastrointestinal surgery 
that could affect the absorption of pazopanib 
22. History of prior malignancy except adequately treated basal cell or squamous cell skin cancer 
or adequately treated, with curative intent, cancer from which the patient is currently in 
complete remission per Investigator’s judgment; patients with history of breast cancer and no 
evidence of disease on hormonal therapy to prevent recurrence and patients with prostate 
cancer on adjuvant hormonal therapy with undetectable PSA are eligible 
23. Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome 
(AIDS) related illness 
24. Active infection that requires systemic treatment 
25. Concurrent use or receipt of a strong CYP3A4 inducer within 12 days prior to randomization 
or a strong CYP3A4 inhibitor within 7 days prior to randomization (see Table 10) 
26. History of severe hypersensitivity reaction to any monoclonal antibody 
27. Other severe acute or chronic medical (including bone marrow suppressive diseases) or 
psychiatric condition or laboratory abnormality that may increase the risk associated with 
study participation, impede the ability of the patient to complete all protocol-specified 
activities, or may interfere with the interpretation of study results and, in the judgment of the 
Investigator, would make the patient inappropriate for this study 
TRC105 investigational product dose and mode of administration:  
Patients randomized to the combination arm (Arm B) will receive intravenous TRC105 at 10 mg/kg 
weekly beginning on cycle 1 day 1 (C1D1) following appropriate premedication. Treatment must 

Combining TRC105 with Pazopanib (TAPPAS) 
 
TRACON Pharmaceuticals, Inc. 
Clinical Study Protocol: 105SAR301 
 
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start within 3 days of randomization. Each cycle is 21 days in duration. Dose modification of 
TRC105 is allowed per patient tolerance.   
Pazopanib dose and administration: 
Adult and adolescent patients with a BSA > 1.8 m2 will receive 800 mg of pazopanib beginning on 
C1D1 and once daily thereafter, in the absence of toxicity. All other pediatric patients will receive 
600 mg of pazopanib beginning on C1D1 and once thereafter, in the absence of toxicity.  Treatment 
must start within 3 days of randomization. Dose modification of pazopanib is allowed per patient 
tolerance. 
Duration of treatment:  
Patients are eligible for treatment until disease progression, unacceptable toxicity or withdrawal of 
consent, or other reasons.  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 confirmed by central radiographic review. 
2. A need for surgery, radiation, or other anticancer therapy not permitted under this protocol. 
3. Lost to follow-up or substantial noncompliance with the protocol. 
4. Pregnancy.  Pregnant patients should be followed for the duration of the pregnancy and the 
outcome of the pregnancy should be documented. 
5. Arterial thrombosis of any grade (including that causing cerebrovascular ischemia, cardiac 
ischemia/infarction, or peripheral or visceral arterial ischemia) or grade 4 venous thrombosis 
(including grade 4 pulmonary thromboembolism).   
6. Missed study drug treatment for > 8 consecutive weeks (i.e., both TRC105 and pazopanib 
dosing if assigned to the combination arm or pazopanib if assigned to the pazopanib alone 
arm). Patients in the combination arm who cannot tolerate pazopanib or TRC105 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 single agent 
therapy may continue on study on TRC105 or pazopanib alone.  
Statistical Considerations: 
Efficacy Analyses 
The study population for efficacy (i.e., the intent-to-treat, ITT, population) will include all 
randomized adult patients. Patients age 12 to 17 will not be randomized and will receive treatment 
with TRC105 and pazopanib and therefore will not be included in the ITT population. The primary 
endpoint is PFS and the primary analysis will compare the TRC105 plus pazopanib and the single-
agent pazopanib groups using a one-sided, stratified by angiosarcoma location (cutaneous versus non-
cutaneous) and by number of lines of prior systemic chemotherapy for angiosarcoma (0 versus 1-2) 
log rank test at the two-tailed alpha = 0.05 level of significance. Estimates of median PFS will be 
provided along with 2-sided 95% confidence intervals. The PFS distributions in the two arms will be 
summarized using the Kaplan-Meier method.  The primary analyses of efficacy endpoints dependent 
on disease assessments (PFS and ORR) will be performed in the ITT population based on results of 
the independent central application of modified RECIST 1.1. Imaging will be performed every 42 
days from date of randomization. 
Sample Size Justification 
A hazard ratio of 0.55 is considered to be clinically relevant.  Based on 1:1 randomization and the use 
of log-rank test at the 2-sided alpha of 0.05 level of significance, 95 events provides 83% power to 
detect a hazard ratio of 0.55.  

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Clinical Study Protocol: 105SAR301 
 
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The expected PFS of angiosarcoma patients treated with pazopanib who have progressed following 
first line treatment is 4 months. A hazard ratio of 0.55 corresponds to an improvement of median PFS 
from 4 months to 7.27 months. Due to the uncertainty of the treatment effect, and heterogeneity 
among the cutaneous and non-cutaneous subgroups, an adaptive enrichment design will be employed.  
The initial study design calls for enrolling two cohorts, with 120 adult patients in cohort 1 and 70 
adult patients in cohort 2. The initially planned final analysis will be conducted when 60 events are 
observed from cohort 1 and 35 events are observed from cohort 2, whichever comes at a later time. A 
formal interim analysis based on unblinded data review by the Independent Data Monitoring 
Committee (IDMC) will be conducted and the trial might be expanded to enroll a total of 340 adult 
patients from the full population or enriched to enroll a total of 280 adult patients including 120 adult 
patients from cohort 1 from full population and 160 adult cutaneous disease patients for cohort 2 from 
the cutaneous subgroup only.  
The operational and statistical details for implementing this adaptive enrichment are included in the 
statistical analysis plan (SAP). 
 
 
 

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Clinical Study Protocol: 105SAR301 
 
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TABLE OF CONTENTS 
PROCEDURES IN CASE OF EMERGENCY ...............................................................................2 
1. 
SYNOPSIS ...................................................................................................................3 
TABLE OF CONTENTS ...............................................................................................................12 
LIST OF TABLES .........................................................................................................................16 
LIST OF FIGURES .......................................................................................................................17 
2. 
BACKGROUND ........................................................................................................21 
2.1. 
Angiosarcoma .............................................................................................................21 
2.2. 
Angiogenesis and Cancer ...........................................................................................21 
2.2.1. 
Endoglin (CD105) and Angiogenesis .........................................................................22 
2.2.2. 
Endoglin and Angiosarcoma .......................................................................................23 
2.3. 
TRC105 Background ..................................................................................................24 
2.3.1. 
Studies with TRC105 ..................................................................................................24 
2.3.1.1. 
Study 105ST101 Phase 1 Monotherapy .....................................................................24 
2.3.1.2. 
Study 105SAR101 Phase 1b/2a with Pazopanib ........................................................28 
2.4. 
Study 105SAR301 Rationale ......................................................................................30 
2.5. 
Population to be Studied .............................................................................................30 
2.6. 
Potential Risks and Benefits to Human Patients .........................................................31 
2.6.1. 
Potential Risks ............................................................................................................31 
2.6.1.1. 
TRC105 .......................................................................................................................31 
2.6.1.2. 
Pazopanib ....................................................................................................................31 
2.6.1.3. 
Other Study Risks .......................................................................................................32 
2.6.2. 
Potential Benefits ........................................................................................................32 
2.7. 
Study Conduct ............................................................................................................33 
3. 
TRIAL OBJECTIVES AND ENDPOINTS ...............................................................34 
3.1. 
Primary Objective .......................................................................................................34 
3.2. 
Secondary Objectives .................................................................................................34 
3.3. 
Exploratory Objectives ...............................................................................................34 
4. 
TRIAL ENDPOINTS .................................................................................................35 
4.1. 
Primary Endpoint ........................................................................................................35 
4.2. 
Secondary Endpoints ..................................................................................................35 
5. 
INVESTIGATIONAL PLAN .....................................................................................37 

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5.1. 
Overall Study Design and Plan ...................................................................................37 
5.1.1. 
Overview .....................................................................................................................37 
5.1.2. 
Trial Procedures ..........................................................................................................38 
5.1.2.1. 
Screening ....................................................................................................................38 
5.1.2.2. 
Trial Period .................................................................................................................39 
5.1.3. 
End of Study Assessments ..........................................................................................41 
5.1.4. 
Post-Treatment Follow-up ..........................................................................................42 
6. 
SELECTION AND WITHDRAWAL OF PATIENTS ..............................................51 
6.1. 
Study Population .........................................................................................................51 
6.1.1. 
Inclusion Criteria ........................................................................................................51 
6.1.2. 
Exclusion Criteria .......................................................................................................52 
6.2. 
Patient Withdrawal Criteria ........................................................................................54 
6.2.1. 
Withdrawal of Consent ...............................................................................................54 
7. 
STUDY TREATMENTS ............................................................................................56 
7.1. 
Description of TRC105 Study Drug ...........................................................................56 
7.1.1. 
Composition of TRC105 .............................................................................................56 
7.1.2. 
TRC105 Dose Level ...................................................................................................56 
7.1.3. 
TRC105 Packaging and Labeling ...............................................................................56 
7.1.4. 
TRC105 Storage and Shipping ...................................................................................56 
7.1.5. 
TRC105 Preparation ...................................................................................................56 
7.1.6. 
TRC105 Administration .............................................................................................57 
7.1.7. 
TRC105 Dose Delay and Modification ......................................................................59 
7.1.8. 
Management of TRC105 Infusion-Related Reactions ................................................61 
7.1.9. 
TRC105 Study Drug Accountability ..........................................................................62 
7.1.10. 
TRC105 Study Drug Handling and Disposal .............................................................62 
7.2. 
Description of Pazopanib ............................................................................................63 
7.2.1. 
Composition of Pazopanib ..........................................................................................63 
7.2.2. 
Pazopanib Dose Level ................................................................................................63 
7.2.3. 
Pazopanib Packaging and Labeling ............................................................................63 
7.2.4. 
Pazopanib Storage Handling and Disposal .................................................................63 
7.2.5. 
Pazopanib Dosing .......................................................................................................63 
7.2.6. 
Pazopanib Dose Modification .....................................................................................63 
7.2.7. 
Pazopanib Drug Accountability ..................................................................................64 

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7.3. 
Concomitant Medications ...........................................................................................64 
7.4. 
Treatment Compliance ................................................................................................66 
7.4.1. 
TRC105 Treatment Compliance .................................................................................66 
7.4.2. 
Pazopanib Treatment Compliance ..............................................................................66 
7.5. 
Patient Randomization ................................................................................................66 
8. 
ASSESSMENT OF EFFICACY ................................................................................68 
8.1. 
Radiological and Photographic Tumor Assessments .................................................68 
8.1.1. 
Measurability of Tumor Lesions ................................................................................69 
8.1.1.1. 
Obtaining Cutaneous Lesion Measurements from 2D Photography ..........................69 
8.1.1.2. 
Recording Tumor Measurements ...............................................................................70 
8.1.2. 
Definitions of Tumor Response ..................................................................................70 
8.1.2.1. 
Target Lesions ............................................................................................................70 
8.1.2.2. 
Non-Target Lesions ....................................................................................................70 
8.1.2.3. 
Determination of Overall Response ............................................................................71 
8.1.3. 
Central  Review of Disease Assessments ...................................................................71 
8.2. 
Primary Endpoint ........................................................................................................72 
8.3. 
Secondary Endpoints ..................................................................................................73 
8.3.1. 
Objective Response Rate ............................................................................................73 
8.3.2. 
Overall Survival ..........................................................................................................73 
8.3.3. 
Safety ..........................................................................................................................73 
9. 
ASSESSMENT OF SAFETY .....................................................................................74 
9.1. 
Safety Parameters .......................................................................................................74 
9.1.1. 
Laboratory Safety Assessments ..................................................................................74 
9.1.1.1. 
Hematology, Serum Chemistry, Coagulation, and Pregnancy Test ...........................74 
9.1.1.2. 
Urinalysis ....................................................................................................................74 
9.1.1.3. 
Physical Examination .................................................................................................75 
9.1.1.4. 
Vital Signs ..................................................................................................................75 
9.1.1.5. 
Performance Status .....................................................................................................75 
9.1.1.6. 
ECG ............................................................................................................................75 
9.1.1.7. 
Patient Reported Outcomes ........................................................................................75 
9.2. 
Adverse Events ...........................................................................................................76 
9.2.1. 
Definition of Adverse Event .......................................................................................76 
9.2.2. 
Serious Adverse Events ..............................................................................................77 

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9.2.2.1. 
Hospitalization ............................................................................................................78 
9.3. 
Reporting Adverse Events ..........................................................................................78 
9.3.1. 
Eliciting Adverse Event Information ..........................................................................78 
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 of Adverse Event to TRC105 and Pazopanib Study Drugs ...................81 
9.3.7. 
Expectedness Assessment ...........................................................................................82 
9.3.8. 
Exposure in Utero .......................................................................................................82 
9.3.9. 
Follow-up of Unresolved Adverse Events ..................................................................83 
9.4. 
Safety Monitoring .......................................................................................................83 
9.5. 
Steering Committee ....................................................................................................84 
10. 
OTHER ASSESSMENTS ..........................................................................................85 
10.1. 
Other Laboratory Assessments ...................................................................................85 
10.1.1. 
Pharmacokinetics ........................................................................................................85 
10.1.1.1. 
TRC105 and Pazopanib Concentrations .....................................................................85 
10.1.2. 
TRC105 Immunogenicity ...........................................................................................85 
10.1.3. 
Protein Biomarkers .....................................................................................................85 
10.1.4. 
Circulating Tumor Cells .............................................................................................85 
10.1.5. 
Archival Tumor Specimens ........................................................................................85 
11. 
STATISTICS ..............................................................................................................87 
11.1. 
Sample Size ................................................................................................................87 
11.1.1. 
Definition of Analyzed Study Populations .................................................................89 
11.2. 
Data Analysis ..............................................................................................................90 
11.2.1. 
Analysis of Primary Objective ....................................................................................90 
11.2.2. 
Analysis of Pharmacokinetics .....................................................................................91 
11.2.3. 
Analysis of Protein Biomarkers ..................................................................................91 
11.2.4. 
Analysis of Circulating Tumor Cells ..........................................................................91 
11.2.5. 
Analysis of Immunogenicity .......................................................................................91 
12. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS .........................................92 
13. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................93 
14. 
ETHICS ......................................................................................................................94 

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14.1. 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) ..................94 
14.2. 
Ethical Conduct of the Study ......................................................................................94 
14.3. 
Written Informed Consent ..........................................................................................94 
14.4. 
Patient Compensation .................................................................................................95 
15. 
DATA HANDLING AND RECORDKEEPING .......................................................96 
15.1. 
Inspection of Records .................................................................................................96 
15.2. 
Retention of Records ..................................................................................................96 
16. 
DEFINITION OF END OF TRIAL ...........................................................................98 
16.1. 
End of Trial in all Participating Countries ..................................................................98 
16.2. 
TRACON Study Discontinuation Criteria ..................................................................98 
17. 
PUBLICATION OF TRIAL RESULTS ....................................................................99 
18. 
FINANCING AND INSURANCE ...........................................................................100 
19. 
INVESTIGATOR PROTOCOL AGREEMENT: 105SAR301 ...............................101 
20. 
REFERENCES .........................................................................................................102 
21. 
APPENDICES ..........................................................................................................106 
21.1. 
Appendix 1:  National Cancer Institute (NCI) Common Terminology 
Criteria for Adverse Events (CTCAE) .....................................................................106 
21.2. 
Appendix 2:  ECOG Performance Status .................................................................107 
21.3. 
Appendix 3: Quality of Life Questionnaire - EQ-5D-5L Example ..........................108 
21.4. 
Appendix 4: Quality of Life Questionnaire – EORTC QLQ-C30 Example ............111 
 
LIST OF TABLES 
Table 1: 
Emergency Contact Information ...................................................................................2 
Table 2: 
Abbreviations and Specialist Terms ...........................................................................18 
Table 3: 
Schedule of Assessments Arm A: Single Agent Pazopanib .......................................43 
Table 4: 
Schedule of Assessments Arm B: TRC105 plus Pazopanib Combination 
Therapy .......................................................................................................................47 
Table 5: 
TRC105 10 mg/kg Weekly Initial Administration Schema .......................................59 
Table 6: 
TRC105 10 mg/kg Weekly Administration after Missed Dose ..................................60 
Table 7: 
Allowable TRC105 Dose Modifications ....................................................................60 
Table 8: 
Management of TRC105 Infusion-Related Reactions ................................................62 
Table 9: 
Examples of Drugs Prolonging QT interval and/or Inducing Torsades de 
Pointesa .......................................................................................................................65 

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Table 10: Examples of Strong CYP3A4 Inducers and Inhibitorsa ..............................................66 
Table 11: Response Evaluation Criteria in Solid Tumors ..........................................................71 
Table 12: Adverse Event Grading ...............................................................................................81 
 
LIST OF FIGURES 
Figure 1:  Single-Dose and Multiple-Dose Pharmacokinetic Data from Study 
105ST101 ....................................................................................................................25 
Figure 2: 
Trial Design Schema ...................................................................................................37 
Figure 3: 
 Schematic Representation of Adaptive Trial Design .................................................89 

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Table 2: Abbreviations and Specialist Terms  
Abbreviation or specialist 
term 
Explanation 
2D 
Two Dimensional 
ADA 
Anti-Drug Antibody 
ADCC 
Antibody-Dependent Cell-mediated Cytotoxicity 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
ALKs 
Activin receptor-Like Kinases 
ALT 
Alanine Aminotransferase 
ANC 
Absolute Neutrophil Count 
AST 
Aspartate Aminotransferase 
AUC 
Area Under the Curve 
AUClast 
Time of Last Measurable Concentration of Area Under the Curve 
BMP 
Bone Morphogenic Protein 
BUN 
Blood Urea Nitrogen 
CABG 
Coronary Artery Bypass Graft 
CA-125 
Cancer Antigen 125 
CBC 
Complete Blood Count 
CEA 
Carcinoembryonic Antigen 
CFR 
Code of Federal Regulations 
CHO 
Chinese Hamster Ovary 
CL 
Clearance 
Cmax 
Maximum Serum Concentration 
CR 
Complete Response 
CRF 
Case Report Form 
CT 
Computed Tomography 
CTC 
Common Terminology Criteria 
CTC 
Circulating Tumor Cell 
CTCAE 
Common Terminology Criteria for Adverse Events 
DEHP 
Di(2-ethyl-hexyl)phthalate 
DICOM 
Digital Imaging and Communications in Medicine 
dL 
Deciliter 
DLT 
Dose-Limiting Toxicity 
DR 
Duration of Response 
ECG 
Electrocardiogram 
ECL 
Electrochemiluminescent 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
EDTA 
Ethylenediamine Tetra-Acetic Acid 
EGFR 
Epidermal Growth Factor Receptor 
ELISA 
Enzyme-Linked ImmunoSorbent Assay 
EMA 
European Medicines Agency 

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EORTC 
European Organisation for Research and Treatment of Cancer  
EOS 
End of Study 
EU 
European Union 
FDA 
Food and Drug Administration 
Fe 
Iron 
FGF 
Fibroblast Growth Factor 
g 
Gram 
GCP 
Good Clinical Practice 
GIST 
Gastrointestinal Stromal Tumor 
HACA 
Human Anti-Chimeric Antibodies 
HAMA 
Human Anti-Murine Antibodies 
HHT-1 
Hereditary Hemorrhagic Telangiectasia Type 1 
HIF-1-α 
Hypoxia-Inducible Factor-1-α 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human Immunodeficiency Virus 
HUVECs 
Human Umbilical Vein Endothelial Cells 
IB 
Investigational  Brochure 
ICH 
International Conference on Harmonisation 
ID 
Identification 
IEC 
Independent Ethics Committee 
IgG 
Immunoglobulin G 
i.m. 
Intramuscular 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IUD 
Intrauterine Device 
i.v. 
Intravenous 
kg 
Kilogram 
L 
Liter 
μL 
Microliter 
mg 
Milligram 
MI 
Myocardial Infarction 
mL 
Milliliter 
mm 
Millimeter 
mM 
Millimolar 
mm HG 
Millimeters of Mercury 
MRI 
Magnetic Resonance Imaging 
MTD 
Maximum-Tolerated Dose 
NCI 
National Cancer Institute 
NICE 
National Institute for Health and Care Excellence 
NE 
Non-evaluable 
ng 
Nanogram 
NSO 
Murine Myeloma Cell Line 
OS 
Overall Survival 

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PBS 
Phosphate-Buffered Saline 
PD 
Progressive Disease 
PET 
Positron Emission Tomography 
PFS 
Progression Free Survival 
PIGF 
Placental Growth Factor 
pM 
Picomolar 
p.o. 
Orally 
PPM 
Pixels Per Millimeter 
PR 
Partial Response 
PSA 
Prostate-Specific Antigen 
PTCA 
Percutaneous Transluminal Coronary Angioplasty 
QA 
Quality Assurance 
QT 
QT Wave Interval on ECG 
RECIST 
Response Evaluation Criteria in Solid Tumors 
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 
STS 
Soft tissue sarcoma 
TGF-β 
Transforming Growth Factor - Beta 
TSH 
Thyroid Stimulating Hormone 
UK 
United Kingdom 
ULN 
Upper Limit of Normal 
UPCR 
Urine Protein-Creatinine Ratio 
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 
WHO 
World Health Organization 

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2. 
BACKGROUND 
2.1. 
Angiosarcoma 
Sarcomas are rare tumors that originate from mesenchymal tissues (e.g., bone, cartilage, fat and 
muscle).  In the United States, the incidence of bone and soft tissue sarcomas is approximately 
13,000 new cases per year, leading to more than 5,000 deaths annually [1].  According to the 
WHO classification of 2002, over 70 different types of sarcoma have been described [2].  
Localized tumors are curable but patients with metastatic disease have a median survival of 
approximately 12 months[3].  Standard systemic chemotherapy regimens are poorly tolerated 
and of limited usefulness with response rates in the range of 10-40% [3].   
Angiosarcomas are rare, aggressive, and heterogenous tumors of endothelial cell origin 
accounting for approximately 2% of soft tissue sarcoma (STS) [4]. Anigiosarcoma can arise in 
any soft-tissue structure or viscera. About half of patients present with a primary cutaneous 
lesion (skin, scalp). The pathogenesis of this presentation includes prior radiation exposure as 
well as inflammatory damage in chronically sun exposed skin. Non-cutaneous angiosarcoma 
(soft tissue, bone, viscera) can occur in the setting of prior radiation exposure or other unknown 
causes.  Angiosarcoma has also been associated with prolonged lymphedema from any cause. 
Although complete resection with curative intent followed by adjuvant radiotherapy is the 
treatment of choice for localized disease amenable to surgery, approximately 50% of these 
patients will develop metastasis and die from the disease. Furthermore, metastases are frequently 
present at the time of diagnosis [5]. The surgical removal of metastatic lesion is rarely feasible 
[6]. Treatment options are limited for advanced disease and of modest benefit. The median 
overall survival is <12 months for patients with metastatic disease [5, 7, 8].  There are no 
approved therapies specifcially for angiosracoma. Aside from pazopanib, standard regimens for 
advanced angiosarcoma include taxanes, anthracyclines, and gemcitabine. Tumor control with 
these therapies have been short-lived with median PFS ranging from 3.9 to 6.6 months [5, 9]. 
Recently, the VEGFR TKI pazopanib was approved based on improved progression free survival 
(PFS) in the United States for the treatment of patients with advanced soft tissue sarcoma who 
have received prior chemotherapy and approved in Europe for adult patients with selective 
subtypes of advanced soft tissue sarcoma who have received prior chemotherapy for metastatic 
disease or who have progressed within 12 months after (neo) adjuvant therapy.  Pazopanib 
improved PFS in chemotherapy refractory patients compared to placebo (PFS of 4.6 months with 
pazopanib versus 1.6 months with placebo) and was generally well tolerated, with the most 
common AEs seen at higher levels than in patients treated with placebo being fatigue, diarrhea, 
nausea, weight decreased and hypertension. However, activity in angiosarcoma is limited; no 
complete responses and median PFS of 3.02 months were observed in the largest series of 
angiosarcoma patients (n=30) treated with pazopanib reported to date [10].  Studies of other 
VEGFR TKIs confirm a poor response rate and PFS of < 4 months [5]. 
The short time to progression following current treatment emphasizes that angiosarcoma is a 
disease in need of more effective and well tolerated treatment options. 
2.2. 
Angiogenesis and Cancer 
Angiogenesis is required for the survival and growth of solid cancers [11, 12].  It is generally 
accepted that solid cancers have two phases, an avascular phase and a vascular phase [12].  

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During the initial avascular phase, tumors exist as small aggregates of malignant cells supported 
by simple diffusion of oxygen and nutrients. The progressive growth of solid cancers beyond 
clinically occult sizes requires the continuous formation of new blood vessels, a process known 
as tumor angiogenesis. Tumor growth and metastasis require angiogenesis. Therefore, inhibition 
of tumor angiogenesis and selective inhibition of the tumor vasculature represent potentially 
effective strategies for the prevention and treatment of solid cancers.   
Therapies that are directed against targets implicated in the development of tumor angiogenesis 
are attractive for many reasons. First, except for female reproduction and wound healing, 
angiogenesis in adults is generally part of a pathologic process such as tumor growth or 
choroidal neovascularization. Second, treatments that interrupt tumor angiogenesis should apply 
broadly to all solid cancers. Third, angiogenic targets are present in the plasma or on endothelial 
cells themselves. These targets are readily accessible to antibody treatments, in contrast to targets 
expressed within tumors that are more difficult for antibodies to access. Fourth, angiogenic 
targets on vascular endothelial cells are less prone to genetic mutation than targets expressed by 
genetically unstable cancer cells. As a result, development of resistance may be more predictable 
for agents that target endothelial cell functions than for those targeting cancer cells. 
Indeed, agents that target pathways required for tumor angiogenesis have an important role in the 
therapy of cancer patients. The monoclonal antibody bevacizumab, which binds to the 
angiogenic cytokine VEGF, significantly prolongs overall survival for patients with advanced 
colorectal cancer or non-small cell lung cancer when added to standard chemotherapy regimens 
[13, 14]. Bevacizumab is also effective therapy for renal cell cancer and malignant glioma [15-
17]. Orally available small molecule VEGF inhibitors include sunitinib, sorafenib, pazopanib, 
and axitinib, which have been shown to prolong survival in patients with metastatic renal cell 
cancer, hepatocellular cancer, colorectal cancer, and sarcoma [18-21].   
2.2.1. 
Endoglin (CD105) and Angiogenesis 
Endoglin (CD105) is a homodimeric cell membrane glycoprotein that was initially identified as a 
human leukemia-associated antigen [22] and later also found on endothelial cells [23, 24].  
Endoglin is a transforming growth factor-β (TGF-β) coreceptor that is essential for angiogenesis 
[25, 26] and is strongly expressed on the proliferating vascular endothelium of solid tumors [24, 
27]. Endoglin acts to modulate signaling of multiple kinase receptor complexes of the TGF-β 
superfamily, including TGF-β receptors, activin receptor-like kinases (ALKs), bone 
morphogenic protein (BMP) receptors, and activin receptors [28].  TGF-β binds to endoglin 
complexed with TGF-β receptors causing phosphorylation of SMAD 2 and 3 proteins, which 
inhibit endothelial cell growth. However, BMP activates endoglin complexed with BMP receptor 
2, causing phosphorylation of SMAD 1 and 5, which activate endothelium by overriding the 
growth inhibitory effects of TGF-β receptor signaling on endothelium [29]. Not surprisingly, 
prevention of endoglin activation by endoglin antibody acts synergistically with TGF-β to inhibit 
endothelial cell growth [30].   
Endoglin expression is required for endothelial cell proliferation and is upregulated in the setting 
of hypoxia through the induction of hypoxia-inducible factor-1-α (HIF-1-α) [31, 32]. Endoglin 
has also been shown to protect hypoxic cells from apoptosis [33]. In adults, endoglin expression 
is limited to vascular endothelial cells, activated monocytes, activated fibroblasts, and 
proerythroblasts, a red blood cell precursor [34]. All of these properties make endoglin an 

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attractive target for the antiangiogenic therapy of cancer [35]. In animal models, endoglin 
targeted therapy has demonstrated antiangiogenic effects by inducing regression of established 
tumors as well as by preventing new tumor formation and inhibiting expansion of existing 
tumors [24, 36-39]. Therefore, endoglin offers a novel alternative target relative to the VEGF 
inhibitors currently available for antiangiogenesis therapy.   
Importantly, endoglin expression is upregulated in tumor endothelial cells following inhibition of 
the VEGF pathway.  Endoglin expression increased more than 2-fold in human pancreatic 
cancers grown in mice treated with an antibody that binds VEGF [40]. As well, treatment of 
human bladder cancers grown in mice with an antibody that blocks activation of the VEGF 
receptor increased endoglin expression within the core tumor vasculature [41]. Preclinical data 
suggest that targeting the endoglin pathway and the VEGF pathway concurrently is a more 
effective means of inhibiting angiogenesis than targeting either pathway individually [42, 43].  
Endoglin is critical for normal human blood vessel development [44]. Endoglin 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 telangiectasia involving the nasal, buccal, gastrointestinal 
mucosa and skin microvasculature. Telangiectasia also occur in vessels from internal organs 
including the lungs, liver and brain [45]. 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, indicating the specific role of endoglin in vascular development [46].   
2.2.2. 
Endoglin and Angiosarcoma 
Endoglin is also expressed on the tumor tissue of certain tumor types in addition to the tumor 
vasculature. Endoglin is a marker of mesenchymal stem cells, the normal cell type from which 
sarcomas originate [47, 48]. Endoglin-expressing sarcomas are relatively frequent and express 
endoglin at higher density than carcinoma cell lines. In one report, high surface expression of 
endoglin by whole cell flow cytometry was seen in 7 of 8 sarcoma cell lines compared to only 4 
of 16 carcinoma cell lines [49]. Moreover, the level of endoglin expression correlated with 
proliferative capacity, and the addition of neutralizing endoglin antibodies reversed the increase 
in proliferation. 
Endoglin expression in human sarcoma tumor tissue has been reported by several groups.  
Gromova et al. found endoglin on 26 of 49 human gastrointestinal stromal tumors (GIST), and 
higher expression correlated with more aggressive tumors and high risk disease [50]. Moreover, 
endoglin knockdown reversed the increased tumor cell plasticity, invasiveness, and anchorage 
independent growth associated with endoglin expression [51].  Other endoglin-expressing 
sarcomas identified in the literature include angiosarcoma, osteosarcoma, leiomyosarcoma, 
malignant fibrous histiocytoma (undifferentiated pleomorphic sarcoma), Kaposi’s sarcoma, 
Wilms tumor, and chondrosarcoma [52-56]. 
Endoglin expression was evaluated by immunohistochemistry on archival tumor samples from 
almost 150 patients with various types of sarcoma [57]. Among the sarcoma tumor types 
evaluated, angiosarcoma expressed endoglin on tumor tissue most universally (19 of 20 samples) 
and densely. TRC105 is expected to be more active in tumor types, particularly angiosarcoma, 
that densely express endoglin on tumor tissue in addition to tumor vasculature.   

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2.3. 
TRC105 Background 
TRC105 is a novel immunoglobulin G1 (IgG1) antibody that binds endoglin with high avidity. 
TRC105 is a genetically engineered human/murine chimeric monoclonal antibody directed 
against human endoglin [58], a growth proliferation receptor found on the surface of normal and 
proliferating endothelial cells [24, 32, 36].   
The antibody is an IgG1 kappa immunoglobulin containing murine variable region sequences 
and human constant region sequences [58].  TRC105 has an approximate molecular weight of 
148 kilodaltons (kDa).  TRC105 has a binding avidity for human endoglin of approximately 5 
pM. TRC105 binds to the endoglin orphan domain and competitively inhibits BMP binding, 
thereby inhibiting SMAD 1/5/8 phosphorylation necessary for endothelial cell activation [29]. 
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 
inhibit the growth of tumor xenografts [37].  Reactivity with carcinoma tissue is restricted to the 
tumor endothelium, as endoglin is not generally expressed on epithelial tumor cells [36].  
TRC105 induces antibody-dependent cell-mediated cytotoxicity (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 HUVECs. Combination therapy was found to be more potent in 
decreasing HUVEC proliferation, migration, and tubular network formation than bevacizumab or 
TRC105 treatment alone [39].  Furthermore, TRC105 induced apoptosis in HUVEC, and 
promotes SMAD2/3 phosphorylation while inhibiting SMAD1/5/8 signaling, thereby inhibiting 
angiogenesis in response to VEGF and basic fibroblast growth factor (FGF) [29]. Finally, 
antibody to mouse endoglin potentiated the activity of multitargeted kinase inhibition that targets 
the VEGFR-2, in mouse bearing cancer xenografts [59].  For these reasons, endoglin blockade 
using TRC105 in combination with VEGF inhibition by pazopanib may provide greater clinical 
benefit than would be seen with either drug alone. 
2.3.1. 
Studies with TRC105  
Several studies with TRC105 are underway or have been completed.  As of the date of this 
report, there have been 10 completed clinical trials of CD105, and four trials are ongoing.  A 
total of 438 patients had been exposed to TRC105 monotherapy or combination therapy, of 
whom 99 received the combination of TRC105 and pazopanib.  For a complete review of clinical 
information, please refer to the current TRC105 Investigational Brochure (IB). 
2.3.1.1. 
Study 105ST101 Phase 1 Monotherapy 
2.3.1.1.1. Study 105ST101 Phase 1 Monotherapy Pharmacokinetics 
In the initial, safety Study 105ST101, TRC105 pharmacokinetics were assessed on patients with 
advanced or metastatic solid tumors (including renal cell, uterine, colorectal, synovial sarcoma, 
prostate, and GIST) enrolled at doses up to 15 mg/kg weekly.  Detailed TRC105 
pharmacokinetics are available from Study 105ST101, the first in human dose escalation study, 

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which explored a broad range of doses (0.01 to 15 mg/kg) and schedules (every 2 weeks and 
weekly).  
Doses of 3 mg/kg, 10 mg/kg and 15 mg/kg dose levels produced measurable serum 
concentrations of TRC105 beyond the initial day of dosing. Volume of distribution at these doses 
was similar to plasma volume, which was consistent with preclinical toxicokinetics and would be 
expected for an antibody administered intravenously. Area under the curve (AUC) exposure 
increased supra-proportionally with dose whereas the maximum concentration (Cmax) appeared 
to be dose proportional. TRC105 clearance was consistent with target mediated disposition, and 
decreased clearance at higher doses was consistent with target saturation. Serum concentrations 
were achieved continuously in most but not all patients at a dose of 15 mg/kg every 2 weeks and 
were achieved continuously in all patients at a dose of 10 mg/kg weekly. TRC105 accumulated 
at a dose of 15 mg/kg weekly. Importantly, as shown in Figure 1, weekly dosing with 10 mg/kg 
produced continuous mean TRC105 serum concentrations above the target concentration of 
25 μg/mL shown to saturate endoglin receptors and produce maximum inhibition of HUVEC 
activation in vitro (i.e., maximal inhibition of SMAD1 phosphorylation in response to BMP). 
Figure 1:  
Single-Dose and Multiple-Dose Pharmacokinetic Data from Study 105ST101 
 
2.3.1.1.2. Study 105ST101 Phase 1 Monotherapy Safety  
A total of 50 patients  with advanced or metastatic solid tumors (including renal cell, uterine, 
colorectal, synovial sarcoma, prostate, and GIST) 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 2 weeks and then 
10 and 15 mg/kg weekly.  Dose escalation proceeded stepwise until the top dose was reached.  
The maximum tolerated dose (MTD) 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 2 

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weeks.  Three of 4 patients at 15 mg/kg weekly developed grade 3 hypoproliferative anemia 
(without leucopenia or thrombocytopenia) in cycle 2, and 1 of the 3 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 endoglin [34].  Anemia was reversible and 
manageable with dose reduction and standard supportive measures including erythropoietin and 
blood transfusion.   
Infusion-related reactions, anemia, fatigue, epistaxis and headache were the most frequently 
observed AEs considered related to TRC105. The majority of treatment-related AEs were grade 
1 or 2. 
Infusion-related reactions were initially reported in the phase 1 study of TRC105 monotherapy 
(105ST101) in patients without premedication who received TRC105 produced in non-secreting 
murine myeloma (NS0) cells. Two of 21 patients treated up to 1.0 mg/kg with NS0 TRC105 drug 
supply experienced infusion-related reactions to TRC105.  Both patients were among 6 treated at 
the 1.0 mg/kg NS0 TRC105 dose level. One patient experienced Grade 2 fever and Grade 1 
chills after the initial infusion of TRC105, which resolved with oral acetaminophen and did not 
recur with acetaminophen premedication on subsequent infusion.  A patient experienced Grade 3 
hypersensitivity (allergic reaction) with the second infusion of TRC105. The hypersensitivity 
reaction consisted of symptomatic bronchospasm, urticaria, and hypotension that required 
parenteral medications and resulted in discontinuation of study treatment. TRC105 produced in 
Chinese hamster ovary (CHO) cells was known to more potently engage ADCC in vitro than 
TRC105 produced in NS0 cells. Because of this, the initial dose level for patients receiving 
CHO-produced TRC105 was de-escalated to 0.3 mg/kg. Despite dose de-escalation, the first 2 
patients at 0.3 mg/kg treated with CHO-produced TRC105 experienced Grade 2 and Grade 3 
infusion-related reactions with the first dose of TRC105 in the absence of premedication (the 
Grade 3 infusion-related reaction included diaphoresis, dyspnea, tachycardia and rigors). The 
Phase 1 105ST101 protocol was therefore amended to require a premedication regimen 
consisting of a glucocorticoid, acetaminophen, famotidine or a similar H2-histamine blocker, and 
an H1-histamine blocker such as diphenhydramine, and extend the initial infusion duration from 
1 to 4 hours. 
Mandating such premedication and extending the duration of the initial TRC105 infusion 
duration successfully reduced the frequency and severity of infusion-related reactions and 
allowed dose escalation to continue in the 105ST101 phase 1 study.  One additional patient who 
received CHO-produced TRC105 at 1 mg/kg developed a Grade 3 infusion-related reaction with 
the third dose given over 2 hours despite premedication. This patient had experienced a Grade 2 
infusion-related reaction when the dose was initially administered over 4 hours with 
premedication.  In all 3 patients with Grade 3 infusion-related reactions, TRC105 was not 
detectable in serum at the time of dosing, which therefore allowed de novo binding of TRC105 to 
CD105 expressing endothelium within the vasculature.  Grade 3 infusion-related reactions were 
not observed in patients dosed at 10 or 15 mg/kg in the Phase 1 105ST101 study who maintained 
TRC105 serum levels known to saturate CD105 binding sites for the full dosing interval.  Only 7 
patients have experienced a Grade 3 and only 1 patient experienced a Grade 4 infusion-related 

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reaction (of vasovagal reaction) out of 462 patients (1.7%) treated with TRC105 since the 
institution of the premedication regimen. For study 105SAR301 premedication will not include 
an H2-histamine blocker, as neutral stomach pH is known to decrease pazopanib exposure by up 
to 40% and H2-histamine blockade is not felt to significantly ameliorate typical signs and 
symptoms of TRC105 infusion-related reactions.  
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 endoglin 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 (DLT) evaluation period.  
Fatigue was one of the more common AEs attributable to TRC105 and was more prevalent at 
doses above 3 mg/kg.   
One patient developed DLT of grade 4 hemorrhage presenting as melena from a gastric ulcer 
within 5 days of the initial TRC105 infusion at 0.1 mg/kg. He discontinued TRC105 treatment, 
was transfused 2 units of packed red blood cells and the bleeding resolved with nonsurgical 
management by the time of upper endoscopy.  Serious bleeding was not observed following 
protocol amendment to exclude patients with a history of peptic ulcer disease (unless healing was 
documented) and patients on ulcerogenic medications including non-steroidal anti-inflammatory 
drugs.  
Classic toxicities associated with VEGF inhibition, including hypertension, proteinuria and 
thrombosis were not prominent.  One patient with recurrent anal cancer treated with TRC105 
0.1 mg/kg developed proteinuria considered a suspected adverse reaction to TRC105, but 
proteinuria was also noted prior to TRC105 dosing. Transient hypertension (156/112 mm Hg) 
without QT interval changes on electrocardiogram 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.    
2.3.1.1.3. Study 105ST101 Phase 1 Monotherapy Efficacy 
In study 105ST101 stable disease ≥ 2 months was observed in 21 of evaluable 45 patients (47%) 
and stable disease ≥ 4 months in 6 of 44 patients (14%) with advanced or metastatic solid 
tumors.  Decreases in carcinoembryonic antigen (CEA), prostate-specific antigen (PSA), or 
cancer antigen 125 (CA-125) were noted in 7 of 21 patients (33%). One patient with castrate-
refractory prostate cancer remains on TRC105 treatment after 8 years at a TRC105 dose of 
0.01 mg/kg every 2 weeks.  He has an ongoing complete PSA response, with resolution of bone 
pain and bone scan normalization. One patient with metastatic carcinosarcoma manifested 
decreased tumor burden on computerized tomographic scanning and maintained stable disease 
for 20 months on therapy. The latter is especially notable when one considers that this patient 
had received 3 prior treatments - carboplatin + paclitaxel for 4 months, anastrozole for 8 months, 

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and ifosfamide for 2 months - and had manifested tumor progression on each.  In effect, TRC105 
provided the most favorable clinical outcome and did so as a fourth-line therapy.   
2.3.1.2. 
Study 105SAR101 Phase 1b/2a with Pazopanib 
2.3.1.2.1. Study 105SAR101 Summary of Safety, Pharmacokinetics, and Immunogenicity 
Study 105SAR101 was a Phase 1b/2 trial evaluating the combination of TRC105 and pazopanib 
in patients with advanced soft tissue sarcoma.  In the Phase 1b dose escalation portion, the safety 
of TRC105 dosed weekly at 8 mg/kg and then 10 mg/kg given with pazopanib at 800 mg taken 
orally daily was evaluated.  Because the single agent pazopanib dose is frequently de-escalated 
during the first month of dosing to ameliorate toxicity, the trial contained a 2- to 4-week run-in 
period of single agent pazopanib treatment, so that a tolerable dose would be determined in each 
patient prior to the introduction of TRC105.  Using this schema, 3 patients were treated with 
TRC105 at 8 mg/kg weekly in and 15 patients were treated at 10 mg/kg weekly in the Phase 1b 
portion of the trial.  There were no DLTs and the addition of TRC105 to pazopanib did not 
increase pazopanib toxicities [20].   
Given the non-overlapping toxicity profile, Investigators recommended concurrent dosing of 
TRC105 with pazopanib starting on day 1 for the Phase 2 portion of the Phase 1b/2 study.  
Safety data from the Phase 2 portion of the trial that enrolled 63 soft tissue sarcoma patients 
indicate that toxicities remain non-overlapping and pazopanib dose adjustment can be made 
based on its product labeling, irrespective of concurrent dosing with TRC105. The toxicity 
profile of TRC105 was similar to that noted in single agent studies, recurrent infusion-related 
reactions were not observed, chronic steroid premedication was not required, and signs of the 
Osler-Weber-Rendu syndrome (e.g., low grade telangiectasia with associated epistaxis and 
gingival bleeding) were observed routinely.  The safety profile for TRC105 in combination with 
pazopanib has been consistent with that observed in other studies of TRC105 where AEs 
characteristic of each individual drug did not increase in frequency or severity, with the possible 
exception of pneumothorax, when the two drugs were administered together.  
AEs commonly (>10%) experienced by patients and believed by the sponsor to be reflective of 
the currently recognized toxicity profile of TRC105 include the following, which were 
predominantly grade 1-2:  epistaxis (grade 1-3), headache (grade 1-3), fatigue (grade 1-3), 
gingival bleeding (grade 1), anemia (grade 1-3), infusion-related reaction (grade 1-3) and 
telangiectasia (grade 1).  Patients also commonly (>10%) experienced the following AEs, judged 
by the investigator as being at least possibly related to TRC105: nausea (grade 1-2), vomiting 
(grade 1-3), flushing (grade 1-2), decreased appetite (grade 1-3), stomatitis (grade 1-2).  One 
grade 4 suspected adverse drug reaction of acute respiratory distress syndrome (ARDS) was 
reported, from which the patient recovered. One suspected adverse drug reaction of grade 2 
transient ischemic attack was reported.  One patient experienced grade 3 colitis, 1 patient 
experienced grade 3 embolism and 1 patient experienced grade 1 bronchopulmonary 
hemorrhage.  
Seven patients treated with the combination of TRC105 and pazopanib experienced a 
pneumothorax, a known adverse reaction associated with the use of pazopanib in soft tissue 
sarcoma. The frequency of pneumothorax was similar to the frequency reported with single agent 

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pazopanib [60, 61]. All 7 patients had lung metastases and grade 3 was the highest grade 
reported. 
At 10 mg/kg weekly, continuous serum concentrations of TRC105 were achieved in 12 of 15 
patients at exposures above the target concentration of 25 µg/mL by the time of the third weekly 
dose (N=15; mean: 97 µg/mL)) and were achieved in 27 of 28 patients at exposures above the 
target concentration of 25 µg/mL by the time of the fifth weekly dose (N=28; mean: 127 µg/mL).  
Notably, trough concentrations were similar following dosing with TRC105 at 10 mg/kg as a 
single agent or with pazopanib. Immunogenicity was rarely observed: 3 patients had samples 
with a moderate to high signal defined as greater than 3 times above the assay cut point. Further, 
steady state pazopanib plasma concentrations when dosed with TRC105 were similar to those 
reported following single agent dosing.   
A TRC105 dose reduction schedule (starting with dose de-escalation to 8 mg/kg weekly) has 
been established to manage drug related toxicity. The majority of patients requiring a dose 
reduction of TRC105 dose reduced to 8 mg/kg weekly. TRC105 dose reductions have resulted in 
observations of improved tolerability and have not compromised response, while maintaining 
TRC105 concentrations necessary to avoid recurrent infusion-related reactions.  All 3 patients 
remain in CR after reducing the TRC105 dose to 8 mg/kg weekly (3 patients) and then to 6 
mg/kg weekly (1 patient). Although there is expected inter-patient and intra-patient variability, 
dose reductions have generally resulted in decreased serum exposures.  For a dose reduction 
from 10 to 8 mg/kg (a 20% reduction in dose), paired before and after data are available for 13 
patients and show a percent reduction in pre-dose concentration by an average of 14% (SD 83%) 
and median 52%.  For dose reduction from 8 to 6 mg/kg (a 25% reduction in dose), paired data 
are available for only 2 patients and show a percent reduction in pre-dose concentration by an 
average of 8% (SD 52%) and median 8%.  One patient required dose reduction to 4 mg/kg 
weekly and remained on study for 5 weeks at the reduced dose. In some cases a dose reduction 
did not decrease TRC105 exposure. The lack of an observed decrease in exposure in patients 
who had dose reduction may reflect decreased endoglin expression, consistent with a reduction 
in tumor burden as a result of treatment response.  Because TRC105 is cleared by target 
mediated disposition, clearance is expected to decrease in patients with lower numbers of 
endoglin-expressing tumor vessels as a consequence of a reduction in tumor burden.  This 
phenomenon may explain the variability and non-linearity of systemic exposure as a function of 
dose level. 
Infusion-related reactions have been rare with repeat dosing in patients who have dose reduced. 
Two patients experienced 1 infusion-related reaction each, which was not observed on 
subsequent infusions: 1 patient on the day of dose reduction and the second patient on day 1 of 
cycle 18.   
2.3.1.2.2. Study 105SAR101 Summary of Efficacy 
Preliminary clinical data from the phase 1b portion of study 105SAR101 demonstrate that the 
combination is well tolerated with signs of clinical activity. Six of 18 soft tissue sarcoma patients 
(33% of those evaluable for efficacy) exhibited >10% tumor reduction by RECIST 1.1, including 
1 patient with cutaneous angiosarcoma that experienced a durable CR that is ongoing for 25 
months as of October, 2016. Duration of therapy ranged from 2 to 27+ cycles (in the phase 1b 

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portion of the study, each cycle was 28 days with the exception of cycle 1, when pazopanib was 
given as a single agent, for 2-4 weeks.  
A total of 5 patients with angiosarcoma were initially treated in the phase 1b and 2a portions of 
study 105SAR101 and all 5 patients had radiographic reductions in tumor volume. Two of these 
5 patients had durable CR (including the patient noted above), 1 cutaneous angiosarcoma patient 
had a 25% reduction in tumor volume before exiting the study at week 10 due to an unrelated AE 
of duodenal ulcer. The other 2 patients, both with visceral angiosarcoma, experienced tumor 
reductions of 7% and 14%. Notably the median PFS in these patients as of June 2016 was greater 
than 12.9 months as assessed by RECIST 1.1. 
Data available from the patients in the angiosarcoma expansion cohorts continue to demonstrate 
activity and tolerability of TRC105 in combination with pazopanib. 
2.4. 
Study 105SAR301 Rationale 
The rationale for combining TRC105 with pazopanib for the treatment of angiosarcoma is three-
fold.  First, several nonclinical studies indicate endoglin is a dominant mechanism of escape 
from VEGF inhibitor therapy.  Pazopanib is a VEGF inhibitor indicated for the treatment of adult 
patients with selective subtypes of advanced STS, including angiosarcoma, who have received 
prior chemotherapy for metastatic disease or who have progressed within 12 months following 
(neo) adjuvant therapy.  Nonclinical and preliminary clinical data suggest that targeting the 
endoglin pathway and VEGF pathway concurrently is a more effective means of inhibiting 
angiogenesis than targeting either pathway alone; accordingly, the combination of TRC105 and 
pazopanib may be a more effective means of treating sarcoma compared to single agent 
pazopanib.  Second, endoglin is expressed densely on tumor cells in angiosarcoma, a malignancy 
of endothelial cells, providing an additional mechanism of direct targeting of cancer cells (in 
addition to targeting proliferating tumor vasculature). Finally, because they target distinct 
pathways, the toxicity profile of TRC105 and pazopanib are non-overlapping and the drugs have 
been tolerable when given concurrently for more than 24 months. 
Clinical data from Phase 1b/2 study 105SAR101 validate the biological rationale, in that robust 
activity, including durable complete responses, was observed in angiosarcoma. The combination 
of the recommended TRC105 dose of 10 mg/kg weekly with standard dose pazopanib was also 
shown to be well tolerated.  Importantly, the tolerability of the combination allows for extended 
dosing durations in contrast to more toxic chemotherapy regimens. 
2.5. 
Population to be Studied 
Patients with histologically-confirmed angiosarcoma that is not amenable to curative intent 
surgery (e.g., metastatic or bulky disease and disease for which surgical resection would carry an 
unacceptable risk to the patient) who have not received pazopanib or TRC105 previously will be 
enrolled in this trial.   
Due to the rarity of angiosarcoma, and lack of standard of care for patients 12 to 17 year of age, 
these patients, who are eligible only after enrollment in Cohort 1 is complete, will not be 
randomized and will receive only the combination TRC105 and pazopanib treatment. 

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2.6. 
Potential Risks and Benefits to Human Patients 
Please refer to the current TRC105 Investigational Brochure (IB) for a complete review of 
potential risks and benefits of TRC105. 
2.6.1. 
Potential Risks 
2.6.1.1. 
TRC105 
Common (≥ ~10%) TRC105 suspected AEs 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 hypoproliferative and non-hemolytic in nature, reversible with interruption of 
treatment, and may be managed with transfusion, erythropoietin or darbepoetin, and other 
interventions as appropriate. Anemia may also be related to blood loss from epistaxis or gingival 
bleeding that result from mucocutaneous telangiectasia. 
Infusion-related reactions have been observed following TRC105 administration and may 
include one or more of the following signs or symptoms: rigors, chills, flushing, headache, 
bronchospasm, urticaria, fever, rash, dyspnea, nausea, vomiting, change in blood pressure, and 
change in heart rate.  Infusion-related reactions generally occurred with the initial infusion in 
patients dosed at recommended phase 2 doses of 10 mg/kg or 15 mg/kg every 2 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-related 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 AE associated with the use of pazopanib, 
particularly in sarcoma patients with lung metastases. However, pneumothorax was observed in 
1 patient, also with lung metastases, receiving single-agent TRC105. 
2.6.1.2. 
Pazopanib 
The most common adverse reactions in patients with advanced soft tissue sarcoma (≥ 20%) are  
fatigue, diarrhea, nausea, decreased weight, hypertension, decreased appetite, hair color changes, 
vomiting, tumor pain, dysgeusia, headache, musculoskeletal pain, myalgia, gastrointestinal pain, 
and dyspnea..  

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Further details are available in the current product labeling for pazopanib, such as the current 
package insert. 
2.6.1.3. 
Other Study 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 breast-
feed while on this study.  Women of childbearing potential must have a negative serum 
pregnancy test before taking part in this study. 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 acceptable methods of birth control, one of which must be highly effective (see 
below), at the same time during study treatment (including during temporary breaks from 
treatment), and for at least 180 days after stopping TRC105 or pazopanib.  Men with pregnant 
partners and men with non-pregnant partners that are of childbearing potential must agree to use 
a condom with spermicide, during study treatment (including during temporary breaks from 
treatment), and for at least 180 days after stopping TRC105 or pazopanib. The long term risk of 
infertility is unknown.  Ovarian failure has been observed with other antiangiogenic agents.  
Acceptable birth control methods considered highly effective are the following: 
 bilateral tubal ligation 
 intrauterine device (IUD) 
 vasectomy that has received medical confirmation of surgical success 
 Sexual abstinencea 
aIn the context of this protocol, sexual abstinence is considered a highly effective method of birth control only if 
refraining completely from heterosexual intercourse during the entire period of risk (i.e., during study treatment, 
including during temporary breaks from treatment, and for at least 180 days after stopping TRC105 or pazopanib). 
If sexual abstinence is the highly effective method of birth control used, a second acceptable method is not 
required.  
Acceptable birth control methods not considered highly effective include the following: 
 male or female condom with spermicidea 
 cap, diaphragm or sponge with spermicide 
aA female condom and a male condom should not be used together as friction between the two can result in either 
product failing. 
2.6.2. 
Potential Benefits 
TRC105 is an investigational product, and its efficacy has not been established.  Although not 
approved specifically for angiosarcoma, pazopanib is approved in the United States for the 
treatment of patients with advanced soft tissue sarcoma (including angiosarcoma) who have 
received prior chemotherapy and approved in Europe for adult patients with selective subtypes of 
advanced soft tissue sarcoma (including angiosarcoma) who have received prior chemotherapy 
for metastatic disease or who have progressed within 12 months after (neo) adjuvant therapy. 
Together, the use of TRC105 with pazopanib may result in more effective angiogenesis 
inhibition and improved clinical efficacy over that seen with pazopanib alone. 

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2.7. 
Study Conduct 
This study will be conducted in accordance with Good Clinical Practice (GCP), as defined by the 
International Conference on Harmonisation (ICH) and in accordance with the ethical principles 
underlying the European Union Directive 2001/20/EC and the United States Code of Federal 
Regulations (CFR), Title 21, Part 50 (21CFR50). 
The study will be conducted in compliance with the protocol. The protocol and any protocol 
amendments and the subject informed consent must receive Institutional Review 
Board/Independent Ethics Committee (IRB/IEC) approval/favorable opinion prior to initiation of 
the study. 

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3. 
TRIAL OBJECTIVES AND ENDPOINTS 
3.1. 
Primary Objective  
 To compare PFS of TRC105 and pazopanib vs single agent pazopanib in patients 
with unresectable angiosarcoma 
3.2. 
Secondary Objectives 
 To compare the objective response rate (ORR) of TRC105 and pazopanib vs single 
agent pazopanib in patients with unresectable angiosarcoma 
 To compare overall survival (OS) of TRC105 and pazopanib vs single agent 
pazopanib in patients with unresectable angiosarcoma 
 To assess the overall safety and tolerability of TRC105 and pazopanib vs single agent 
pazopanib in patients with unresectable angiosarcoma 
 To characterize patient reported outcomes between the two arms of the study    
 To characterize the pharmacokinetic (PK) profile of TRC105 and pazopanib between 
the two arms of the study 
 To assess PFS and ORR by Investigator assessment between the two arms of the 
study 
 To characterize the immunogenicity of TRC105 
3.3. 
Exploratory Objectives 
 To correlate efficacy endpoints (e.g., PFS, ORR and OS) with endoglin expression on 
angiosarcoma tumor samples 
 To correlate efficacy endpoints (e.g., PFS, ORR and OS) with circulating angiogenic 
protein biomarkers  
 To correlate efficacy endpoints (e.g., PFS, ORR and OS) with numbers of endoglin 
expressing circulating tumor cells (CTCs) 

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4. 
TRIAL ENDPOINTS 
4.1. 
Primary Endpoint  
 PFS is defined as time from randomization to either first disease progression (per 
independent radiology review of images by RECIST 1.1) or death from any cause.  
For the purpose of analysis for patients who are alive at the time of analysis and have 
not had disease progression, the following rules will apply:  (1) The patient will be 
censored on the date of the last tumor assessment documenting absence of 
progressive disease; (2) if the patient was given antitumor treatment other than study 
drug treatment, the patient will be censored as of the date of the last tumor assessment 
prior to initiating that antitumor therapy; (3) if the patient was removed from study 
for toxicity or other reason, the patient will be censored as of the date of the last 
tumor assessment on study. With regard to missed tumor assessments, in the event of 
one missed tumor assessment followed by a subsequent assessment of progressive 
disease (PD), the subsequent PD assessment qualifies as objective tumor progression. 
In the event of more than one consecutive missing tumor assessment followed by a 
subsequent assessment of PD, the patient will be censored at the last adequate tumor 
assessment. 
4.2. 
Secondary Endpoints  
 Objective response rate (ORR) is defined as the number of patients with a best 
response of CR or PR divided by the number of randomized patients. ORR is defined 
as the best response designation recorded between the date of randomization and the 
date of documented progression, as determined by Central Radiographic Review 
according to RECIST 1.1, or date of subsequent therapy, whichever occurs first. For 
patients without documented progression or subsequent therapy, all available 
response designations will contribute to the ORR determination. A designation of CR 
or PR in this study requires confirmation at a subsequent consecutive assessment at 
least 4 weeks following the initial designation of CR or PR, respectively. Duration of 
response (DR) will be reported in patients who achieve ORR, but without a formal 
statistical comparison between arms. 
 Overall Survival (OS) is defined as the time between the date of randomization and 
the date of death from any cause.  Overall survival will be calculated in days as: Date 
of Death – Date of Randomization +1.  Subjects alive or lost to follow-up at the time 
of analysis will be censored at the date when they were last known to be alive. 
 Type, incidence, severity (graded by NCI CTCAE, Version 4.03), timing, 
seriousness, and relatedness of AEs and laboratory abnormalities. 
 Patient reported outcomes as measured by the EuroQol five dimensions questionnaire 
(EQ-5D-5L) and the EORTC QLQ-C30 questionnaire. 
 TRC105 and pazopanib concentrations will be measured using validated methods 
from peak and trough samples. 

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 Anti-TRC105 antibodies will be measured using validated methods and anti-drug 
antibody (ADA) titers will be correlated with PK parameters and AEs. 

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5. 
INVESTIGATIONAL PLAN 
5.1. 
Overall Study Design and Plan 
This is a multinational, multicenter, randomized, open label, parallel group, phase 3 study of 
TRC105 in combination with standard dose pazopanib compared to pazopanib alone in patients 
with angiosarcoma not amenable to curative intent surgery (e.g., metastatic or bulky disease and 
disease for which surgical resection would carry an unacceptable risk to the patient) who have 
not received pazopanib or TRC105 previously.  
Adult patients will be randomized in a 1:1 ratio to TRC105 in combination with standard dose 
pazopanib (Arm B) vs standard dose pazopanib alone (Arm A). Patients will be stratified by 
angiosarcoma type (cutaneous vs non-cutaneous) and the number of lines of prior systemic 
therapy for angiosarcoma (0 versus 1 or 2). For the purposes of this study, cutaneous 
angiosarcoma will include primary skin/scalp angiosarcoma; all other angiosarcoma including 
primary subcutaneous angiosarcoma will be categorized as non-cutaneous (e.g., visceral, bone, 
soft tissue). 
Due to possible differences in treatment effect on the cutaneous and non-cutaneous 
angiosarcoma subgroups, an adaptive enrichment design will be employed. An interim analysis 
is planned after 40 events or 30 days after the enrollment of 120 patients from Cohort 1 and will 
result in one of the following decisions: (1) no change to the study design and sample size, (2) no 
change to the study design but an increase in the sample size, or (3) termination of enrollment of 
an unresponsive non-cutaneous angiosarcoma subtype and adjustment of the sample size of the 
remaining cutaneous subtype. Cohort 1 is defined as the adult patients enrolled prior to the 
interim analysis.  Enrollment at a given site will be limited to a maximum of 15% of total 
patients. Additionally, enrollment of Cohort 1 will be monitored to ensure that no more than 50% 
of the total adult patients enrolled will have the non-cutaneous subtype. 
Treatment in the assigned arm must start within 3 calendar days of randomization.  
Figure 2: 
Trial Design Schema 
 
 
 
5.1.1. 
Overview 
All patients must sign a consent form (and assent if under 18) prior to undertaking any protocol-
specified procedures.  Prospective patients will be screened to determine if they qualify for the 

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study within 28 days of randomization. Treatment in the assigned arm must start within 3 days of 
randomization. Toxicities will be graded according to the NCI CTCAE Version 4.03.   
All adult and adolescent patients with a BSA > 1.8 m2 will initially receive pazopanib 800 mg 
p.o. daily either as single agent or in combination with TRC105. All other patients 12-17 years of 
age, who are eligible for only Cohort 2, must weigh ≥ 40 kg at study enrollment will initially 
receive pazopanib 600 mg p.o. daily in combination with TRC105.  The dose of TRC105, 
administered in the combination treatment arm with pazopanib (Arm B) will be the same for 
patients of all ages, and consist of TRC105 at 3 mg/kg on day 1, 7 mg/kg on day 4, and 10 mg/kg 
on day 8 and weekly thereafter. 
Dose reductions of pazopanib 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 3 and Table 4).  
5.1.2.1. 
Screening 
The following screening procedures must be performed within 28 days prior to the first day of 
study therapy and will be performed according to the Schedule of Assessments (Table 3 and 
Table 4), with data collected in the eCRFs (except for data pertaining to central radiographic 
review).  
 Patient signature on current IRB/EC-approved informed consent form.  Prior to 
undergoing any study-specific procedure, patients must read and sign the current 
IRB/EC-approved informed consent form.  Patients may sign consent (and assent if under 
18) prior to the 28-day screening period. 
 Medical history, baseline signs and symptoms, prior cancer therapy (along with the best 
response to each prior chemotherapy regimen and the reason for discontinuation of each 
regimen), prior cancer surgery, prior radiation therapy, the suspected cause of the 
angiosarcoma (to the extent it may be known or suspected), the specific reason the 
angiosarcoma tumor is considered not amenable to surgery, drug allergies, primary 
diagnosis and demographics. 
 Physical examination including examination of all major body systems, Eastern 
Cooperative Oncology Group (ECOG) performance status, and vital signs. 
 Hematology (including serum iron, transferrin and ferritin), coagulation (INR) and serum 
chemistry (including thyroid stimulating hormone [TSH]) to be performed locally. 
 Serum pregnancy test for all females of childbearing potential to be performed locally. 
 Urinalysis (e.g., dipstick) to be performed locally.  Microscopic analysis and/or urine 
protein-creatinine ratio (UPCR) should be performed as clinically indicated. 
 All patients: Computerized tomography (CT) or magnetic resonance imaging (MRI) 
scans of chest, abdomen and pelvis in addition to any other applicable sites of disease 
within 7 days of randomization. Brain and bone scans to be performed prior to starting 
the study if metastasis is suspected.  

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 Patients with cutaneous tumors: digital 2-dimensional (2D) color photography will be 
used to assess cutaneous lesions.  
 12-lead electrocardiogram (ECG) in triplicate (QTc, 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.  
 Tumor Tissue Specimens: angiosarcoma tumor specimen for each study participant. See 
Section 10.1.5 and separate laboratory guide for further collection and shipment 
information. 
 Patient questionnaires to characterize quality of life to be collected prior to 
randomization. 
 Pediatric patients: plain films (anterior-posterior and lateral) of right and left distal 
femur to evaluate the epiphyseal plates 
5.1.2.2. 
Trial Period 
Screening radiographic and photographic assessments, qualifying hematology (including iron 
studies), blood chemistry (including TSH testing), coagulation, urinalysis, physical examination, 
ECG, pregnancy test and quality of life questionnaires do not need to be repeated on cycle 1 day 
1 (C1D1) if acceptable screening assessments are performed within 7 days prior to 
randomization.  Following randomization, C1D1 lab results do not need to re-meet eligibility 
criteria. However, lab abnormalities should be corrected as needed, per the investigator 
discretion, prior to treatment initiation. On days of TRC105 administration for patients assigned 
to Arm B, all assessments should be performed prior to dosing with TRC105 unless otherwise 
indicated in the Schedule of Assessments (Table 4).  
Patients who cannot tolerate pazopanib or TRC105 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 single agent therapy may continue on study on TRC105 or 
pazopanib alone. The following will be performed according to the Schedule of Assessments 
(Table 3 and Table 4), with data collected in the eCRFs (except for data pertaining to central 
radiographic review). 
 Physical examination (may be performed up to 3 days prior to day 1 of each cycle) 
including examination of all major body systems, ECOG performance status, weight and 
vital signs (heart rate, temperature, blood pressure, respiratory rate).  
 Assessment of vital signs during TRC105 infusion (Arm B): 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-related reaction that has not 
yet resolved).  

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 Hematology, coagulation (INR) and serum chemistry (including TSH) to be performed 
locally. 
 Serum pregnancy test for all females of childbearing potential to be performed locally. 
 12-lead ECG in triplicate (QTc, PR and QRS intervals and heart rate will be captured). 
 In case of prolongation of QTc interval > 500 msec, pazopanib will be held and 
appropriate investigations will be performed (e.g., cardiologist consultation, 
repeat ECG, continuous ECG monitoring, etc.).  Rechallenge with pazopanib will 
be guided by cardiology input and will require authorization by TRACON. 
 Urinalysis (e.g., dipstick) to be performed locally. Microscopic analysis and/or urine 
protein-creatinine ratio (UPCR) should be performed as clinically indicated. 
 Blood sampling for TRC105 and pazopanib pharmacokinetics to be analyzed by a central 
laboratory (see laboratory manual for specific instructions regarding collection times, 
procedures, processing, storage and shipment). 
 Blood sampling for immunogenicity to be analyzed by a central laboratory (see 
laboratory manual for specific instructions regarding collection, processing, storage and 
shipment). 
 Blood sampling for protein biomarker analysis by a central laboratory (see laboratory 
manual for specific instructions regarding collection processing, storage and shipment) 
 Blood sampling for CTCs by a central laboratory (see laboratory manual for specific 
instructions regarding collection processing, storage and shipment) 
 All patients: CT or MRI scans of chest, abdomen and pelvis in addition to any other 
applicable sites of disease for all patients. Scan of the chest, abdomen, and pelvis to be 
performed on-study as outlined in the Schedule of Assessments. 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 studies 
is +/- 7 days. Brain scans to be performed if metastasis is detected prior to starting the 
study or if suspected during study conduct.   
 Patients with cutaneous tumors: digital 2D color photography will be used to assess 
cutaneous lesions.  Assessment of cutaneous lesions to be performed as outlined in the 
Schedule of Assessments. Known areas of disease should be consistently followed 
throughout the study.  Assessments should be performed whenever disease progression is 
suspected.  Allowable window is +/- 7 days. 
 Tumor assessments will continue to be collected on protocol schedule for all patients who 
come off study drug for reasons other than RECIST 1.1 defined PD until RECIST 1.1 
defined PD or start of a new therapy. 
 Administration of TRC105 for patients in Arm B. TRC105 diluted in normal saline will 
be administered as a 1 to 4 hour infusion (+/- 15 minutes) following premedication (see 
Section 7.1.6) according to the Schedule of Assessments.  
 Pazopanib dosing. The oral dose of pazopanib is 800 mg for adult and for adolescent 
patients with a BSA > 1.8 m2 and 600 mg for all other patients < 18 year of age (who 

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must weight ≥ 40 kg at study enrollment) once daily, in the evening except on cycle 1 
day 15 per the footnote in the Schedule of Assessments, when the patient will be 
administered the pazopanib dose for that day in the clinic, without food (recommend 
at least 1 hour before or 2 hours after a meal) beginning on cycle 1 day 1. 
 Patient questionnaires to characterize quality of life will be collected at the time points 
indicated in the Schedule of Assessments. 
 Assessment of AEs. 
 Assessment of concomitant medications and concomitant treatments. 
 Pediatric patients: plain films (anterior-posterior and lateral) of right and left distal 
femur to evaluate the epiphyseal plates. 
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 6 weeks on study for radiologic/photographic tumor assessments).  The following will be 
performed according to the Schedule of Assessments (Table 3 and Table 4), with data collected 
in the eCRFs (except for data pertaining to central radiographic review). 
 Physical examination including examination of all major body systems, ECOG 
performance status, and vital signs. 
 12-lead ECG in triplicate (QT, PR and QRS intervals and heart rate will be captured). 
 Hematology, and serum chemistry (including TSH) to be performed locally. 
 Urinalysis (e.g., dipstick) to be performed locally.  Microscopic analysis and/or urine 
protein-creatinine ratio (UPCR) should be performed as clinically indicated. 
 Blood sampling for TRC105 and pazopanib pharmacokinetics to be analyzed by a central 
laboratory (see laboratory manual for specific instructions regarding collection times, 
procedures, processing, storage and shipment). 
 Blood sampling for immunogenicity to be analyzed by a central laboratory (see 
laboratory manual for specific instructions regarding collection, processing, storage and 
shipment). 
 Blood sampling for protein biomarker analysis by a central laboratory (see laboratory 
manual for specific instructions regarding collection processing, storage and shipment) 
 All patients: CT or MRI scans of chest, abdomen and pelvis in addition to any other 
applicable sites of disease.   
 Patients with cutaneous tumors: digital 2D color photography should be used to assess 
cutaneous lesions.   
 Tumor assessments will continue to be collected on protocol schedule for all patients 
who come off study drug for reasons other than RECIST 1.1 defined PD until 
RECIST 1.1 defined PD or start of a new therapy. 

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 Assessment of AEs. 
 Assessment of concomitant medications and concomitant treatments. 
 Pediatric patients: plain films (anterior-posterior and lateral) of right and left distal 
femur to evaluate the epiphyseal plates. 
5.1.4. 
Post-Treatment Follow-up 
The following will be performed according to the Schedule of Assessments (Table 3 and 
Table 4), with data collected in the eCRFs (except for data pertaining to central radiographic 
review).  Samples should be collected and assessments performed even if new anti-cancer 
therapy commences during the follow-up period.  
 Assessment of AEs. The Investigator should continue to report any study treatment 
related or suspected AEs that occur beyond the AE reporting period. 
 Blood sampling for TRC105 and pazopanib pharmacokinetics will be analyzed by a 
central laboratory (see laboratory manual for specific instructions regarding collection 
times, procedures, processing, storage and shipment). 
 Blood sampling for immunogenicity to be analyzed by a central laboratory (see 
laboratory manual for specific instructions regarding collection, processing, storage and 
shipment). 
 Serum pregnancy test for all females of childbearing potential to be performed locally. 
 Assessment of concomitant medications and concomitant treatments. 
 Overall Survival follow-up via telephone or routine visit should occur every 3 months 
following the last dose of TRC105 or pazopanib until death.   
 
 
 
 

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Table 3: 
Schedule of Assessments Arm A: Single Agent Pazopanib 
Protocol Activities 
Screening 
Cycle 1 [25] 
Cycle 2 [25] 
Cycle 3+ [22] [25] 
End 
of 
Treatment 
[3] 
28-Day 
Follow-
up [23] 
Overall 
Survival  
[24] 
Day -28 
Day 1  
[1] [2] 
Day 8 
[1] 
Day 15  
[1] 
Day 1  
[1] 
Day 8  
[1] 
Day 15 
[1] 
Day 1  
[1] 
Day 8  
[1] 
Day 15 
[1] 
Baseline Documentation 
 
Informed Consent [4] 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/Oncology History [5] 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Baseline Signs and Symptoms [5] 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination [6] 
X 
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 
 
X 
X 
 
 
X 
 
 
X 
 
 
Coagulation [8] 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Blood Chemistry [8] 
X+TSH 
X+TSH 
 
X 
X+TSH 
 
 
X+TSH 
 
 
X+TSH 
 
 
Pregnancy Test [9] 
X 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
Urinalysis [10] 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Treatment w/ Study Drug 
 
Pazopanib [11] 
 
Daily 
 
 
 
Tumor Assessments 
 
Tumor Imaging [12] 
X 
Every 42 days from randomization 
X 
 
 
2D Photography [13] 
X 
Every 42 days from randomization 
X 
 
 
Other Clinical Assessments 
 
12-Lead ECG [14] 
X 
X 
 
X 
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 
 
Special Laboratory Assessments 
 
Pazopanib PK [17]  
 
 
 
X 
X 
 
 
Even 
Cycles 
 
 
X 
X 
 
Protein Biomarkers [18] 
 
X 
 
 
X 
 
 
Even 
Cycles 
 
 
X 
 
 
CTCs [19] 
 
X 
 
 
 
 
 
Cycle 3 
 
 
 
 
 
Archival Tumor Tissue [20] 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Other Assessments 
 
Patient Reported Outcomes [21] 
Day -7 
 
 
 
 
 
 
C3, C4 & 
C5 
 
 
 
 
 
Overall Survival  
 
Phone Call  [24] 
 
 
 
 
 
 
 
 
 
 
 
 
Every 3 
Months 
 
Patients randomized to receive pazopanib alone (Arm A) are required to complete clinic visits only on Days 1 beyond Cycle 2 (starting with Cycle 3). Adverse events 
and concomitant medications/treatments assessments can be completed via documented phone call.  
 

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Arm A Schedule of Assessments Footnotes  
1. Clinic Visit Days: All assessments should be performed prior to pazopanib dosing unless otherwise indicated.  Each cycle is 21 days in duration. If 
pazopanib dosing is held, all other required assessments should still be performed in accordance with the schedule of assessments.  
2. Cycle 1 day 1: Treatment must start within 3 calendar days of randomization. C1D1 activities should be completed prior to beginning study drug 
treatment.  Hematology (including iron studies), blood chemistry (including TSH testing), urinalysis, physical examination, ECG, pregnancy test and quality 
of life questionnaires 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 (EOS) visit should generally occur within 7 days (+/- 2 days) of the last dose of study drug. Assessments other than 
pharmacokinetics, and protein biomarkers do not need to be repeated if performed within the previous 2 weeks (previous 6 weeks for 
radiologic/photographic tumor assessments). Follow-up visits should occur 28 days following the last dose of 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; may be performed up to 3 days prior to clinic visit date.  
7. Vital Signs: Heart rate, temperature, blood pressure, respiratory rate, weight.  
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 only if screening assessments were performed more than 7 days prior to cycle 
1 day 1.  Iron studies (Fe: serum iron, ferritin, transferrin) 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 clinic visit. In addition to the assessments scheduled for the clinical trial, patients should 
undergo assessment as appropriate to ensure safe treatment. See Section 9.1.1.1 for specific panel collection requirements.  
9. Pregnancy Test: Testing to be performed locally. All female patients of childbearing potential must have a negative serum pregnancy test within 7 days 
prior to cycle 1 day 1, day 1 of every cycle and 28 days following the last dose of pazopanib. 
10. Urinalysis: To be performed locally. Cycle 1 day 1 urinalysis (e.g., dipstick) 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. Pazopanib Dosing: Oral pazopanib will be dosed once daily in the evening at 800 mg starting on cycle 1 day 1 in the absence of toxicity on days 1-21 of 
each 21-day cycle according to the pazopanib package insert.  Dose reductions are allowed based on individual patient tolerability beginning with cycle 1. 
See Section 7.2 for specific dosing guidelines.  
12. Tumor Imaging: All patients will undergo radiographic imaging. CT or MRI scans of chest, abdomen, and pelvis with contrast to be performed at screening 
within 7 days prior to randomization and every42 days from the date of randomization (+/- 7 days). If subjects are unable to receive CT contrast due to CT 
contrast medium allergy or renal insufficiency, enhanced MRI scans may be used. A combination of non-contrast CT and MRI studies (such as chest CT 
without contrast and abdominal MRI with contrast) may be used. The same method of assessment must be used throughout the course of the study thereafter.  
Similarly, if a subject develops a contraindication to CT contrast during the course of the study; assessments may shift to non-contrast CT of the chest and 
contrast-enhanced MRI of the abdomen for subsequent scans.  In addition, a brain MRI or CT with contrast to be performed at screening and on study as 
needed if metastases are suspected. A bone scan is to be performed at screening if bone metastases is suspected. If a bone scan documents bone disease at 
baseline, it needs to be repeated only when complete response is identified or progression in bone is suspected. All other known areas of disease should be 
consistently followed throughout the study.  Assessments should be performed whenever disease progression is suspected. A designation of CR or PR in 
this study requires confirmation at a subsequent consecutive assessment separated by at least 4 weeks following the initial designation of CR or PR, 

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respectively. Tumor imaging will continue to be collected on protocol schedule for all patients who come off study drug for reasons other than 
RECIST 1.1 defined PD until RECIST1.1 defined PD or start of a new therapy. Allowable window for tumor imaging studies is +/- 7 days.   
13. 2D photography: Patients with cutaneous tumors will undergo digital 2D color photography in addition to radiographic imaging, which will be performed at 
screening within 7 days prior to randomization and every 42 days from the date of randomization (+/- 7 days). Screening assessment will be centrally 
reviewed in real time. Assessments should be performed whenever disease progression is suspected. 2D photography will continue to be collected on 
protocol schedule for all patients who come off study drug for reasons other than RECIST 1.1 defined PD until RECIST1.1 defined PD or start of a new 
therapy Allowable window is +/- 7 days.  
14. 12-Lead ECG:  Three consecutive 12-lead ECGs at least 2 minutes apart will be performed at screening, cycle 1 day 1 (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), cycle 1 day 15, day 1 of cycle 2 and EOS. Note: on cycle 
1 day 15 pazopanib dosing will occur in the clinic and ECGs will then be performed no sooner than 2 hours following pazopanib dosing (at the time 
of expected Cmax).  However, pazopanib dosing should not be repeated if the patient dosed within 12 hours at home. On the ECG assessment on day 1 
of cycle 2, dosing in the clinic is not required.  If the patient develops an arrhythmia, the ECG should be repeated on day 1 of each subsequent cycle. In case 
of prolongation of QTc interval > 500 msec, pazopanib will be held and appropriate investigations will be performed (e.g., cardiologist consultation, repeat 
ECG, continuous ECG monitoring, etc.).  Rechallenge with pazopanib will be guided by cardiology input and will require authorization by TRACON.  
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 through 28 days following the last dose of study treatment.  
16. Adverse Events: The AE reporting period for this trial begins with informed consent and ends following the completion of the 28-day-follow-up visit or at 
least 28 days after the last dose of pazopanib is administered, whichever occurs later.  All AEs that occur in trial patients during the AE reporting period 
must be reported to TRACON, whether or not the event is considered study treatment-related. 
17. Pazopanib Pharmacokinetics: A 5 mL blood sample for pazopanib concentration to be collected at the time-points indicated in the Schedule of 
Assessments. In addition, on cycle 1 day 15 pazopanib dosing will occur in the clinic to assess Cmax and the sample should be collected no sooner than 
2 hours following pazopanib dosing. However, pazopanib dosing should not be repeated if the patient dosed within 12 hours at home. On the 
pazopanib pharmacokinetic assessment on day 1 of cycle 2, pazopanib dosing in the clinic is not required.   Samples will be stored at approximately -70°C. 
Samples will be batch shipped as indicated in the laboratory manual to a central 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 or after dose reductions.  
18. Protein Biomarkers: One 10 mL purple top (K2EDTA) 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. 
19. CTCs: One 10 mL EDTA tube will be collected at the time-points indicated in the Schedule of Assessments and be analysed by a central laboratory. See 
separate laboratory guide for further collection and shipment information. 
20. Archival Tumor Tissue: Tumor specimens (formalin-fixed, paraffin-embedded) of the primary cancer and/or metastatic cancer specimen for each study 
participant, if available. See Section 10.1.5  and separate laboratory guide for further collection and shipment information. 
21. Patient Reported Outcomes: Patient questionnaires to characterize quality of life will be collected at the time-points indicated in the Schedule of 
Assessments. Baseline assessment must be completed prior to randomization.  
22. Cycle 3+ Treatment: Patients who demonstrate a response of CR, PR or SD will be eligible for additional treatment until progression. 
23. 28-Day Follow-up: The follow-up visit should occur 28 days following the last dose of pazopanib. The allowable visit window is +/- 7 days.  
24. Overall Survival:  Telephone or routine visit should occur every 3 months following the last dose of TRC105 until death.  Allowable window for each visit 
is +/- 1 week. 

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25. Allowable window for each visit within the cycle is +/- 2 days unless otherwise stated. The +/-2 day window does NOT apply to randomization. Cycle 1 
day 1sets the clock for study visits, and all study visits should be scheduled in reference to cycle 1 day 1. For example, if cycle 1 day 1 was on June 1st, and 
patient is not able to return for C1D8 until June 10th the C1D15 visit should take place on June 15th (15 days from cycle 1 day1).  
 
 

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Clinical Study Protocol: 105SAR301 
 
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Table 4: Schedule of Assessments Arm B: TRC105 plus Pazopanib Combination Therapy 
Protocol Activities 
Screening 
Cycle 1 [28] 
Cycle 2 [28] 
Cycle 3+ [25] [28] 
End 
of 
Treatment 
[3] 
28 -
Day 
Follow
-up[26] 
Overall 
Survival  
[27] 
Day -28 
Day 1  
[1] [2] 
Day 4 
[1] 
Day 8 
[1] 
Day 15  
[1] 
Day 1  
[1] 
Day 8  
[1] 
Day 15 
[1] 
Day 1  
[1] 
Day 8  
[1] 
Day 15 
[1] 
Baseline Documentation 
 
Informed Consent [4] 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/Oncology History [5] 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Baseline Signs and Symptoms [5] 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination [6] 
X 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
Vital Signs [7] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Laboratory Studies 
 
Hematology [8] 
X+Fe 
X 
 
 
X 
X 
 
 
X 
 
 
X 
 
 
Coagulation [8] 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Blood Chemistry [8] 
X+TSH 
X+TSH 
 
 
X 
X+TSH 
 
 
X+TSH 
 
 
X+TSH 
 
 
Pregnancy Test [9] 
X 
X 
 
 
 
X 
 
 
X 
 
 
X 
X 
 
Urinalysis [10] 
X 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
Treatment w/ Study Drug 
 
TRC105 Dosing [11] 
 
X Split 
X Split 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Pazopanib [12] 
 
Daily 
 
 
 
Tumor Assessments 
 
 
Tumor Imaging [13] 
X 
Every 42 days from randomization 
X 
 
 
2D Photography [14] 
X 
Every 42 days from randomization 
X 
 
 
Other Clinical Assessments 
 
Pediatric radiographic imaging 
[30] 
X 
Every 42 days from enrollment via the randomization system 
X 
 
 
12-Lead ECG [15] 
X 
X 
 
 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
Medications/Treatments [16] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Adverse Events [17] 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Special Laboratory 
Assessments 
 
Anti-TRC105 Antibody [18] 
 
X 
 
 
 
X 
 
 
Even Cycles 
 
 
X 
X 
 
TRC105 PK: pre-infusion [19] 
 
 
X 
X 
X 
X 
 
X 
Even Cycles 
 
 
 
 
 
TRC105 PK: end of infusion [19] 
 
X 
X 
X 
 
 
 
 
 
 
 
X 
X 
 
Pazopanib PK: pre-infusion [20]  
 
 
 
 
X 
X 
 
 
Even Cycles 
 
 
X 
X 
 
Pediatric PK [29] 
 
X 
X 
X 
X 
X 
 
X 
Even Cycles 
 
 
X 
X 
 
Protein Biomarkers [21] 
 
X 
 
 
 
X 
 
 
Even Cycles 
 
 
X 
 
 
CTCs [22] 
 
X 
 
 
 
 
 
 
Cycle 3 
 
 
 
 
 
Tumor Tissue [23] 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Other Assessments 
 
Patient Reported Outcomes [24] 
Day -7 
 
 
 
 
 
 
 
C3, C4 & C5 
 
 
 
 
 

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Overall Survival  
 
Phone Call [27] 
 
 
 
 
 
 
 
 
 
 
 
 
 
Every 3 
Months 
Arm B Schedule of Assessments Footnotes  
1. Days of Treatment with TRC105: All assessments should be performed prior to TRC105 infusion and pazopanib dosing unless otherwise indicated.  Each 
cycle is 21 days in duration. If TRC105 dosing is held, all other required assessments should still be performed in accordance with the Schedule of 
Assessments.  
2. Cycle 1 day 1: Treatment must start within 3 calendar days of randomization. C1D1 activities should be completed prior to beginning study drug 
treatment except for vital signs after start of infusion. Hematology (including iron studies), blood chemistry (including TSH testing), urinalysis, physical 
examination, ECG, pregnancy test and quality of life questionnaires 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 (EOS) visit should generally occur within 7 days (+/- 2 day) of the last dose of study drug. Assessments other than 
pharmacokinetics, immunogenicity and protein biomarkers do not need to be repeated if performed within the previous 2 weeks (previous 6 weeks for 
radiologic/photographic tumor assessments). Follow-up visits should occur 28 days following the last dose of 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; may be performed up to 3 days prior to clinic visit date.  
7. Vital Signs: Heart rate, temperature, blood pressure, respiratory rate, weight. Assessment 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-related 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: serum iron, ferritin, transferrin) 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 9.1.1.1 for specific panel collection requirements.  
9. Pregnancy Test: Testing to be performed locally. All female patients of childbearing potential must have a negative serum pregnancy test within 7 days 
prior to cycle 1 day 1, day 1 of every cycle and 28 days following the last dose of TRC105. 
10. Urinalysis: To be performed locally. Cycle 1 day 1 urinalysis (e.g., dipstick) 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 weekly 
dose of TRC105 (10 mg/kg) is then given on cycle 1 day 8 and weekly thereafter. See Section 7.1.6  for specific TRC105 administration guidelines. 
12. Pazopanib Dosing: Oral pazopanib will be dosed once daily in the evening at 800 mg for adult and for adolescent patients with a BSA > 1.8 m2, and at 600 
mg for all other patients <18 yrs of age (who must weigh ≥ 40 kg at study enrollment), starting on cycle 1 day 1 in the absence of toxicity on days 1-21 of 
each 21-day cycle according to the pazopanib product labelling.  Dose reductions are allowed based on individual patient tolerability beginning with cycle 1. 
See Section 7.2  for specific dosing guidelines.    

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13. Tumor Imaging: All patients will undergo radiographic imaging. CT or MRI scans of chest, abdomen, and pelvis with contrast to be performed at 
screening, within 7 days prior to randomization and every 42 days from the date of randomization (+/- 7 days). If subjects are unable to receive CT contrast 
due to CT contrast medium allergy or renal insufficiency, enhanced MRI scans may be used. A combination of non-contrast CT and MRI studies (such as 
chest CT without contrast and abdominal MRI with contrast) may be used. The same method of assessment must be used throughout the course of the study 
thereafter.  Similarly, if a subject develops a contraindication to CT contrast during the course of the study; assessments may shift to non-contrast CT of the 
chest and contrast-enhanced MRI of the abdomen for subsequent scans.  In addition, a brain MRI or CT with contrast to be performed at screening and on 
study as needed if metastases are suspected. A bone scan is to be performed at screening if bone metastases is suspected. If a bone scan documents bone 
disease at baseline, it needs to be repeated only when complete response is identified or progression in bone is suspected. All other known areas of disease 
should be consistently followed throughout the study.  Assessments should be performed whenever disease progression is suspected. A designation of CR 
or PR in this study requires confirmation at a subsequent consecutive assessments separated by at least 4 weeks following the initial designation of 
CR or PR, respectively. Tumor imaging will continue to be collected on protocol schedule for all patients who come off study drug for reasons other 
than RECIST 1.1 defined PD until RECIST 1.1 defined PD or start of a new therapy. Allowable window for tumor imaging studies is +/- 7 days. 
14. 2D photography: Patients with cutaneous tumors will undergo digital 2D color photography in addition to radiographic imaging, which will be performed 
at screening within 7 days prior to randomization and every 42 days from the date of randomization (+/- 7 days). Screening assessment will be centrally 
reviewed in real time. Assessments should be performed whenever disease progression is suspected. 2D photography will continue to be collected on 
protocol schedule for all patients who come off study drug for reasons other than RECIST 1.1 defined PD until RECIST1.1 defined PD or start of a new 
therapy Allowable window is +/- 7 days.  
15. 12-Lead ECG: Three consecutive 12-lead ECGs at least 2 minutes apart will be performed at screening, cycle 1 day 1 (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.) cycle 1 day 15, day 1 of cycle 2, and EOS. Note: on 
cycle 1 day 15 pazopanib dosing should occur in the clinic (prior to TRC105 pre-medications and infusion) and ECGs will then be performed 
following completion of the TRC105 infusion and no sooner than 2 hours following pazopanib dosing (at the time of expected Cmax). However, 
pazopanib dosing should not be repeated if the patient dosed within 12 hours at home. On day 1 of cycle 2, pazopanib dosing in the clinic is not 
required and ECGs may be performed prior or following TRC105 dosing.  If the patient develops an arrhythmia, the ECG should be repeated on day 1 of 
each subsequent cycle. In case of prolongation of QTc interval > 500 msec, pazopanib will be held and appropriate investigations will be performed 
(e.g., cardiologist consultation, repeat ECG, continuous ECG monitoring, etc.).  Rechallenge with pazopanib will be guided by cardiology input and will 
require authorization by TRACON. Additional ECGs may be performed on study as clinically indicated.  
16. Concomitant Medications and Treatments: Concomitant medications and treatments will be recorded from 28 days prior to the start of study treatment 
and through 28 days following the last dose of study treatment. Required TRC105 premedications should be recorded on TRC105 premedications CRF. 
17. Adverse Events: The AE reporting period for this trial begins with informed consent and ends following the completion of the 28-day follow-up visit or at 
least 28 days after the last dose of pazopanib or TRC105 study drug is administered, whichever occurs later. All AEs that occur in trial patients during the 
AE reporting period must be reported to TRACON, whether or not the event is considered study treatment-related.  
18. Anti-TRC105 Antibodies: 5 mL blood sample will be collected to assess Anti-TRC105 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 central laboratory. See separate laboratory guide for further collection and shipment information. Additional Anti-TRC105 Antibody samples may also 
be collected at the time of unexpected clinical events. 
19. TRC105 Pharmacokinetics Concentration: A 5 mL blood sample for TRC105 pharmacokinetics to be collected at the time-points indicated in the 
Schedule of Assessments. Pre infusion: if an acceptable window time is required to be stated, it is recommended that the samples be obtained no earlier than 
6 hours prior to the start of the infusion. Post infusion: Sample should be collected 15 minutes after the completion of the infusion (including the flush), 
there is a +/- 15 minute window. A separate IV line is not required for PK blood draws if the IV line has been adequately flushed, the same line can be used 
for infusions and PK sampling. Samples will be stored at approximately -70°C. Samples will be batch shipped as indicated in the laboratory manual to a 
central 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.  

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20. Pazopanib Pharmacokinetics: A 5 mL blood sample for pazopanib concentration to be collected at the time-points indicated in the Schedule of 
Assessments prior to starting the TRC105 infusion. In addition, on cycle 1 day 15 pazopanib dosing will occur in the clinic to assess Cmax and the sample 
should be collected no sooner than 2 hours following pazopanib dosing. However, pazopanib dosing should not be repeated if the patient dosed 
within 12 hours at home. On the pazopanib pharmacokinetic assessment on day 1 of cycle 2, pazopanib dosing in the clinic is not required. 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 or after dose 
reductions. 
21. Protein Biomarkers: One 10 mL purple top (K2EDTA) 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. 
22. CTCs: One 10 mL EDTA tube will be collected at the time-points indicated in the Schedule of Assessments and be analysed by a central laboratory. See 
separate laboratory guide for further collection and shipment information. 
23. Archival Tumor Tissue: Tumor specimens (formalin-fixed, paraffin-embedded) of the primary cancer and/or metastatic cancer specimen for each study 
participant, if available. See Section 10.1.5 and separate laboratory guide for further collection and shipment information. 
24. Patient Reported Outcomes: Patient questionnaires to characterize quality of life will be collected at the time-points indicated in the Schedule of 
Assessments. Baseline assessment must be completed prior to randomization. 
25. Cycle 3+ Treatment: Patients who demonstrate a response of CR, PR or SD will be eligible for additional treatment until progression. 
26. Follow-up:  The follow-up visit should occur 28 days following the last dose of TRC105 or pazopanib, whichever occurs later. Allowable visit window is 
+/- 7 days.  
27. Overall Survival: Telephone or routine visit should occur every 3 months following the last dose of TRC105 until death.  Allowable window for each visit 
is +/- 1 week. 
28. Allowable window for each visit within the cycle is +/- 2 days unless otherwise stated. The +/-2 day window does NOT apply to randomization. Cycle 1 day 
1sets the clock for study visits, and all study visits should be scheduled in reference to cycle 1 day 1. For example, if cycle 1 day 1 was on June 1st, and 
patient is not able to return for C1D8 until June 10th the C1D15 visit should take place on June 15th (15 days from cycle 1 day1).  
29. Pediatric PK:  TRC105: A 5 mL blood sample for TRC105 pharmacokinetics to be collected on cycle 1 day 1 and cycle 2 day 15 predose, 5 minutes post-
dose and 1, 2 and 4 hours post-dose. On cycle 1 day 4, cycle 1 day 8, cycle 1 day 15, and cycle 2 day 1 samples will be collected predose and 5 minutes post-
dose.  Following this, samples will be collected pre-dose only day 1 of cycle 3 and subsequent even cycles.  Trough concentrations will also be collected at 
the end of study visit and the 28-day follow-up visit. Samples will be stored at approximately -70°C. Samples will be batch shipped as indicated in the 
laboratory manual to a central 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. Pazopanib: A 5 mL blood sample for pazopanib pharmacokinetics to be collected on cycle 1 day 4, cycle 
1 day 8, cycle 1 day 15, cycle 2 day 1 and day 1 of even cycles prior to starting the TRC105 infusion.  Trough concentrations will also be collected at the end 
of study visit and the 28-day follow-up visit. On cycle 1 day 15 pazopanib dosing will occur in the clinic; however, pazopanib dosing should not be repeated 
if the patient dosed within 12 hours at home. Sample should be collected no sooner than 2 hours following pazopanib dosing. On the pazopanib 
pharmacokinetic assessment on day 1 of cycle 2, pazopanib dosing in the clinic is not required. 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. 
30. Pediatric radiographic imaging:  Plain films (AP and lateral) of the right and left distal femur to evaluate the epiphyseal growth plates. Pediatric patients 
will automatically be assigned to Arm B however they still need to be enrolled via the randomization system.  
 
 
 

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6. 
SELECTION AND WITHDRAWAL OF PATIENTS 
6.1. 
Study Population 
6.1.1. 
Inclusion Criteria 
1. Histologically-confirmed angiosarcoma that is not amenable to curative intent surgery 
(e.g., metastatic or bulky disease and disease for which surgical resection would carry an 
unacceptable risk to the patient).  Pathology report will be reviewed by sponsor prior to 
randomization. 
2. Documented progression on or following most recent systemic chemotherapy regimen 
(not required for chemotherapy-naïve patients), within 4 months prior to screening 
3. Measurable disease by RECIST v1.1 
4. Age of 18 years or older; in addition, patients age 12 to 17 years may enroll beginning in 
Cohort 2 if weight ≥ 40 kg 
5. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1 
6. Resolution of all acute AEs resulting from prior cancer therapies to National Cancer 
Institute Common Terminology Criteria for Adverse Events version 4.03 (NCI CTCAE 
v4.03) grade ≤ 1 or to that patient’s pre-study baseline (except alopecia or neuropathy)  
7. Adequate organ function as defined by the following criteria: 
 Serum aspartate transaminase (AST; serum glutamic oxaloacetic transaminase 
[SGOT]) and serum alanine transaminase (ALT; serum glutamic pyruvic 
transaminase [SGPT]) ≤ 2.5 x upper limit of normal (ULN) or ≤ 5 x ULN in cases of 
liver metastases 
 Total serum bilirubin ≤ 1.5 x ULN 
 Absolute neutrophil count (ANC) ≥ 1500/μL  
 Platelets ≥ 100,000/μL (without transfusion support within 28 days prior to 
randomization) 
 Hemoglobin ≥ 9.0 g/dL (without transfusion support within 14 days prior to 
randomization; erythropoietin or darbepoetin permitted) 
 Serum creatinine ≤ 1.5 times the upper limit of normal or creatinine clearance 
> 30 mL/min by Cockcroft-Gault formula 
 International normalized ratio (INR) ≤ 1.2 unless the patient is receiving a direct 
Factor Xa inhibitor 
8. Willingness and ability to consent (and assent if under age 18) for self to participate in 
study 
9. Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests, 
and other study procedures   

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10. Angiosarcoma tumor specimen, if available 
11. Men who are sterile (including vasectomy confirmed by post vasectomy semen analysis) 
OR agree to use a condom with spermicide (refer to Section 2.6.1.3) and to not donate 
sperm during the study and for at least 180 days following last dose of TRC105 or 
pazopanib. 
12. 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 acceptable methods of birth control, one of which must be highly 
effective, during the study and for at least 180 days after stopping TRC105 or pazopanib 
(refer to Section 2.6.1.3).   
6.1.2. 
Exclusion Criteria 
1. Prior treatment with TRC105 
2. Prior treatment with any VEGF inhibitor 
3. More than two prior lines (may be combination regimens) of chemotherapy for 
angiosarcoma (neoadjuvant/adjuvant treatment does not count as a line of treatment) 
4. Current treatment or participation active on another therapeutic clinical trial 
5. Women who are pregnant or breastfeeding 
6. Receipt of systemic anticancer therapy, including investigational agents, within 5 times 
the agent’s elimination half-life or 14 days of starting study treatment, whichever is 
shorter 
7. Major surgical procedure or significant traumatic injury within 4 weeks prior to 
randomization and must have fully recovered from any such procedure or injury; planned 
surgery (if applicable) or the anticipated need for a major surgical procedure within the 
next six months. Note: the following are not considered to be major procedures and are 
permitted up to 7 days before randomization: Thoracentesis, paracentesis, laparoscopy, 
thoracoscopy, tube thoracostomy, bronchoscopy, endoscopic ultrasonographic 
procedures, mediastinoscopy, skin biopsies, and imaging-guided biopsy for diagnostic 
purposes 
8. Patients who have received wide field radiotherapy ≤ 28 days (defined as > 50% of 
volume of pelvic bones or equivalent) or limited field radiation for palliation < 14 days 
prior to randomization  
9. Uncontrolled hypertension defined as systolic > 150 or diastolic > 100 mm Hg on the 
average of the 3 most recent BP readings. Anti-hypertensives may be started prior to 
randomization.  
10. Ascites or pleural effusion requiring intervention or that required intervention or recurred 
within three months prior to randomization 

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11. Pericardial effusion (except trace effusion identified by echocardiogram) within three 
months prior to randomization 
12. 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 prior to 
randomization 
13. Angina, myocardial infarction, symptomatic congestive heart failure, cerebrovascular 
accident, transient ischemic attack, arterial embolism, pulmonary embolism, 
percutaneous transluminal coronary angioplasty (PTCA) or coronary artery bypass graft 
(CABG) within 6 months prior to randomization. Deep venous thrombosis within 3 
months prior to randomization unrelated to a central venous catheter, unless the patient is 
anti-coagulated without the use of warfarin for at least 2 weeks prior to randomization. In 
this situation, low molecular weight heparin or a direct Factor Xa inhibitor is preferred 
14. Active bleeding or pathologic condition that carries a high risk of bleeding (e.g., 
hereditary hemorrhagic telangiectasia).  Patients with bleeding cutaneous lesions not 
actively requiring transfusions are eligible. Patients who have been uneventfully anti-
coagulated with a direct Factor Xa inhibitor or low molecular weight heparin are eligible 
15. Hemoptysis (> ½ teaspoon [2.5 mL] of bright red blood) within 6 months prior to 
randomization 
16. Thrombolytic use (except to maintain i.v. catheters) within 10 days prior to 
randomization 
17. Known active viral or nonviral hepatitis or cirrhosis 
18. Peptic ulcer within the past 3 months of treatment, unless treated for the condition and 
complete resolution has been documented by esophagogastroduodenoscopy (EGD)  
19. Presence of tumor(s) invading into the heart or great vessels (including carotid artery) or 
another location where bleeding is associated with high morbidity including patients with 
primary cardiac or great vessel angiosarcoma  
20. Gastrointestinal perforation or fistula in the 6 months prior to randomization unless 
underlying risk has been resolved (e.g., through surgical resection or repair) 
21. Presence of a malabsorption syndrome, gastrointestinal disorder, or gastrointestinal 
surgery that could affect the absorption of pazopanib 
22. History of prior malignancy except adequately treated basal cell or squamous cell skin 
cancer or adequately treated, with curative intent, cancer from which the patient is 
currently in complete remission per Investigator’s judgment; patients with history of 
breast cancer and no evidence of disease on hormonal therapy to prevent recurrence and 
patients with prostate cancer on adjuvant hormonal therapy with undetectable PSA are 
eligible 
23. Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome 
(AIDS) related illness 

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24. Active infection that requires systemic treatment 
25. Concurrent use or receipt of a strong CYP3A4 inducer within 12 days prior to 
randomization or a strong CYP3A4 inhibitor within 7 days prior to randomization (see 
Table 10) 
26. History of severe hypersensitivity reaction to any monoclonal antibody 
27. Other severe acute or chronic medical (including bone marrow suppressive diseases) or 
psychiatric condition or laboratory abnormality that may increase the risk associated with 
study participation, impede the ability of the patient to complete all protocol-specified 
activities, or may interfere with the interpretation of study results and, in the judgment of 
the Investigator, would make the patient inappropriate for this study 
6.2. 
Patient Withdrawal Criteria 
Patients are eligible for treatment until disease progression, unacceptable toxicity or withdrawal 
of consent, or other reasons.  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 confirmed by central radiographic review. 
2. A need for surgery, radiation, or for other anticancer therapy not permitted under this 
protocol. 
3. Lost to follow-up or substantial noncompliance with the protocol. 
4. Pregnancy. Pregnant patients should be followed for the duration of the pregnancy and 
the outcome of the pregnancy should be documented. 
5. Arterial thrombosis of any grade (including that causing cerebrovascular ischemia, 
cardiac ischemia/infarction, or peripheral or visceral arterial ischemia) or grade 4 venous 
thrombosis (including grade 4 pulmonary thromboembolism).   
6. Missed study drug treatment for > 8 consecutive weeks (i.e., both TRC105 and pazopanib 
dosing if assigned to the combination arm or pazopanib if assigned to the pazopanib 
alone arm). Patients in the combination arm who cannot tolerate pazopanib or TRC105 
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 single agent therapy may continue on study on TRC105 or pazopanib alone.  
6.2.1. 
Withdrawal of Consent 
Patients who request to discontinue study treatment will remain in the study and must continue to 
be followed for protocol-specified follow-up procedures. The only exception to this is when a 
patient specifically withdraws consent for any further contact with him/her or persons previously 
authorized by the patient to provide this information. Patients should notify the Investigator of 
the decision to withdraw consent from future follow-up in writing, whenever possible. The 
withdrawal of consent should be explained in detail in the medical records by the Investigator, as 
to whether the withdrawal is from further treatment with study drug only or also from study 
procedures and/or post-treatment follow-up, and entered in the appropriate case report form 

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(CRF) page. In the event that vital status (whether patient is alive or dead) is being measured 
publicly available data should be used to determine vital status only as appropriately directed in 
accordance with local law. 

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7. 
STUDY TREATMENTS 
7.1. 
Description of TRC105 Study Drug 
TRC105 (carotuximab) is a genetically engineered human/murine chimeric monoclonal antibody 
directed against human endoglin found on the surface of proliferating endothelial cells and tumor 
cells of some tumor types.   
7.1.1. 
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.  
7.1.2. 
TRC105 Dose Level 
Each patient will be dosed with 10 mg/kg up to a maximum dose of 850 mg of TRC105 for 
women and 1,000 mg of TRC105 for men (i.e., 85 kg for women and 100 kg for men is the 
maximum weight that should be used for purposes of dose calculation on this study).  
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. There is no body weight limit for enrollment purposes except for 
patients < 18 years of age (ages 12-17), who must weigh ≥ 40 kg at the time of study 
enrollment.  
The dose of TRC105, administered in the combination treatment arm with pazopanib (Arm B) 
will be the same for patients of all ages. The first weekly dose will be split into 2 doses whereby 
3 mg/kg will be administered on cycle 1 day 1 and the balance will be administered on cycle 1 
day 4.  The entire weekly dose of TRC105 (10 mg/kg) is then given on cycle 1 day 8 and weekly 
thereafter (Table 5). 
7.1.3. 
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 (25 mg TRC105/mL) in one or more of 
the following presentations.  
200 mg TRC105/8 mL single-use vial 
400 mg TRC105/16 mL single-use vial 
7.1.4. 
TRC105 Storage and Shipping 
TRC105 must be stored between 2°C and 8°C (36°F to 46°F) and protected from light. 
7.1.5. 
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 

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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. 
 For a 70 kg patient, for example: (70 kg x 10 mg/kg)/(25 mg/mL) = 28 mL of TRC105 
product to be administered (i.e., 28 mL from the total of 32 mL from two 16-mL vails) 
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. 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 TRC105 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 must 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 has 
not been completely infused within 8 hours of preparation (i.e., the prepared infusion has been 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). 
7.1.6. 
TRC105 Administration 
Patients should be encouraged to drink abundant fluid (e.g., two 8 ounce glasses of water or 
juice) prior to the first treatment.  Intravenous 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.  
In order to ameliorate the signs and symptoms of infusion-related reactions to TRC105, 
which are believed to be due to an ADCC mechanism of action with release of cytokines, 
the administration of the following TRC105 premedication regimen, including the 
methylprednisolone infusion, should be completed at least 30 minutes and no more than 2 
hours prior to the start of TRC105 infusion as indicated below (see Table 5):   
 Acetaminophen 650 mg p.o. x 1 or paracetamol 1000 mg p.o. x 1 (analgesic and 
antipyretic given as prophylaxis for fever and headache) 
 Methylprednisolone 100 mg i.v. will be given prior to the cycle 1 day 1 and cycle 1 day 4 
infusions (glucocorticoid given as prophylaxis for signs and symptoms of infusion-related 
reactions, including bronchospasm, urticaria, fever, and rash).  Methylprednisolone may 
be discontinued starting with cycle 1 day 8 in the absence of infusion-related reaction 
with the prior dose.  

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 Cetirizine 10 mg i.v. or p.o. x 1 (or similar oral or intravenous H1-antihistamine) 
(H1-histamine antagonist given as prophylaxis for signs and symptoms of infusion-
related reactions, including bronchospasm, urticaria, fever, rash, and flushing).  Cetirizine 
(or similar oral or intravenous H1-antihistimine) may be discontinued starting with Cycle 
2, in the absence of infusion-related reactions with the prior dose. 
 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. 
As a precaution, resuscitation equipment should be immediately available at the location where 
TRC105 is being infused. 
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.   
Following the appropriate premedication regimen, the first weekly TRC105 dose will be split 
into 2 administrations whereby 3 mg/kg is administered on cycle 1 day 1 over 4 hours (+/- 15 
minutes) and the balance (e.g., 7 mg/kg) is administered on day 4 over 2 hours (+/- 15 minutes).  
Do not increase the infusion rate above 25 mg/min.  Thereafter, the full dose of 10 mg/kg 
TRC105 dose will be administered i.v. weekly over 1 hour (+/- 15 minutes).   
Patients must complete at least one 4-hour infusion without the development of any infusion-
related reactions in order to reduce the duration of the subsequent TRC105 infusion to 2 hours 
(+/- 15 minutes) and, in turn, complete a 2-hour infusion without the development of any 
infusion-related reactions in order to reduce the duration of the subsequent TRC105 infusions to 
1 hour (+/- 15 minutes). See Table 5 for ideal dosing schemas.  Patients with infusion-related 
reactions of any kind should be managed appropriately (see Section 7.1.8) and are not 
permitted to reduce the duration of the next planned infusion. 
The rate of TRC105 infusion must not exceed 25 mg/min.  When the i.v. bag containing TRC105 
is empty, flush the i.v. line with sufficient saline to clear the tubing.  The dose level, time of 
transfer to i.v. bag, and the infusion start and stop times must be recorded in the source 
documents. 

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Table 5: 
TRC105 10 mg/kg Weekly Initial Administration Schema 
Cycle/Day 
C1D1 
C1D4 
C1D8 
C1D15 
C2D1 + 
TRC105 Dose (mg/kg) 
3 
7 
10 
10 
10 
Infusion Duration (hours) 
4 
2 
1 
1 
1 
Premedication 
Methylprednisolone (mg) i.v. 
100 
100 
0 
0 
0 
Cetirizine (mg) i.v. or p.o. 
(or similar H1-antihistamine) 
10 
10 
10 
10 
0 
Acetaminophen (mg) p.o. 
650 
650 
650 
650 
650 
CYCLE 2 AND BEYOND: TRC105 premedication regimen should be reinstituted if a patient 
develops an infusion-related reaction grade ≥ 2 in association with the immediate prior infusion. 
Premedication, with the exception of acetaminophen, can be discontinued over time in the 
absence of subsequent infusion-related reaction. 
7.1.7. 
TRC105 Dose Delay and Modification 
TRC105 dose reductions and delays should be avoided, if possible.  TRC105 dose must be held 
for grade 3 or 4 related AEs. When the event improves to grade 1 or to the patient’s pre-study 
baseline (including anemia), TRC105 may be resumed at a reduced dose (with the exception of 
infusion-related reactions, which will not trigger dose reductions because infusion-related 
reactions could be exacerbated by dose reductions). Treatment dose delays cannot exceed 8 
consecutive weeks (i.e., both TRC105 and pazopanib dosing held for patients in Arm B or 
pazopanib alone if in Arm A). However, patients who cannot tolerate pazopanib or TRC105 
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 single agent 
therapy may continue on study on TRC105 or pazopanib alone per Section 6.2.  
TRC105 (and pazopanib) should be held for at least 1week prior to scheduled surgery, the 
decision to resume treatment after surgery should be based on clinical judgment of adequate 
wound healing. Port placement prior to treatment initiation does not require a 7 day wait period; 
treatment can be initiated as early as the following day.  
TRC105 DOSING DELAY:  If a patient misses a weekly TRC105 dose and dosing is resumed 
≥ 10 days after the last dose, premedication and TRC105 is administered as described in Table 6. 
Split dosing is not required. However, it is recommended that if the patient experienced a severe 
headache with a previous infusion, the initial dose is split over 2 days and Table 5 is followed for 
premedication and TRC105 infusion. 
The Schedule of Assessment should be followed with regards to visits, labs, and any other 
required assessments even if TRC105 dosing is held (Table 4). In cases of dosing delay of 
more than 3 weeks, hematology results within  3 weeks of dosing resumption should be known 
and within the specified protocol eligibility criteria prior to resuming treatment.  In addition, in 
cases of dosing delay of more than 6 weeks, chemistry (including TSH) results within  6 weeks 
of dosing resumption should also be known and within the specified protocol eligibility criteria 
prior to resuming treatment.  

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Table 6: 
TRC105 10 mg/kg Weekly Administration after Missed Dose 
Cycle/Day 
CxDy 
(1st dose 
after missed 
dose) 
CxDy 
(2nd dose 
after missed 
dose) 
CxDy 
(3rd dose 
after missed 
dose) 
CxDy 
(4th dose 
after missed 
dose) 
TRC105 Dose (mg/kg) 
10 
10 
10 
10 
Infusion Duration (hours) 
4 
2 
1 
1 
Premedication 
 
Methylprednisolone (mg) i.v. 
100 
100 
0 
0 
Cetirizine (mg) i.v. or p.o. 
(or similar H1-antihistamine) 
10 
10 
10 
0 
Acetaminophen (mg) p.o. 
650 
650 
650 
650 
Table 7: 
Allowable TRC105 Dose Modifications 
Toxicity Attributed to TRC105 
Dose Adjustment for Next Dose of TRC105  
Dose Schedule/Level 
10 mg/kg weekly 
Grade 1 or 2 
Maintain Dose Level 
Grade 3a or 4a 
 
 
1st appearance 
8 mg/kg weekly 
 
2nd appearance 
6 mg/kg weekly 
 
3rd appearance 
4 mg/kg weekly 
 
4th appearance 
Discontinue TRC105 treatment permanently 
aPatients with Grade 3 infusion-related reactions do not need to dose reduce, because infusion-related reactions 
could be exacerbated by dose reductions.  Patients with Grade 4 infusion-related reactions should discontinue 
TRC105 treatment (see Table 8). 
See Section 9.3.5 (Table 12) for AE grading scale.  
Patients with any grade arterial thrombosis or grade 4 venous thrombosis should be discontinued 
from study treatment.  Patients with grade 1-3 venous thrombosis who require anticoagulation 
will have their TRC105 therapy interrupted.  TRC105 therapy for such patients may resume once 
the following criteria are met:   
 The patient is on a stable dose of heparin or low molecular weight heparin.  
 The patient has a platelet count > 100,000. 
 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 (e.g., no evidence of disease 
progression). 

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7.1.8. 
Management of TRC105 Infusion-Related 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-related reactions, the infusion may be 
restarted at half of the previous rate if and when the infusion-related reaction has resolved, and 
then increased per patient tolerance to a maximum of 25 mg/min.  For grade 4 infusion-related 
reactions, the infusion should not be restarted and the patient should be discontinued from 
TRC105 treatment.  Infusion-related reactions will be recorded as AEs in the CRF.  
The list below provides a representative, but not exhaustive, list of some potential infusion-
related adverse reactions, and any other event considered as an infusion-related event should be 
reported in the CRF if they occur within 24 hours following completion of the infusion: 
 
Rigors/Chills  
 
 
 
 
 
 
Pruritus 
 
 
Anaphylactic reaction and symptoms  
Urticaria 
Nausea 
 
 
 
 
 
 
 
 
Flushing 
Vomiting  
 
 
 
 
 
 
 
Rash (specify location and aspect) 
Tachycardia 
 
 
 
 
 
 
 
Hypertension/Elevated BP 
Bradycardia 
 
 
 
 
 
 
 
Hypotension/Decreased BP 
Tachypnea  
 
 
 
 
 
 
 
Headache 
Dyspnea  
 
 
 
 
 
 
 
Fever 
Wheezing  
 
 
 
 
 
 
 
Pain low back  
Bronchospasm  
 
 
 
 
 
 
Oedema/Swelling (specify location, e.g. swollen lips) 
Anaphylactoid reaction and symptoms 
Cytokine release syndrome and symptoms 
Arthralgias 
 
 
 
 
 
 
 
Diaphoresis 
Myalgias  
 
 
 
 
 
 
 
Dizziness/Syncope 
Angioedema  
 
 
 
 
 
 
Purpura 
 
 
Interventions should be documented as concomitant medications or concomitant treatments as 
appropriate.   

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Table 8: 
Management of TRC105 Infusion-Related Reactions 
Infusion-Related 
Reaction Severity 
Recommended Management 
Grade 1 (mild) 
1. No intervention 
2. Continue infusion unless symptoms worsen 
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 treatment unless other factors that contributed to the 
infusion-related reaction are identified and corrected 
Grade 4 (life-
threatening) 
1. Discontinue infusion 
2. Treat with symptomatic medicationsa 
3. Hospitalize patient 
4. Discontinue TRC105 treatment 
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). Resuscitation equipment should be immediately available at the location where 
TRC105 is being infused. 
7.1.9. 
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. 
7.1.10. 
TRC105 Study Drug Handling and Disposal 
TRC105 vials must be stored between 2°C and 8°C (36°F to 46°F) and protected from light. The 
Investigator should not return or destroy 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 

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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. 
7.2. 
Description of Pazopanib 
See the current approved product label.  
7.2.1. 
Composition of Pazopanib 
See the current approved product label.  
7.2.2. 
Pazopanib Dose Level 
The initial dose is pazopanib 800 mg for adult and for adolescent patients with a BSA > 1.8 m2 
and at 600 mg for patients < 18 year of age (who must weigh ≥ 40 kg at study enrollment) p.o. 
once daily starting on cycle 1 day 1.   
7.2.3. 
Pazopanib Packaging and Labeling 
See the current approved product label. 
7.2.4. 
Pazopanib Storage Handling and Disposal 
See the current approved product label. 
7.2.5. 
Pazopanib Dosing 
The starting dose of pazopanib for adult and adolescent patients with a BSA >1.8 m2 is 800 mg 
orally once daily, in the evenings, without food (recommend at least 1 hour before or 2 hours 
after a meal). The dose of pazopanib will not exceed 800 mg. For all other patients < 18 years of 
age (who must weigh ≥ 40 kg at study enrollment) the starting dose of pazopanib is 600 mg 
orally once daily in the evenings.  All patients age 12 to 17 year of age, who are eligible only for 
Cohort 2, will not be randomized and will receive treatment with TRC105 and pazopanib.  
Pazopanib dose reductions are allowed based on individual patient tolerability. 
Do not crush tablets due to the potential for increased rate of absorption, which may affect 
systemic exposure. 
If it is confirmed, by the patient, that a pazopanib tablet has been vomited, that amount of 
pazopanib can be re-dosed.   
If a dose is missed, it should not be taken if it is less than 12 hours until the next dose. 
7.2.6. 
Pazopanib Dose Modification 
Dose adjustments and management of side effects of pazopanib should be guided at least in part 
by the applicable current approved product labeling.  Dose increase or reduction is recommended 
based on individual safety and tolerability.  Decrease or increase should be in 200-mg steps 
based on individual tolerability.  The dose of pazopanib will not exceed 800 mg for adult and for 
adolescent patients with a BSA >1.8 m2 and not exceed 600 mg for all other patients < 18 years 
of age, who must weigh ≥ 40 kg at study enrollment. If a dose is missed, it should not be taken if 
it is less than 12 hours until the next dose.  

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In case of prolongation of QTc interval > 500 msec, pazopanib will be held and appropriate 
investigations will be performed (e.g., cardiologist consultation, repeat ECG, continuous ECG 
monitoring, etc.).  Rechallenge with pazopanib will be guided by cardiology input and will 
require authorization by TRACON. 
The Schedule of Assessments should be followed with regards to visits, labs, and any other 
required assessments even if dosing is held (Table 3 and Table 4). 
7.2.7. 
Pazopanib Drug Accountability 
Patients will be asked to return any unused tablets from the previous cycle for proper drug 
accountability and destruction according to institution guidelines. A new prescription will be 
dispensed for the following cycle.  
Investigators must maintain an accurate accounting of pazopanib lots used for this trial.  During 
the study, the following information must also be recorded if TRACON provides the pazopanib: 
 Date of purchase, quantity and lot number  
 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 
Drug Accountability Logs should be maintained by the site and must be readily available for 
inspection. 
7.3. 
Concomitant Medications 
No approved or investigational anticancer treatment other than the 2 study drugs (i.e., TRC105 
and pazopanib) 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. 
Narcotic analgesics, acetaminophen, nonsteroidal anti-inflammatory drugs, and triptans 
(e.g., sumatriptan) may be offered as needed for relief of pain or headaches. Ketorolac may be 
used prophylactically following the initial dose of TRC105 to reduce the frequency and severity 
of headache that often occurs the evening following completion of the initial TRC105 dose.  H1-
antihistamines and decongestants may be offered for the treatment of conditions such as sinus 
congestion.  
Packed red blood cells, colony stimulating factors, and platelet transfusions should be 
administered as clinically indicated for anemia, neutropenia, and thrombocytopenia, respectively.  
QT Prolongation and torsades de pointes: pazopanib should be used with caution in patients with 
a history of QT interval prolongation, in patients taking antiarrhythmics or other medications that 
may prolong QT interval, and those with relevant pre-existing cardiac disease.  
Table 9 provides a representative but not exhaustive list of medications known to prolong QT 
interval.  

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Table 9: Examples of Drugs Prolonging QT interval and/or Inducing Torsades de Pointesa 
aA continuously updated list of these drugs is available at www.torsades.org (accessed December 16, 2012). CNS: 
Central Nervous System. 
Consistent with the product labeling for pazopanib, in general, short-acting antacids should be 
considered in place of proton pump inhibitors and H2-histamine receptor antagonists 
(e.g., famotidine) for patients taking pazopanib to avoid the risk of reducing pazopanib exposure. 
Class 
Generic Name 
Anesthetic 
Sevoflurane 
Anti-anginal 
Ranolazine, Bepridil 
Anti-arrhythmic 
Sotalol, Quinidine, Amiodarone, Ibutilide, Disopyramide, Procainamide, Flecainide, 
Dofetilide, Dronedarone 
Antibiotic 
Moxifloxacin, Clarithromycin, Ciprofloxacin, Gemifloxacin, Ofloxacin 
Telithromycin, Levofloxacin, Roxithromycin, Trimethoprim-Sulfa, Gatifloxacin, 
Sparfloxacin, Azithromycin Erythromycin 
Anti-cancer 
Tamoxifen, Lapatinib, Nilotinib, Arsenic trioxide, Eribulin, Sunitinib, Vandetanib 
Anti-convulsant 
Fosphenytoin, Felbamate 
Anti-depressant 
Mirtazapine, Citalopram, Venlafaxine, Paroxetine, Fluoxetine, Sertraline, 
Trazodone, Escitalopram, Clomipramine, Amitriptyline, Imipramine, Nortriptyline, 
Desipramine, Doxepin, Trimipramine, Protriptyline 
Anti-fungal 
Voriconazole, Fluconazole, Ketoconazole, Itraconazole 
Antihistamine 
Astemizole, Terfenadine, Diphenhydramine, Diphenhydramine 
Anti-hypertensive 
Nicardipine, Isradipine, Moexipril/HCTZ 
Anti-infective 
Pentamidine 
Antilipemic 
Probucol 
Anti-malarial 
Artenimol + piperaquine, Chloroquine, Halofantrine 
Anti-mania 
Lithium 
Anti-nausea/antiemetic 
Granisetron, Dolasetron, Ondansetron 
Anti-psychotic 
Clozapine, Ziprasidone, Thioridazine, Risperidone, Mesoridazine, Quetiapine, 
Haloperidol, Pimozide, Amisulpride, Sertindole, Sertindole, Iloperidone, 
Paliperidone, Chlorpromazine 
Anti-viral 
Foscarnet, Ritonavir, Atazanavir 
Appetite suppressant 
Phentermine, Fenfluramine, Sibutramine 
Bladder Antispasmodic 
Tolterodine 
α1-Blocker 
Alfuzosin 
Bronchodilator/decongestant 
Albuterol, Salmeterol, Metaproterenol, Terbutaline, Metaproterenol, Levalbuterol, 
Ephedrine, Phenylpropanolamine, Pseudoephedrine 
Cholinesterase inhibitor 
Galantamine 
CNS stimulant 
Amphetamine, Methylphenidate, Amphetamine, Dexmethylphenidate, 
Methylphenidate, Lisdexamfetamine 
Diuretic 
Indapamide 
Dopaminergic/anti-viral/anti-infective/ 
Amantadine 
Endocrine 
Ocreotide 
GI stimulant 
Cisapride 
H2-histamine receptor antagonist 
Famotidine 
Imaging contrast agent 
Perflutren lipid microspheres 
Immunosuppressant 
Tacrolimus, Fingolimod 
Inotropic agent/vasconstrictor 
Dopamine, Isoproterenol, Dobutamine, Epinephrine, Norepinephrine, 
Phenylephrine 
Local anesthetic 
Cocaine 
Muscarinic receptor anatagonist 
Solifenacin 
Muscle relaxant 
Tizanidine 
norepinephrine reuptake inhibitor 
Atomoxetine 
Opiate agonist 
Methadone, Levomethadyl 
Oxytocic 
Oxytocin 
phosphodiesterase inhibitor/vasodilator 
Vardenafil 
Sedative 
Chloral hydrate 
Sedative; Anti-nausea/anesthesia 
adjunct 
Droperidol 
Uterine relaxant 
Ritodrine 
Vasconstrictor 
Midodrine
a
 

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It is recommended to separate antacid and pazopanib dosing by several hours to avoid a 
reduction in pazopanib exposure.  
CYP3A4 Inhibitors: Avoid use of strong inhibitors (Table 10); co-administration of pazopanib 
with strong inhibitors of CYP3A4 increases pazopanib concentrations. Patients may not have 
received a strong CYP3A4 inhibitor within 7 days prior to cycle 1 day 1. If co-administration is 
warranted, reduce the dose of pazopanib to 400 mg. Grapefruit or grapefruit juice should be 
avoided as it inhibits CYP3A4 activity and may also increase plasma concentrations of 
pazopanib. 
CYP3A4 Inducers: Consider an alternate concomitant medication with no or minimal enzyme 
induction potential; CYP3A4 inducers may decrease plasma pazopanib concentrations. Patients 
may not have received a strong CYP3A4 inducer within 12 days prior to cycle 1 day 1. 
CYP Substrates: Concomitant use of pazopanib with agents with narrow therapeutic windows 
that are metabolized by CYP3A4, CYP2D6, or CYP2C8 is not recommended.  
Concomitant use of pazopanib and simvastatin increases the risk of ALT elevations and should 
be undertaken with caution and close monitoring.  
Table 10: 
Examples of Strong CYP3A4 Inducers and Inhibitorsa 
Inducers: 
 
*aInhibitors: 
 
 
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/. 
7.4. 
Treatment Compliance 
7.4.1. 
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.  
7.4.2. 
Pazopanib Treatment Compliance 
Patients will be asked to record the day and time of pazopanib home dosing on a TRACON 
supplied log to be reviewed by site personnel prior to initiation of each new cycle.  
7.5. 
Patient Randomization 
Each adult patient’s randomization assignment to Arm A (pazopanib alone) or Arm B (TRC105 
+ pazopanib), will be obtained by the investigational site after all screening procedures have 

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been completed. An 8 digit patient number will be assigned by the randomization system (4 digit 
site number + 4 digit patient number), and this 8 digit number will be used to identify patients 
throughout their participation in the trial. Treatment must start within 3 calendar days of 
randomization. 
Detailed training and instructions for the enrollment process will be provided by TRACON.  

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8. 
ASSESSMENT OF EFFICACY 
8.1. 
Radiological and Photographic Tumor Assessments 
The primary determination of efficacy will be based on objective tumor assessments made by the 
independent blinded Central Radiographic Review according to RECIST version 1.1 [62] 
modified as noted in Section 8.1.1.1.  RECIST 1.1 PD MUST be centrally confirmed prior to 
withdrawing patients from the study on the basis of PD.  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.  
All patients should receive CT or MRI scans of chest, abdomen, and pelvis with contrast.  If 
subjects are unable to receive CT contrast due to CT contrast medium allergy or renal 
insufficiency, enhanced MRI scans may be used. A combination of non-contrast CT and MRI 
studies (such as chest CT without contrast and abdominal MRI with contrast) may be used. For a 
given patient, the same method of assessment must be used throughout the course of the study 
thereafter. 
Similarly, if a patient develops a contraindication to CT contrast during the course of the study, 
assessments may shift to non-contrast CT of the chest and contrast-enhanced MRI of the 
abdomen for subsequent scans. Such a situation does not imply mandatorily a non-evaluable 
(NE) overall response designation.  
Patients with cutaneous tumors will undergo 2D color photography of all visible cutaneous 
lesions. In addition, a brain MRI or CT with contrast is to be performed at screening and on 
study as needed if metastases are suspected. A bone scan is to be performed at screening if bone 
metastases are suspected. If a bone scan documents bone disease at baseline, it needs to be 
repeated only when complete response is identified or progression in bone is suspected. All other 
known areas of disease should be consistently followed throughout 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 rather than clinical examination is the required technique when both could be 
used to assess the antitumor effect of the treatment.  Radiology-based evaluation over 
photography-based evaluation is preferred when both could be used to assess the antitumor effect 
of the treatment.   
Tumor evaluation by positron emission tomography (PET) scan or by ultrasound may not 
substitute for CT or MRI scans. The CT portion of a PET/CT could be acceptable as long as it is 
of diagnostic quality. (5mm slice thickness, and readable). 
Tumor assessments will be performed at screening and every 6 weeks from randomization as 
outlined in the Schedule of Assessments (Table 3 and Table 4), and whenever disease 
progression is suspected. Known areas of disease should be consistently followed throughout the 
study. Another tumor assessment will be performed at the End of Study Visit if an assessment 
has not been performed within the prior 6 weeks.  All patient files and radiological images must 
be available for CRF source verification.     

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8.1.1. 
Measurability of Tumor Lesions 
Measurable disease is defined by the presence of at least 1 measurable lesion. At baseline, 
individual tumor lesions will be categorized by the Investigator as measurable or non-measurable 
according to modified RECIST 1.1 as described below. 
 Measurable  Must be accurately measured in at least 1 dimension (longest diameter in 
the plane of measurement is to be recorded) with a minimum size of: 
 10 mm by CT scan or MRI (CT scan slice thickness no greater than 5 mm) 
 10 mm cutaneous lesion measured by digital 2D color photography: lesion 
measurements are generated from the 2D photographs by the Independent Central 
Radiographic Review panel; the measurements are reported by longest diameter  
 Malignant lymph nodes: To be considered pathologically enlarged and 
measurable, a lymph node must be ≥ 15 mm in short axis when assessed by CT 
scan (CT scan slice thickness recommended to be no greater than 5 mm). At 
baseline and follow-up, only the short axis will be measured and followed 
Lytic bone lesions, with an identifiable soft tissue component, evaluated by CT or MRI, can 
be considered 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.    
 Non-Measurable:  All other lesions, including small lesions (longest diameter < 10 mm 
or pathological lymph nodes with ≥ 10 to < 15 mm short axis) as well as truly non-
measurable lesions. Lesions considered to be truly non-measurable are bone lesions (lytic 
lesions or mixed osteolytic-osteoblastic lesions without identifiable soft tissue 
components, and osteoblastic lesions), leptomeningeal disease, ascites, pleural/pericardial 
effusions, cutaneous or pulmonary lymphangitis, inflammatory breast disease, abdominal 
masses not confirmed by imaging techniques, and cystic lesions.  
8.1.1.1. 
Obtaining Cutaneous Lesion Measurements from 2D Photography 
The following modifications will be applied when using RECIST 1.1 criteria to evaluate visible 
cutaneous lesions via 2D color photography. 
 Up to 5 target cutaneous lesions 
 2D color photographs are reviewed by independent medical experts. 
 The reviewer determines whether each lesion can best be measured digitally or via a 
tape measure included in the lesion photograph. 
 For each lesion, the Central Radiographic Review panel is provided with all available 
photographs. 
 The Central Radiographic Review panel incorporates the measurements into their 
RECIST 1.1 assessment. 

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8.1.1.2. 
Recording Tumor Measurements 
Measurable lesions up to a maximum of 10 total, including 5 cutaneous lesions and up to 5 non-
cutaneous lesions representative of all involved organs (with a maximum of 2 lesions per organ, 
other than skin, where up to 5 target lesions may be used) should be identified as target lesions 
and measured and recorded at baseline and at the stipulated intervals during treatment.  Target 
lesions should be selected on the basis of their size (lesions with the longest diameters) and their 
suitability for accurate repetitive measurements (by the selected imaging techniques).  Target 
lesions may include lymph nodes with a short axis > 15 mm and cutaneous lesions > 10 mm in at 
least 1 dimension. 
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 diameters for all target lesions at baseline 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 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,” “stable,” “absent,” “increased,” or “decreased.” 
8.1.2. 
Definitions of Tumor Response 
8.1.2.1. 
Target Lesions 
 Complete response (CR): Disappearance of all target lesions. Any pathological lymph 
nodes (whether target or non-target) must have reduction in short axis to < 10 mm. 
 Partial response (PR): A least a 30% decrease in the sum of diameters of the target 
lesions, taking as a reference the baseline sum diameters. 
 Progressive disease (PD): At least 20% increase in the sum of diameters of target 
lesions, taking as a reference the smallest sum on study (this includes the baseline sum if 
that is the smallest on study). In addition to the relative increase of 20%, the sum must 
also demonstrate an absolute increase of at least 5 mm. The appearance of 1 or more new 
lesions is also considered progression. 
 Stable disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase 
to qualify for PD, taking as reference the smallest sum diameters while on study.  
8.1.2.2. 
Non-Target Lesions 
 Complete response (CR): Disappearance of all non-target lesions. All lymph nodes must 
be non-pathological in size (< 10 mm short axis). 
 Non-CR/non-PD: Persistence of ≥ 1 non-target lesion(s). 
 Progressive disease (PD): Unequivocal progression of existing non-target lesions, or the 
appearance of ≥ 1 new lesion. 

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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  
8.1.2.3.1. RECIST 1.1 
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 11.  A designation of CR or PR in this study requires confirmation at a subsequent 
consecutive assessments separated by at least 4 weeks following the initial designation of CR or 
PR, respectively. Per RECIST 1.1, a modest increase in the size of 1 or more non-target lesions 
is usually not sufficient to qualify for unequivocal progression status.  
Table 11: 
Response Evaluation Criteria in Solid Tumors 
Target Lesionsa 
Non-Target Lesionsb 
New Lesionc 
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 non-measurable lesion.  
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. 
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. 
8.1.3. 
Central  Review of Disease Assessments 
Independent blinded central review of imaging studies, photographs and clinical information 
documenting disease status will be performed in real time to verify disease response and 
progression during study.  It is important to the integrity of the study that all imaging studies and 

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clinical information, including photographs, are forwarded to the review center as each patient 
enrolls and progresses through the study.   
Materials for central review are the following: 
1. All imaging studies performed on study, preferably in digital format on compact disc or 
optical disc.  All digital media must be in DICOM format.  Films may be forwarded for 
review if necessary; all films must be originals (second original films acceptable) rather 
than copies of films.   
2. 2D photographs of sites of all target and non-target lesions. It is important to the integrity 
of the study that all 2D photographs, including annotation of baseline 2D photographs 
with target lesion border demarcation, are forwarded to the review laboratory as each 
patient enrolls and progresses through the study.   
Details concerning clinically assessed lesions will be collected on the CRFs.    
Further information on materials to be forwarded for central review is provided in separate 
manuals provided by the vendors. 
8.2. 
Primary Endpoint 
PFS is defined as time from randomization to either first disease progression (per independent 
radiology review of images by RECIST 1.1) or death from any cause.  For the purpose of 
analysis for patients who are alive at the time of analysis and have not had disease progression, 
the following rules will apply:  (1) The patient will be censored on the date of the last tumor 
assessment documenting absence of progressive disease; (2) if the patient was given antitumor 
treatment other than study drug treatment, the patient will be censored as of the date of the last 
tumor assessment prior to initiating that antitumor therapy; (3) if the patient was removed from 
study for toxicity or other reason, the patient will be censored as of the date of the last tumor 
assessment on study. With regard to missed tumor assessments, in the event of one missed tumor 
assessment followed by a subsequent assessment of progressive disease (PD), the subsequent PD 
assessment qualifies as objective tumor progression.   In the event of more than one consecutive 
missing tumor assessment followed by a subsequent assessment of PD, the patient will be 
censored at the last adequate tumor assessment. 
Rarely, a patient not amenable to curative intent surgery enrolled onto study therapy may 
become amenable due to treatment effect. Patients who undergo surgery with curative intent will 
be censored at the time of surgery in the primary endpoint of PFS. These patients will continue to 
be evaluated with tumor assessments, as scheduled, until progression, death, or receipt of other 
anti-cancer therapy. A secondary analysis of the data will be conducted without censoring such 
patients. 
Pediatric patients will not be randomized and will not be analyzed in the determination of 
primary or secondary endpoints.  Individual efficacy data will be reported for pediatric patients 
who enroll in the trial. 
 

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8.3. 
Secondary Endpoints 
8.3.1. 
Objective Response Rate 
Objective response rate (ORR) is defined as the number of patients with a best response of CR or 
PR divided by the number of randomized patients. ORR is defined as the best response 
designation recorded between the date of randomization and the date of documented progression, 
as determined by Central Radiographic Review and Central Photographic Review according to 
RECIST 1.1 criteria, or date of subsequent therapy, whichever occurs first. For patients without 
documented progression or subsequent therapy, all available response designations will 
contribute to the ORR determination. A designation of CR or PR in this study requires 
confirmation at a subsequent consecutive assessments separated by at least 4 weeks following 
the initial designation of CR or PR, respectively. 
Patients who undergo curative intent surgery on study due to treatment response and are 
determined to have a pathologic CR, best overall response for these patients will be CR. If 
patients do not have pathologic CR, best overall response is that determined prior to the surgery. 
Duration of response (DR) is defined as the time from first objective response (CR or PR) to the 
date of the first documented tumor progression, as determined by Central Radiographic Review 
and Central Photographic Review according to RECIST 1.1 criteria or date of death due to any 
cause, whichever occurs first. For subjects who neither progress nor die, the duration of response 
will be censored at the same time they were censored for the definition of PFS. This endpoint 
will only be evaluated in subjects with objective response of CR or PR and without a formal 
statistical comparison between treatment arms 
8.3.2. 
Overall Survival 
Overall survival (OS) is defined as the time from randomization to the date of death. A patient 
who has not died will be censored from OS analysis as of the last known alive date. 
8.3.3. 
Safety 
Safety will be analyzed through incidence of AEs, both serious and non-serious, ECGs, physical 
examinations and vital signs, ECOG performance status, and specific laboratory abnormalities in 
each treatment arm. See Section 9 Assessment of Safety. 

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9. 
ASSESSMENT OF SAFETY 
9.1. 
Safety Parameters 
Adverse events (AEs) will be characterized in terms of the type, timing, frequency, severity 
(graded by the National Cancer Institute [NCI] Common Terminology Criteria for Adverse 
Events [CTCAE], Version 4.03), seriousness, and relatedness to study therapy (individually to 
TRC105 and to pazopanib).  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, and serum or urine pregnancy testing. Serum will also be assessed for 
immunogenicity to TRC105 (including anti-TRC105 antibody titers).  In addition, 12-lead ECGs 
will be performed at the time points indicated in the Schedule of Assessments (Table 3 and 
Table 4).   
9.1.1. 
Laboratory Safety Assessments 
Abnormal and clinically significant laboratory tests should be recorded as AEs.  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, and Pregnancy Test  
Assessments will be performed at the time points indicated in the Schedule of Assessments 
(Table 3 and Table 4) and analyzed at local laboratories.  Investigators may have additional 
blood tests performed for the purpose of planning treatment administration, or for following AEs 
as clinically indicated.  
 Hematology: Complete blood count (CBC) with differential and platelet count.  Iron 
studies (serum iron, transferrin and ferritin) are obtained only a Screening, and then on 
study only if clinically indicated. 
 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 or serum urea, creatinine, 
magnesium, TSH, and glucose 
 Pregnancy Test: Serum pregnancy tests will be performed locally on all female patients 
of childbearing potential.  
9.1.1.2. 
Urinalysis  
Urinalysis (without microscopic analysis, unless indicated) will be performed at time points 
indicated in the Schedule of Assessments (Table 3 and Table 4) and analyzed by local 
laboratories.  Microscopic analysis, urine protein-creatinine ratio (UPCR), and 24-urine 
collection for protein should be performed as clinically indicated. 

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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 3 and Table 4).  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 3 and Table 4).  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 Table 3 and Table 4 (Schedule of 
Assessments).  
9.1.1.5. 
Performance Status  
The ECOG scale (Section 21.2) will be used to assess performance status at Screening.  
9.1.1.6. 
ECG  
Three consecutive 12-lead ECGs at least 2 min apart will be performed.  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 3 and Table 4) and 
as clinically indicated throughout the study.  
Prolonged QT intervals and torsades de pointes have been observed in association with 
pazopanib administration.  Pazopanib is absorbed orally with median time to achieve peak 
concentrations of 2 to 4 hours after the dose.  The timing of the ECG at day 15 should reflect the 
cardiac status at the anticipated maximal plasma concentrations of pazopanib based on the 
protocol-specified timing of pazopanib dosing on the days when ECG is performed. 
9.1.1.7. 
 Patient Reported Outcomes 
Patient reported outcome questionnaires will be performed at the time points indicated in the 
Schedule of Assessments (Table 3 and Table 4).  
The EuroQol Group Patient Questionnaire (EQ-5D-5L) quality of life questionnaire comprises 
the following 5 dimensions:  mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression.  On the EQ-5D-5L, each dimension has 5 levels (e.g., no problems, slight 
problems, moderate problems, severe problems, and unable).  EQ-5D is one of a handful of 
measures recommended for use in cost-effectiveness analyses by the Washington Panel on Cost 
Effectiveness in Health & Medicine.  In the UK, NICE has issued revised guidance that argues 
for the use of measures like EQ-5D that have been weighted according to the social preferences 
of the UK population.  The more specific ways in which EQ-5D is being used: 
 Monitoring the health status of patient groups at different moments in time, e.g. 
referral, admission, discharge, follow-up of outpatients. 

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 Evaluation and audit of health care, by measuring changes in health status in 
individual patients and in groups of patients. 
 Assessing the seriousness of conditions at different moments in time. 
 Providing relevant information for resource allocation at a variety of levels. 
 Assisting in providing evidence about medical effectiveness in processes where drugs 
or procedures have to be approved. 
Establishing levels of population health status both locally and nationally.  Examples include 
health surveys carried out in Canada, Finland, Spain (1994 Catalan health survey interview) UK 
(UK Department of Health Omnibus Sample Survey 1996, Health Survey for England) and the 
US (current Medical Expenditure Panel Survey by the Agency for Healthcare Research and 
Quality) [63-66]. 
EORTC QLQ-C30 is a questionnaire developed to assess the quality of life of cancer patients. 
The QLQ-C30 is composed of both functional scales and symptom scales. All the scales range in 
score from 0 to 100. A high scale score represents a higher response level. Thus a high score for 
a functional scale represents a high / healthy level of functioning, while a high score for a 
symptom scale / item represents a high level of symptomatology / problems.  
9.2. 
Adverse Events 
All observed or volunteered AEs regardless of suspected causal relationship to TRC105 and/or 
pazopanib study drugs will be reported as described below. The CRF page will collect onset time 
and signs and symptoms of infusion-related reactions. 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 AE 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:  
 Signs and symptoms resulting from drug overdose, abuse, misuse, withdrawal, 
sensitivity, dependency, interaction or toxicity.   
 All possibly related and unrelated illnesses, including the worsening of a 
preexisting illness.  
 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 AEs.   
 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). 

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 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.): 
 Test result that is associated with accompanying symptoms 
 Test result that requires additional diagnostic testing or medical/surgical 
intervention 
 Test result that leads to a change in TRC105 study drug dosing outside of 
protocol-stipulated dose adjustments or discontinuation from the trial, significant 
additional concomitant drug treatment, or other therapy 
 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 a serious AE 
(SAE): 
 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.  
Serious also includes any other event that the Investigator or sponsor judges to be serious, or 
which is defined as serious by a regulatory authority 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 an AE unless the outcome is fatal during the trial or within the safety 
reporting period, in which case it should be reported as an SAE. Hospitalization due to signs and 
symptoms of disease progression should not be reported as an SAE. If the patient expires 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).  

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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 
serious:  
 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 
AEs as follows: 
 Admission for treatment of preexisting condition not associated  with the 
development of a new or worsened AE  
 Social admission 
 Administrative admission (e.g., for yearly physical exam) 
 Protocol-specified admission during a clinical trial 
 Optional admission not associated with a precipitating clinical AE (e.g., for 
elective cosmetic surgery) 
 Preplanned treatments or surgical procedures that are not related to an SAE 
 Hospitalization for observation without an AE 
 Diagnostic and therapeutic noninvasive and invasive procedures, such as surgery, should 
not be reported as AEs.  The medical condition for which the procedure was performed 
should be reported if it meets the definition of an AE (e.g., acute appendicitis that begins 
during the AE reporting period should be reported as an AE 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?” 

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9.3.2. 
Adverse Event Reporting Period 
The AE reporting period for this trial begins with informed consent and ends following the 
completion of the 28-day follow-up visit or at least 28 days after the last dose of pazopanib or 
TRC105 study drug is administered, whichever occurs later.  Data for patients who screen fail 
will not be collected in the clinical database.  However, if a screen fail patient experiences an AE 
that is considered related to study conduct or study procedures during the screening period, the 
event will be tracked on the Screening Log and the event will be assessed for reportability.  All 
events that occur following randomization, even if the patient does not go on to receive study 
treatment, will be entered on CRFs.  AEs occurring prior to the initiation of the study treatment 
will be considered “baseline-emergent adverse events” and will be recorded on the 
corresponding CRFs. 
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 a suspected adverse reaction to the investigational medications/products 
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 
serious adverse event 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 serious adverse events (e.g., change in seriousness criteria, relationship to study 
drug etc.) should also 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 
Email: ctheuer@traconpharma.com  
Cell Phone:  1.858.344.9400 
Office Phone:  1.858.550.0780 x233 
 
SECONDARY MEDICAL MONITOR 
James Freddo, MD  
TRACON Pharmaceuticals Inc. 
4350 La Jolla Village Drive, Suite 800 
San Diego, California 92122 
Email: jfreddo@traconpharma.com  
Cell Phone:  1.858.472.2330 
 
 
Following notification, the Investigator will report the SAE in the AE CRF via the data 
management system.  The initial AE CRF is to be updated with more detailed SAE information 
within 5 calendar days of the event whenever possible. 
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, returns to the patient’s pre-treatment baseline 
status, or until such time as the Investigator 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 reported as associated with use of the study drugs TRC105 or 
pazopanib will be submitted to the US Food and Drug Administration (FDA), Competent 
Authorities and Ethics Committees in other countries taking part in the study, as well as all 
participating clinical sites in all countries as required by applicable regulatory authorities. 
Investigators should report to their local IEC/IRB as dictated by their board’s policies and 
procedures. For events which are fatal or life-threatening, unexpected, and reported as associated 
with use of the investigational products, a 7-Day Alert Report will be submitted to the regulatory 
authorities within 7 calendar days of receipt of the SAE information.  For all other AEs that are 
serious, unexpected, and reported as associated with use of the investigational products, a written 
report will 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.  

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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. 
However, the diagnosis term should not be altered to accommodate the CTCAE dictionary. 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 12: 
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 
That event results in immediate risk of patient’s death 
5 
Fatal 
That event results in patient’s death 
Note the distinction between the severity and the seriousness of an AE.  A severe event is not 
necessarily a serious event.  For example, a headache may be severe (interferes significantly with 
patient’s usual function) but would not be classified as serious unless it met 1 of the criteria for 
serious events.     
9.3.6. 
Relationship of Adverse Event to TRC105 and Pazopanib Study Drugs 
In this study, TRC105 study drug may be given in combination with pazopanib.  The relationship 
of an AE to TRC105 study drug and pazopanib should be classified by the Investigator 
independently using the following guidelines: 
 Suspected Adverse Reaction to TRC105: There is a reasonable possibility that TRC105 
caused the AE (i.e., there is evidence to suggest a causal relationship between TRC105 
and the AE). See Section 2.6.1.1 for common TRC105 adverse reactions; however, the 
most current version the TRC105 IB should be referenced.  
 Suspected Adverse Reaction to pazopanib: There is a reasonable possibility that 
pazopanib caused the AE (i.e., there is evidence to suggest a causal relationship between 
pazopanib and the AE). Section 2.6.1.2 for a list of common pazopanib adverse reactions; 
however, the most current version the pazopanib product labeling should be referenced.  

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 Not Related: There is no reasonable possibility that the AE is associated with TRC105 
study drug or pazopanib.  
Causality assessment should be reported for every AE. An AE could be reported as related to one 
study drug, both study drugs or not related to any study drug. Please refer to Section 2.6.1.1 and 
Section 2.6.1.2 for the most common TRC105 and pazopanib adverse reactions; for complete 
reference, please use the most current version the TRC105 IB and the most current version the 
pazopanib product labeling. Note: an AE could be considered as related or possibly related to 
study drug(s) even if not referenced in the IB or the product labeling if in the opinion of the 
investigator there is a reasonable possibility that the drug(s) may have caused the AE.   
9.3.7. 
Expectedness Assessment 
All TRC105 AEs and suspected adverse drug reactions are considered “unexpected” if not listed 
in the applicable section of the current TRC105 Investigator Brochure (IB) or not listed at the 
specificity or severity that has been observed and listed in the IB.  For example, under this 
definition, hepatic necrosis would be unexpected (by virtue of greater severity) if the IB referred 
only to elevated hepatic enzymes or hepatitis.  Similarly, cerebral thromboembolism and cerebral 
vasculitis would be unexpected (by virtue of greater specificity) if the IB listed only cerebral 
vascular accidents.  "Unexpected," as used in this definition, also refers to AEs or suspected 
adverse reactions that are mentioned in the IB 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.  
For the expectedness assessment of AEs related to pazopanib, the most recent product labeling 
will be referenced. 
9.3.8. 
Exposure in Utero 
A pregnant patient will be withdrawn from the study.  If any trial patient (or partner of a trial 
patient) becomes or is found to be pregnant during the study or within 180 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 AE 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 (or partner of a trial 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.  
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]). 

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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 return to the patient’s pre-treatment 
baseline, or the Investigator assesses them as 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 events assessed by the Investigator as suspected adverse 
reaction to the investigational medication/product must continue to be followed even after the 
patient’s participation in the trial is over, until the event is either resolved, improved to the 
patient’s pre-treatment baseline or better, stable without anticipated future change or the patient 
is lost to follow-up, or in the case of a suspected adverse reaction, later determined to be not 
related to the investigational medicinal product.  
9.4. 
Safety Monitoring 
The TRACON Clinical Team will monitor safety throughout the study via the following 
activities:  
 Surveillance and reporting of SAEs according to regulatory guidelines as outlined in the 
safety plan 
 Routine monitoring of non-serious AEs as they are recorded in the CRFs and the source 
documents at study sites 
 Periodic teleconferences with the Principal Investigators to share experiences and ensure 
communication 
 New 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 
 An Independent Data Monitoring Committee (IDMC) will review the data from the trial.  
The IDMC will periodically review the progress of the study and accumulating safety and 
efficacy data.  Following each review, the IDMC will recommend to the Sponsor 
(TRACON Pharma) whether to continue the trial unchanged, modify the conduct of the 
study, or terminate the study early.  The DMC will be comprised of 3 voting members 

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external to the Sponsor, including a clinician specializing in the treatment of 
angiosarcoma, a clinician with broader specialty in oncology clinical studies, and a 
biostatistician with expertise in the design, analysis, and interpretation of oncology 
clinical studies.      
 There are 2 committees monitoring safety across all studies of TRC105, a separate 
charter for each committee will define the roles and responsibilities.  
 A formally chartered external Safety Review Team  
 A formally chartered TRACON in-house Safety Review Team  
9.5. 
Steering Committee 
An external steering committee comprised of sarcoma experts assisted with study design and will 
review study amendments as needed. 

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10. 
OTHER ASSESSMENTS 
10.1. 
Other Laboratory Assessments  
10.1.1. 
Pharmacokinetics  
Samples will be sent to Fisher BioServices for storage until the time of analysis. See separate 
laboratory manual for specific collection, storage and shipping information.  
10.1.1.1. TRC105 and Pazopanib Concentrations 
A 5 mL blood sample for each TRC105 and pazopanib pharmacokinetics (PK) to be collected at 
the time points indicated in the Schedule of Assessments (Table 3 and Table 4) (if applicable).  
Samples will be stored at approximately -70°C. Samples will be batch shipped as indicated in the 
laboratory manual to a central 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. 
10.1.2. 
TRC105 Immunogenicity 
Samples will be sent to Fisher BioServices for storage until the time of analysis. See separate 
laboratory manual for specific collection, storage and shipping information. 
Anti-TRC105 antibody concentrations will be measured using validated enzyme-linked 
immunosorbent assay (ELISA) methods at the time points specified in the Schedule of 
Assessments (Table 4) in all patients.  Anti-TRC105 antibody concentrations will be evaluated in 
the context of PK/pharmacodynamics parameters and AE profiles.  Samples will be separated 
and stored at approximately -70 °C.  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 3 and Table 4).  Samples will be stored at approximately -70°C 
and shipped to Fisher BioServices Inc. for storage until the time of analysis. Protein biomarkers 
to be analyzed include, but are not limited to, VEGF, VEGF-R2, placental growth factor (PIGF), 
and sCD105.  Please see the separate laboratory guide for further collection and shipment 
information.  
10.1.4. 
Circulating Tumor Cells  
One 10 mL EDTA tube of blood for circulating tumor cells (CTCs) will be collected on the days 
indicated within the Schedule of Assessments (Table 3 and Table 4).  Samples will be shipped to 
Apocell Inc. for analysis. Please see the separate laboratory guide for further collection and 
shipment information.  
10.1.5. 
Archival Tumor Specimens 
Specimens (formalin-fixed, paraffin-embedded) of the primary cancer and/or metastatic 
angiosarcoma tumor for each study participant will be obtained and centrally reviewed, 

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retrospectively, to corroborate diagnosis of angiosarcoma.  Other markers that may relate to 
efficacy or toxicity of TRC105 may also be explored. 
It is preferable that the entire paraffin block be submitted, but if this is not feasible, then at least 
10 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. 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. 
Sample Size 
A hazard ratio (HR) of 0.55 is considered to be clinically relevant.  Based on 1:1 randomization 
and the use of log-rank test at the 2-sided alpha of 0.05 level of significance, 95 events provides 
83% power to detect a HR of 0.55.  
The expected PFS of angiosarcoma patients treated with pazopanib who have progressed 
following first line treatment is 4 months.  A HR of 0.55 corresponds to an improvement of 
median PFS from 4 months to 7.27 months.  Due to the uncertainty of the treatment effect, and 
heterogeneity among the cutaneous and non-cutaneous subgroups, an adaptive enrichment design 
will be employed.  The adaptive design calls for enrolling two cohorts, with 120 adult patients in 
Cohort 1, and 70 adult patients in Cohort 2.  The initially planned final analysis will be 
conducted when 60 events are observed from Cohort 1 and 35 events are observed from cohort 2, 
whichever comes at a later time.  A projection of events in Cohort 1 will be done prior to the 
interim analysis, and the sample size of Cohort 1 may be increased by no more than 20% to 
compensate for a lack of expected events.  Similarly, a projection of events in Cohort 2 will be 
done at 55 events in Cohort 1 and the sample size and number of events in Cohort 2 only may be 
increased by no more than 20% to compensate for a lack of or expected time frame of events. 
A formal interim analysis will be performed after observing 40 events or 30 days after enrolling 
120 patients in cohort 1. Based on the results obtained at this interim analysis, the trial will be 
classified into one of four zones: favorable, promising, enrichment, and unfavorable.  The future 
course of the trial may be modified in one of the following ways (Figure 3): 
1. Favorable Zone:  If the conditional power of demonstrating treatment effect with full 
population is high, i.e., CPF > 95%, the trial is considered to fall into the favorable zone. 
In this case, it will continue with the initially planned enrolment of 120 adult patients for 
Cohort 1 and 70 adult patients for Cohort 2 from both cutaneous and non-cutaneous 
patients. The final analysis will be performed on the full population when 60 events are 
observed for Cohort 1 and 35 events for Cohort 2, whichever comes later.  
2. Promising Zone:  If the conditional power of demonstrating treatment effect with full 
population is between 30% and 95% inclusive, the trial is considered to fall into the 
promising zone. If the trial falls into promising zone, enrollment into Cohort 2 will be 
increased from 70 adult patients to 220 adult patients from the full population and the 
events in Cohort 2 will be increased from 35 to 110. The final analysis will be performed 
on the full population when 60 events are observed from the 120 adult patients in Cohort 
1 and 110 events are observed from the 220 adult patients in Cohort 2, whichever comes 
later. 
3. Enrichment Zone:  If the conditional power for the full population is < 30% and the 
conditional power for the cutaneous subgroup is > 50%, the enrollment for Cohort 2 will 
be restricted to the cutaneous subgroup only and 160 adult patients will be enrolled.  The 
final analysis will be performed on the cutaneous subgroup only, when 60 events are 
observed from the 120 adult patients in Cohort 1 and when 110 events are observed in 
cutaneous subgroup from both cohorts combined.  

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4. Unfavorable Zone:  If the conditional power for the full population is < 30% and the 
conditional power for cutaneous subgroup is ≤ 50%, the trial is considered to fall into the 
unfavorable zone. In this case, the trial will remain unchanged, enrolling 120 adult 
patients for Cohort 1 and 70 adult patients for Cohort 2 from the full population.  The 
final analysis will be performed on full population when 60 events are observed from the 
120 adult patients in Cohort 1 and 35 events are observed from the 70 adult patients 
whichever comes later. 
The IDMC might recommend termination of the trial for futility by exercising its judgment based 
on the totality of the data at interim time if TRC105 seems doing worse than the control group. 
In order to preserve the statistical integrity of the adaptive design it is pre-specified that 120 
subjects will be enrolled in Cohort 1, and followed until 60 events are obtained. This 
specification was based on initial assumptions about patient enrollment rates and HRs.  The 
actual rates could vary from these initial assumptions.  In addition it has not been factored in the 
impact of possible patient drop-outs.  If there are too many drop-outs from Cohort 1, it may 
either become impossible to obtain the required 60 events or the duration of patient follow-up 
may become excessively prolonged.  To mitigate these risks, the sample size of Cohort 1 and 
Cohort 2 may increase by a maximum of 20% as detailed in the statistical analysis plan (SAP) in 
a manner that does not increase the Type 1 error rate. 

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Figure 3: 
 
Schematic Representation of Adaptive Trial Design 
 
11.1.1. 
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 either TRC105 or pazopanib. If a patient actually received study drug not 
according to their randomized treatment arm, they will be analyzed for safety in the 
treatment arm according to the study drug they actually received. 

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 The study population for efficacy will include all randomized adult patients (intent-
to-treat, ITT). 
11.2. 
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 (anti-TRC105 antibodies), efficacy, PK 
parameters, protein biomarkers, and archival tumor tissue.  Data will also be displayed 
graphically, where appropriate.  Additional details of data analyses for the study may be found in 
the statistical analysis plan (SAP). 
11.2.1. 
Analysis of Primary Objective  
PFS is defined as time from randomization to either first disease progression (per independent 
radiology review of images by RECIST 1.1) or death from any cause.  For the purpose of 
analysis for patients who are alive at the time of analysis and have not had disease progression, 
the following rules will apply:  (1) The patient will be censored on the date of the last tumor 
assessment documenting absence of progressive disease; (2) if the patient was given antitumor 
treatment other than study drug treatment, the patient will be censored as of the date of the last 
tumor assessment prior to initiating that antitumor therapy; (3) if the patient was removed from 
study for toxicity or other reason, the patient will be censored as of the date of the last tumor 
assessment on study. With regard to missed tumor assessments, in the event of one missed tumor 
assessment followed by a subsequent assessment of progressive disease (PD), the subsequent PD 
assessment qualifies as objective tumor progression. In the event of more than one consecutive 
missing tumor assessment followed by a subsequent assessment of PD, the patient will be 
censored at the last adequate tumor assessment. 
The primary efficacy analysis will test the null hypothesis that the HR of the experimental arm 
relative to the control arm is 1 against the alternative hypothesis that the HR is less than 1, at the 
2-sided 0.05 level of significance.  The hypothesis test will be based on the method of Jenkins, 
Stone and Jennison [67], thereby ensuring strong control of Type 1 error for this adaptive design.  
Additional supportive analyses will include Kaplan-Meier plots for each treatment arm and the 
p-value and confidence interval for the HR, unadjusted for the adaptive nature of the design.   
A pre-planned assessment of the primary endpoint will additionally be done to determine the 
primary endpoint of PFS without censoring patients with tumor response who undergo curative 
intent surgical resection.  A Cox regression model will be used to explore the potential influences 
of the stratification factors on the primary PFS endpoint.  In addition, the potential influences of 
baseline patient characteristics will be evaluated. 
An exploratory, sensitivity analysis will be conducted that will apply the modified RECIST 1.1 
separately to cutaneous lesions and to non-cutaneous lesions for each patient with both cutaneous 
and non-cutaneous sites of disease.   
The secondary endpoints will be tested in a hierarchical order only if the test for primary 
endpoint is significant at 2-sided significance level 0.05. More specifically, if the test for PFS is 
significant at the final analysis time, the objective response rate (ORR) will be tested next at the 
same 2-sided 0.05 level followed by the test for overall survival (OS) at the same level. 

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11.2.2. 
Analysis of Pharmacokinetics  
Serum TRC105 and plasma pazopanib concentrations will be measured using validated methods 
and assessed for potential correlations with response, PFS, survival, AEs, and baseline 
characteristics using descriptive statistics and models as appropriate.  To the extent possible 
potential PK drug interaction between pazopanib and TRC105 and the relationship between 
pazopanib exposure and efficacy/safety endpoints in the pazopanib alone arm will be explored, 
and examine the assumption that the exposure-response relationship for pazopanib is flat and that 
there is no drug interaction between pazopanib and TRC105 in the combination arm.  Intensive 
pharmacokinetic data collection with additional analyses will be done for patients 12-17 years of 
age to provide data in support of extrapolation of the treatment effects of TRC105 and pazopanib 
from adults to this pediatric population.  
11.2.3. 
Analysis of Protein Biomarkers 
Angiogenic protein biomarker data for each patient who received at least 1 dose of TRC105 or 
pazopanib will be listed. 
11.2.4. 
Analysis of Circulating Tumor Cells  
Endoglin expressing circulating tumor cell data for each patient who received at least 1 dose of 
TRC105 or pazopanib will be listed. 
11.2.5. 
Analysis of Immunogenicity 
Anti-TRC105 antibody responses will be measured using a validated bridging 
electrochemiluminescent (ECL) assay format (on the MesoScale Discoveries platform) at the 
time points specified in the Schedule of Assessments (Table 4).  This method employs an initial 
acid dissociation step to increase drug tolerance of TRC105 to > 400 μg/mL.  A three-tiered 
approach will be utilized for sample analysis:  screening, confirmatory, and titration 
assays.  Samples that are above the cutpoint in the initial screening assay will be considered 
potentially positive.  The potentially positive samples will then be tested in a confirmatory assay, 
where they will be assessed in the presence or absence of TRC105 to establish whether a sample 
is a true positive or false positive. Samples determined to be true positives in the confirmatory 
assay will be taken to the third tier assay where they will be titrated until the signal falls below 
the assay cutpoint in order to determine a titer for the sample, which reflects the magnitude of 
response.  
Anti-TRC105 antibody responses will be evaluated in the context of PK parameters and AE 
profiles. To the extent possible as provided by the available data, the effect of anti-TRC105 
antibodies on the PK, pharmacodynamics (PD), efficacy, and safety of TRC105 will be 
evaluated.  

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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. 
Protocol deviations will be captured in TRACONs electronic data capture system.    

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14. 
ETHICS 
14.1. 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Before this study starts, the trial protocol, protocol amendments, informed consent forms, and 
any other information provided to study patients will be submitted to the Food and Drug 
Administration (FDA), European Medicines Agency (EMA) or other national health authorities 
and to each IEC/IRB for review, as applicable. As required, the study will not start at a given 
investigational center before the IEC/IRB and health authority (where applicable) for the center 
gives written approval or a favorable opinion. 
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 Harmonisation (ICH) 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 patients 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, ICH E6 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 
CRFs are required and should be completed for each patient who receives any treatment with 
either TRC105 or pazopanib.  Screen failure CRFs 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 a Regulatory Authority and in accordance with Health Portability and Accountability Act 
(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 CRFs 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 in this study.  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.   
Essential documents will be retained until at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or at least 2 years have elapsed since the formal discontinuation of 
clinical development of the investigational product. These documents should be retained for a 

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longer period, however, if required by the applicable regulatory requirements or by an agreement 
with the sponsor.  
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 or another institution.  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 the follow up period, all data collection and clean-up activities have 
been completed, including all query resolution. 
For clinical investigational centers located in the European Union (EU), a declaration of the end 
of the clinical study will be made according to the procedures outlined in Directive 2001/20/ED, 
Article 10(c); for other countries, local regulations will be followed. 
16.2. 
TRACON Study Discontinuation Criteria 
Premature termination of this trial may occur because of a regulatory authority decision, change 
in opinion of the IRB/IEC, study drug safety problems or availability, 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 ongoing 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 Investigators’ Clinical Trial Agreement.  
The sponsor is responsible for ensuring that the public has access to the appropriate information 
about the study by conforming to local and regional requirements for registration and posting of 
results.  
The study will be listed in public databases on clinical studies www.clinicaltrials.gov and the 
European www.clinicaltrialsregister.eu clinical trials database (EudraCT).  The summary of the 
study results will also be available at the appropriate time on www.clinicaltrials.gov and 
www.clinicaltrialsregister.eu websites. 

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

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19. 
INVESTIGATOR PROTOCOL AGREEMENT: 105SAR301 
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, all protocol amendments, and all materials provided to potential 
study patients must be submitted to and approved by the appropriate IRB/IEC prior to 
implementation. 
I have read this protocol and agree that it contains all necessary details for carrying out this 
study. I will conduct the study as outlined herein and will complete the study within the time 
designated. 
I will provide copies of the protocol and all pertinent information to all individuals responsible to 
me who assist in the conduct of this study. I will discuss this material with them to ensure that 
they are fully informed regarding the study drug, the conduct of the study, and the obligations of 
confidentiality. 
Coordinating Investigator (where required): _________________________ 
Name (typed or printed): ________________________________________ 
Institution and Address: _________________________________________ 
 
______________________________________________  
Signature  
 
 
 
Date (Day Month Year)  
 
 
 
Principal (Site) Investigator: ____________________________________ 
Name (typed or printed): _______________________________________ 
Institution and Address: _______________________________________ 
Telephone Number: __________________________________________  
______________________________________________  
Signature  
 
 
 
Date (Day Month Year) 
Note:   If the address or telephone number of the investigator changes during the course of the 
study, written notification will be provided by the investigator to the sponsor. 
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. 
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22. 
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Nolan-Stevaux, O., et al., Endoglin Requirement for BMP9 Signaling in Endothelial Cells 
Reveals New Mechanism of Action for Selective Anti-Endoglin Antibodies. PLOS ONE, 
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Takahashi, N., et al., Antiangiogenic therapy of established tumors in human skin/severe 
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Tsujie, M., et al., Anti-tumor activity of an anti-endoglin monoclonal antibody is 
enhanced in immunocompetent mice. Int J Cancer, 2008. 122(10): p. 2266-73. 

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39. 
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Fritchie, K., et al., CD105: A therapeutic target for sarcomas, in EORTC 2013: Boston. 

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58. 
Shiozaki, K., et al., Antiangiogenic chimeric anti-endoglin (CD105) antibody: 
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Pharmaceutical Statistics, 2011. 10: p. 347-356. 
 

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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 AEs and may be reviewed on-line at 
the following NCI website: 
https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf  
 
 
 

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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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21.3. 
Appendix 3: Quality of Life Questionnaire - EQ-5D-5L Example 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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21.4. 
Appendix 4: Quality of Life Questionnaire – EORTC QLQ-C30 
Example 

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