A Phase 1b Dose-escalation Study of TRC105 in Combination With Paclitaxel/Carboplatin and Bevacizumab in Patients With Stage 4 Non-Squamous Cell Lung Cancer
Phase: PHASE1
Conditions: Non Small Cell Lung Cancer
Sponsor: Tracon Pharmaceuticals Inc.



IND 100522 
 
105LC101 Protocol Amendment #3 
5.3.3.2 Clinical Protocol 
 
7July2015 
Page 2 of 93 
 
Statement of Confidentiality: The information in this document is confidential and proprietary.  Any other distribution, copying or disclosure is 
strictly prohibited unless required by federal regulations or state law.  Persons receiving this information must be notified that it is confidential 
and may not be further disclosed. 

IND 100522 
 
105LC101 Protocol Amendment #3 
5.3.3.2 Clinical Protocol 
 
7July2015 
Page 3 of 93 
 
PROCEDURES IN CASE OF EMERGENCY 
Table 1: 
Emergency Contact Information 
Role in Study 
Name 
Address and Telephone number 
Medical Monitor 
Charles Theuer MD PhD 
8910 University Center Lane, Suite 700 
San Diego, CA 92122 
Office: (858) 550-0780 x233 
Mobile Phone: (858) 344-9400 
Email: ctheuer@traconpharma.com 
Secondary Medical Monitor 
Edwin Alvarez MD 
Mobile Phone: (858) 356-8656 
edwinalvarez@traconpharma.com 
 
 

IND 100522 
 
105LC101 Protocol Amendment #3 
5.3.3.2 Clinical Protocol 
 
7July2015 
Page 4 of 93 
 
1. 
SYNOPSIS 
Name of Sponsor/Company: TRACON Pharmaceuticals, Inc./UAB Cancer Center  
Name of Investigational Product: TRC105 
Name of Active Ingredient: TRC105 
Title of Study:  
A PHASE 1B DOSE-ESCALATION STUDY OF TRC105 IN COMBINATION WITH 
PACLITAXEL/CARBOPLATIN AND BEVACIZUMAB IN PATIENTS WITH STAGE 4 NON-
SQUAMOUS CELL LUNG CANCER 
Study center(s): This study will be performed at University of Alabama at Birmingham 
Principal Investigator: Dr. Francisco Robert 
Studied period (years):  
Estimated date first patient enrolled: September 2015 
Estimated date endpoint obtained: April 2016 
Estimated date last patient completed: December 2016 
Total Numbers of Patients: 18 
Estimated duration of treatment per patient: 6 months 
Phase of development: 1b 
 
Rationale:  
Bevacizumab is a monoclonal antibody to vascular endothelial growth factor (VEGF) that inhibits 
angiogenesis and extends survival in non-squamous non-small cell lung cancer (NSCLC) patients when 
given with carboplatin and paclitaxel.  TRC105 is an antibody to endoglin, an essential angiogenic target 
expressed on proliferating endothelial cells that is distinct from the VEGFR and overexpressed in 
response to VEGF inhibition.  TRC105 inhibits angiogenesis, tumor growth and metastases in 
preclinical models and complements the activity of antibodies and small molecules that target the 
VEGFR.  In a phase 1b study, the combination of TRC105 and bevacizumab produced radiographic 
reductions in tumor volume in bevacizumab-refractory patients, and was well tolerated. TRC105 was 
also well tolerated with chemotherapy in a trial with capecitabine in breast cancer patients.  The use of 
TRC105 with bevacizumab and paclitaxel/carboplatin may result in more effective angiogenesis 
inhibition and improved clinical efficacy over that seen with bevacizumab and paclitaxel/carboplatin 
alone. 
 
 
 
 
 
 
 
 

IND 100522 
 
105LC101 Protocol Amendment #3 
5.3.3.2 Clinical Protocol 
 
7July2015 
Page 5 of 93 
 
Objectives:  
Primary: 
• To evaluate safety and tolerability and determine a  recommended phase 2 dose for 
TRC105 when added to standard dose bevacizumab and paclitaxel/carboplatin in 
treatment-naive patients with stage IV non-squamous NSCLC  
Secondary: 
• To assess preliminary evidence of antitumor activity when TRC105 is added to 
bevacizumab and paclitaxel/carboplatin, by assessing objective response rate, median 
progression-free survival, the proportion (%) of patients progression-free at 6 
months, and the overall survival 
• 
To characterize the pharmacokinetic profile of TRC105 when given with bevacizumab and 
paclitaxel/carboplatin 
• 
To evaluate TRC105 Anti-Product Antibodies  
• 
To explore pharmacodynamic effects on circulating angiogenic biomarkers  
 
Methodology:  
This is a single center, open-label, nonrandomized, phase 1b, dose-finding study of TRC105 in 
combination with standard dose bevacizumab and paclitaxel/carboplatin in treatment-naive patients with 
stage IV non-squamous NSCLC.  Escalating doses of i.v. TRC105 will be administered weekly 
beginning with Dose Level 1 in combination with bevacizumab 15 mg/kg given intravenously every 3 
weeks and paclitaxel 200 mg/m2 and Carboplatin 6 AUC administered intravenously on day 1 of each 21 
day cycle.  Intermediate TRC105 doses (below the MTD established during the trial) may be explored 
based upon clinical, PK, and/or biomarker data. 
 
 
 
 
 
 
 
 
 
 
 

IND 100522 
 
105LC101 Protocol Amendment #3 
5.3.3.2 Clinical Protocol 
 
7July2015 
Page 6 of 93 
 
Level 
Number 
of 
Evaluable 
Subjects 
Bevacizumab 
mg/kg IV 
every 3 
weeks 
Paclitaxel  
mg/m2 IV 
every 3 
weeks 
Carboplatin  
AUC IV 
every 3 
weeks 
TRC105 
mg/kg 
IV, weekly 
(beginning 
cycle 1 day 
8)a 
-1 
3-6 
15 
200 
6 
6 
1  
(starting 
dose) 
3-6 
15 
200 
6 
8  
2 
3-6 
15 
200 
6 
10  
Expanded 
Cohort  
9-12 
(up to 15 
total at the 
MTD) 
15 
200 
6 
MTD 
aThe first weekly TRC105 dose will be split into two doses whereby 3 mg/kg is administered on cycle 1 day 8 and 
the balance is administered on cycle 1 day 11. 
 
Patients will receive 15 mg/kg of bevacizumab, 200 mg/m2 of paclitaxel and 6 AUC of carboplatin every 
3 weeks beginning with cycle 1 day 1.  TRC105 dosing will begin at 8 mg/kg (Dose Level 1) on cycle 1 
day 8.  A -1 Dose Level has also been included (6 mg/kg) and will be enrolled if 8 mg/kg TRC105 dosed 
with bevacizumab, paclitaxel and carboplatin exceeds the MTD.  The DLT evaluation period, for 
purposes of dose expansion, will be the first 6 weeks (42 days) of dosing bevacizumab, paclitaxel, 
carboplatin and TRC105 (e.g., from cycle 1 day 1 through cycle 2 day 21).  Each cycle will be 3 weeks 
(21 days) in duration. 
Three patients will be initially enrolled and treated at each dose level.  If none of these 3 patients 
experiences a dose-limiting toxicity (DLT) during the initial 42-day evaluation period when all drugs are 
dosed together (extending from cycle 1 day 1 through cycle 2 day 21), dose escalation will proceed 
following review of safety data with site staff including the principal investigators at all sites. 
If 1 of 3 patients experiences DLT, the dose level will be expanded to 6 patients.  The maximum 
tolerated dose (MTD) will have been exceeded if ≥ 33% of patients experience DLT at a given dose 
level.  DLT will have occurred when a patient has 1 or more toxicity listed in the table below that is at 
least possibly related to the combination of bevacizumab, paclitaxel, carboplatin and TRC105 during the 
first 42 days of concomitant dosing.  Patients who exit the study for reasons other than DLT prior to 
completion of the 42-day DLT evaluation period will be replaced to ensure an adequate safety 
assessment in each cohort. Patients who experience DLT who receive less than the prescribed dose of 
TRC105 or bevacizumab or paclitaxel or carboplatin due to documented toxicity during the DLT 
evaluation period will be considered evaluable for dose escalation purposes.  A given TRC105 dose 
level may be reenrolled at an intermediate dose level upon agreement of study investigators. 
 
 
 

IND 100522 
 
105LC101 Protocol Amendment #3 
5.3.3.2 Clinical Protocol 
 
7July2015 
Page 7 of 93 
 
Toxicity Category 
Drug-Related Toxicity/Grade 
Hematologic 
Any Grade 4 toxicity 
 
Neutropenic infection: grade ≥ 3 neutropenia 
with grade ≥ 3 infection 
 
Grade ≥ 3 thrombocytopenia and grade ≥ 3 
hemorrhage 
Nonhematologic 
Grade 3 toxicity with the following exceptions: 
• 
Nausea, vomiting or diarrhea for < 48 
hoursa 
• 
Asymptomatic electrolyte abnormalities 
that are corrected to grade 1 or better in 
< 72 hoursb 
Any Grade 4 toxicity 
aPatients with related grade 3 or 4 diarrhea, nausea or vomiting for ≥ 48 hours despite optimal medical therapy will 
require a one-level dose-reduction of TRC105. 
bPatients with related grade 3 or 4 electrolyte abnormalities that persist for ≥ 72 hours will require a one-level dose 
reduction of TRC105.  
 
Up to 15 treatment-naive patients with stage IV non-squamous NSCLC will be treated at the MTD (or 
top dose level if a MTD is not determined) to further characterize safety and tolerability. 
Number of patients (planned):  
Approximately 18 treatment-naive patients with stage IV non-squamous NSCLC will be enrolled. 
Diagnosis and main criteria for inclusion:  
Inclusion Criteria: 
1. Stage 4 Non-Squamous Cell Lung Cancer that has not been treated previously with 
systemic chemotherapy or bevacizumab, but may have received prior targeted treatment 
(e.g., alk1 inhibitor)  
2. Measurable disease by RECIST  
3. Age of 18 years or older 
4. ECOG performance status ≤ 1 
5. Resolution of all acute adverse events resulting from prior cancer therapies to NCI CTCAE 
grade ≤ 1 or baseline (except alopecia or neuropathy)   
6. Adequate organ function as defined by the following criteria: 

IND 100522 
 
105LC101 Protocol Amendment #3 
5.3.3.2 Clinical Protocol 
 
7July2015 
Page 8 of 93 
 
• 
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 times the upper limit of normal 
• 
Absolute neutrophil count (ANC) ≥ 1500/μL  
• 
Platelets ≥ 100,000/μL without transfusion support within the past 28 days 
• 
Hemoglobin ≥ 9.0 g/dL without transfusion support within the past 28 days (erythropoietin 
or darbepoetin permitted) 
• 
Serum creatinine ≤ 1.5 times the upper limit of normal or creatinine clearance >30 mL/min 
by Cockcroft-Gault formula 
• < 1+ proteinuria 
• 
 INR from 0.8 to 1.2 
7. Willingness and ability to consent for self to participate in study   
8. Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests, and 
other study procedures   
9. Men who are sterile (including vasectomy confirmed by post vasectomy semen analysis) OR 
agree to use at least two forms of a reliable and highly effective method of birth control (refer to 
Section 2.5.1) and to not donate sperm and for at least 180 days following last dose of TRC105, 
bevacizumab, paclitaxel, and/or carboplatin 
10. 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, OR woman of child bearing potential who test negative for 
pregnancy at time of enrollment based on serum pregnancy test and agree to use at least 2 forms 
of a reliable and highly effective method of birth control (refer to section Section 2.5.1 ) during 
the study and for at least 180 days after stopping TRC105, bevacizumab, paclitaxel, and/or 
carboplatin 
Exclusion Criteria:   
1. Non-small cell lung cancer of squamous histology 
2. Prior treatment with TRC105 
3. Current treatment on another therapeutic clinical trial 
4. Receipt of a small molecule anticancer agent, including an investigational anticancer small 
molecule, within 14 days of starting study treatment  
5. Receipt of a large molecule anticancer agent (e.g., antibody), including an  investigational 
anticancer antibody, within 28 days of starting study treatment 
6. No major surgical procedure or significant traumatic injury within 6 weeks prior to study 
registration, and must have fully recovered from any such procedure; date of surgery (if 
applicable) 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 

IND 100522 
 
105LC101 Protocol Amendment #3 
5.3.3.2 Clinical Protocol 
 
7July2015 
Page 9 of 93 
 
before therapy initiation: Thoracentesis, paracentesis, port placement, laparoscopy, 
thoracoscopy, tube thoracostomy, bronchoscopy, endoscopic ultrasonographic procedures,  
mediastinoscopy, skin biopsies, incisional biopsies, imaging-guided biopsy for diagnostic 
purposes, and routine dental procedures 
7. 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 study 
registration or those patients who have not recovered adequately from side effects of such 
therapy 
8. Uncontrolled chronic hypertension defined as systolic > 150 or diastolic > 90 despite optimal 
therapy (initiation or adjustment of BP medication prior to study entry is allowed provided that 
the average of 3 BP readings at a visit prior to enrollment is < 140/90 mm Hg) 
9. 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  
10. Angina, MI, symptomatic congestive heart failure, cerebrovascular accident, transient ischemic 
attack, arterial embolism, pulmonary embolism, PTCA or CABG within the past 6 months. 
Deep venous thrombosis within 6 months, unless the patient is anticoagulated without the use of 
warfarin for at least 2 weeks. In this situation, low molecular weight heparin is preferred.  
11. Active bleeding or pathologic condition that carries a high risk of bleeding (e.g. hereditary 
hemorrhagic telangiectasia).  Patients who have been uneventfully anti-coagulated with low 
molecular weight heparin are eligible. 
12. Thrombolytic use (except to maintain i.v. catheters) or anticoagulant use within 10 days prior to 
first day of study therapy 
13. Cardiac dysrhythmias of NCI CTCAE grade ≥ 2 within the last 28 days 
14. Known active viral or nonviral hepatitis or cirrhosis 
15. History of hemorrhage or hemoptysis (> ½ teaspoon bright red blood) within 3 months of 
starting study treatment 
16. History of peptic ulcer disease or erosive gastritis within the past 3 months, unless treated for 
the condition and complete resolution has been documented by esophagogastroduodenoscopy 
(EGD) within 28 days of starting study treatment 
17. History of gastrointestinal perforation or fistula in the past 6 months, or while previously on 
antiangiogenic therapy, unless underlying risk has been resolved (e.g., through surgical 
resection or repair) 
18. Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS) 
related illness 
19. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that 
may increase the risk associated with study participation or may interfere with the interpretation 
of study results and, in the judgment of the Investigator, would make the patient inappropriate 
for this study 

IND 100522 
 
105LC101 Protocol Amendment #3 
5.3.3.2 Clinical Protocol 
 
7July2015 
Page 10 of 93 
 
 
TRC105 investigational product dose and mode of administration:  
Dosing will begin at 8 mg/kg (Dose Level 1); however a -1 Dose Level has also been included (6 
mg/kg) and will be enrolled if 8 mg/kg is found to exceed the MTD.  Following the appropriate 
premedication regimen, the first weekly TRC105 dose (cycle 1 day 8) will be split into two doses 
whereby 3 mg/kg is administered on cycle 1 day 8 and the balance (e.g., 5 mg/kg for Dose Level 1) is 
administered on cycle 1 day 11.  Beginning with cycle 1 day 15 and thereafter, the full (e.g., 8 mg/kg for 
Dose Level 1) TRC105 dose will be administered i.v. weekly during each 21-day cycle.  Intra-patient 
dose reductions are allowed beginning in cycle 2.     
 
Bevacizumab dose and administration: 
Bevacizumab will be administered intravenously at a dose of 15 mg/kg on day 1 of each 21-day 
cycle until disease progression. The initial bevacizumab dose should be delivered over 90 
minutes.  
Dose reduction of bevacizumab for adverse reactions is not recommended.   
Paclitaxel dose and administration: 
Paclitaxel will be administered intravenously following appropriate premedication at 200 
mg/m2 beginning on cycle 1 day 1 and on day 1 of each 21 day cycle for 6 cycles, in the 
absence of toxicity. Paclitaxel will be delivered over 3 hours. Dose reductions are allowed 
beginning in cycle 3 according to the package insert. 
 
Carboplatin dose and administration: 
Carboplatin will be administered intravenously following appropriate premedication at 6 AUC 
beginning on cycle 1 day 1 and on day 1 of each 21 day cycle for 6 cycles, in the absence of 
toxicity.  Carboplatin will be delivered over 30 to 60 minutes. Dose reductions are allowed 
beginning in cycle 3 according to the package insert. 
 
Combination dosing order: 
Dosing will occur in the following order on day 1 of each cycle (Note: TRC105 will not be dosed on 
cycle 1 day 1): 
• 
Pre-medication 
• 
Paclitaxel 200 mg/kg (3 hour IV infusion) 
• 
Carboplatin AUC of 6 (30 to 60 minutes IV infusion) 
• 
Bevacizumab 15 mg/kg (30 minute IV infusion) 
• 
TRC105 8 or 10 mg/kg (1 to 4 hour IV infusion) 
 
TRC105 will be dosed alone on days 8 and 15 of each cycle, following appropriate pre-
medication.  
 
Duration of treatment:  
Patients will be treated with induction therapy with carboplatin, paclitaxel, bevacizumab, and TRC105 
for a maximum of 6 cycles of therapy. Patients who demonstrate a response of CR, PR or SD, after the 

IND 100522 
 
105LC101 Protocol Amendment #3 
5.3.3.2 Clinical Protocol 
 
7July2015 
Page 11 of 93 
 
end of the induction therapy are eligible for maintenance therapy with bevacizumab and TRC105 until 
disease progression, unacceptable toxicity or withdrawal of consent, or other reasons.   Patients who are 
not able to receive more than 4 cycles of induction therapy because significant and persistent > grade 2 
neurotoxicity related to paclitaxel may be eligible for maintenance therapy (i.e., TRC105 + bevacizumab 
alone) if there is no evidence of progressive disease after 4 cycles of induction therapy.  Patients may be 
scanned early at the end of cycle 4 to determine disease status.  
A patient should be withdrawn from study treatment if, in the opinion of the Investigator, it is medically 
necessary, or if it is the wish of the patient.  In addition, patients will be withdrawn from treatment in the 
case of: 
1. RECIST 1.1-defined disease progression. In cases where RECIST cannot be applied, 
progression should be based on unequivocal evidence of progressive disease sufficient to 
require a change in therapy. 
2. A need for surgery, radiation, or for other anticancer therapy not specified in the protocol. 
3. Lost to follow-up or noncompliant. 
4. Any TRC105 dose delay > 14 days, other than a dose delay for planned surgery or 
hematologic toxicity, in which case up to 6 weeks is allowed. 
5. Pregnancy.  Pregnant patients should be followed for the duration of the pregnancy and the 
outcome of the pregnancy should be documented. 
 
Parameters to be assessed: 
Safety: 
 
Safety assessments will include physical exams, performance status, laboratory results (complete blood 
counts and serum chemistry) and 12-lead ECG’s, and additional studies as clinically indicated.  A 
formally chartered Safety Review Team will review safety data.  In addition, recurring teleconferences 
will be held with the Investigator at the clinical site.   
Pharmacokinetics: 
Serum TRC105 concentrations will be measured using validated methods at the time points specified in 
the Schedule of Events. 
Immunogenicity: 
Anti-product antibody titers will be measured using validated methods at time points specified in the 
Schedule of Events. 
Exploratory Biomarkers: 
Concentrations of a panel of angiogenic protein biomarkers in plasma will be measured at baseline and 
during treatment to explore TRC105 pharmacodynamics. 
Efficacy: 
RECIST 1.1 will be applied to measurable disease to assess response and progression.  Tumor markers 
will also be evaluated where available.   
Statistical methods: 
Evaluable Study Population: 
The study population for safety and efficacy includes all patients receiving at least a portion of 1 dose of 
TRC105.  
The number of patients to be enrolled in this study will depend upon the observed safety profile, which 
will determine the number of patients per dose level and the number of dose escalations.  It is 
anticipated that a total of approximately 18 patients will be enrolled in this study. 

IND 100522 
 
105LC101 Protocol Amendment #3 
5.3.3.2 Clinical Protocol 
 
7July2015 
Page 12 of 93 
 
The probability of escalation to the next higher dose for each underlying true DLT rate is shown in the 
table below.  For example, for a toxicity that occurs in 5% of patients, there is a > 95% probability of 
escalating.  Conversely, for a common toxicity that occurs with a rate of 70%, the probability of 
escalating is < 5%. 
Probability of Escalation to the Next Dose for Each True Underlying DLT Rate at a Dose Level 
True Underlying DLT 
Rate 
5% 
10% 20% 30% 40% 50% 60% 70% 80% 
90% 
Probability of Escalating 
Dose 
0.97 
0.91 
0.71 
0.49 
0.31 
0.17 
0.08 
0.03 
0.01 
0.001 
The probability of failing to observe toxicity in a sample size of 3 or 6 patients given various true 
underlying toxicity rates in shown in the table below.  For example, with 6 patients, the probability of 
failing to observe toxicity occurring at least 40% of the time is < 5%.   
Probability of Failing to Observe True Underlying DLT Rate at a Dose Level 
True Underlying 
DLT Rate 
5% 
10% 20% 30% 40% 
50% 
60% 
70% 
80% 
90% 
Probability of 
Failing to Observe 
Toxicity, N = 3 
0.86 
0.73 
0.51 
0.34 
0.22 
0.13 
0.006 
0.027 
0.008 
0.001 
Probability of 
Failing to Observe 
Toxicity, N = 6 
0.74 
0.53 
0.26 
0.12 
0.05 
0.016 0.004 <0.001 <0.001 <0.001 

IND 100522 
 
105LC101 Protocol Amendment #3 
5.3.3.2 Clinical Protocol 
 
7July2015 
Page 13 of 93 
 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES  
TABLE OF CONTENTS 
1. 
SYNOPSIS ...................................................................................................................4 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ..................................13 
2. 
BACKGROUND ........................................................................................................22 
2.1. 
Angiogenesis and Cancer ...........................................................................................22 
2.1.1. 
Angiogenesis and Non-Small Cell Lung Cancer ........................................................22 
2.1.2. 
CD105 and Angiogenesis ...........................................................................................23 
2.2. 
TRC105 Background ..................................................................................................25 
2.2.1. 
Studies with TRC105 ..................................................................................................25 
2.2.1.1. 
105ST101 Phase 1 Monotherapy ................................................................................26 
2.2.1.2. 
Phase 1b 105ST102 Study with Bevacizumab ...........................................................29 
2.3. 
Study Rationale ...........................................................................................................32 
2.4. 
Population to be Studied .............................................................................................32 
2.5. 
Potential Risks and Benefits to Human Patients.........................................................33 
2.5.1. 
Potential Risks ............................................................................................................33 
2.5.2. 
Potential Benefits ........................................................................................................36 
2.6. 
Justification of the Dose, Schedule and Route of Administration of TRC105 ...........36 
2.6.1. 
Justification .................................................................................................................36 
2.7. 
Conduct .......................................................................................................................37 
3. 
TRIAL OBJECTIVES AND PURPOSE ....................................................................38 
3.1. 
Objectives ...................................................................................................................38 
3.1.1. 
Purpose .......................................................................................................................38 
3.1.2. 
Primary objectives ......................................................................................................38 
3.1.3. 
Secondary objectives ..................................................................................................38 
4. 
INVESTIGATIONAL PLAN .....................................................................................39 
4.1. 
Overall Study Design and Plan ...................................................................................39 
4.1.1. 
Overview .....................................................................................................................39 
4.1.1.1. 
Overview .....................................................................................................................39 
4.1.2. 
Trial Procedures ..........................................................................................................41 
4.1.2.1. 
Screening ....................................................................................................................41 
4.1.2.2. 
Trial Period .................................................................................................................42 

IND 100522 
 
105LC101 Protocol Amendment #3 
5.3.3.2 Clinical Protocol 
 
7July2015 
Page 14 of 93 
 
4.1.3. 
End of Study Assessments ..........................................................................................43 
4.1.4. 
Post Treatment Follow-up ..........................................................................................44 
5. 
SELECTION AND WITHDRAWAL OF PATIENTS ..............................................48 
5.1. 
Patient Inclusion Criteria ............................................................................................48 
5.2. 
Exclusion Criteria .......................................................................................................49 
5.3. 
Patient Withdrawal Criteria ........................................................................................50 
6. 
TREATMENT OF PATIENTS ..................................................................................51 
6.1. 
Description of TRC105 Study Drug ...........................................................................51 
6.1.1. 
Composition of TRC105.............................................................................................51 
6.1.2. 
TRC105 Dose Level ...................................................................................................51 
6.1.3. 
TRC105 Packaging and Labeling ...............................................................................51 
6.1.4. 
TRC105 Storage and Shipping ...................................................................................51 
6.1.5. 
TRC105 Preparation ...................................................................................................52 
6.1.6. 
TRC105 Administration .............................................................................................52 
6.1.7. 
TRC105 Dose Modification/Dose Interruptions ........................................................55 
6.1.8. 
Management of TRC105 Infusion Reactions .............................................................56 
6.1.9. 
TRC105 Study Drug Accountability ..........................................................................56 
6.1.10. 
TRC105 Study Drug Handling and Disposal .............................................................57 
6.2. 
Description of Bevacizumab .......................................................................................57 
6.2.1. 
Composition of Bevacizumab .....................................................................................57 
6.2.2. 
Bevacizumab Dose Level ...........................................................................................57 
6.2.3. 
Bevacizumab Packaging and Labeling .......................................................................57 
6.2.4. 
Bevacizumab Storage .................................................................................................57 
6.2.5. 
Bevacizumab Preparation ...........................................................................................57 
6.2.6. 
Bevacizumab Dosing ..................................................................................................57 
6.2.7. 
Bevacizumab Dose Modification ...............................................................................58 
6.2.8. 
Bevacizumab Drug Accountability .............................................................................58 
6.2.9. 
Bevacizumab Drug Handling and Disposal ................................................................58 
6.3. 
Description of Paclitaxel .............................................................................................58 
6.3.1. 
Composition of Paclitaxel...........................................................................................58 
6.3.2. 
Paclitaxel Dose Level .................................................................................................58 
6.3.3. 
Paclitaxel Packaging and Labeling .............................................................................58 
6.3.4. 
Paclitaxel Storage .......................................................................................................58 

IND 100522 
 
105LC101 Protocol Amendment #3 
5.3.3.2 Clinical Protocol 
 
7July2015 
Page 15 of 93 
 
6.3.5. 
Paclitaxel Preparation .................................................................................................59 
6.3.6. 
Paclitaxel Dosing ........................................................................................................59 
6.3.7. 
Paclitaxel Dose Modification .....................................................................................59 
6.3.8. 
Paclitaxel Drug Accountability...................................................................................59 
6.3.9. 
Paclitaxel Handling and Disposal ...............................................................................59 
6.4. 
Description of Carboplatin .........................................................................................59 
6.4.1. 
Composition of Carboplatin .......................................................................................60 
6.4.2. 
Carboplatin Dose Level ..............................................................................................60 
6.4.3. 
Carboplatin Packaging and Labeling ..........................................................................60 
6.4.4. 
Carboplatin Storage ....................................................................................................60 
6.4.5. 
Carboplatin Preparation ..............................................................................................60 
6.4.6. 
Carboplatin Dosing .....................................................................................................60 
6.4.7. 
Carboplatin Dose Modification ..................................................................................60 
6.4.8. 
Carboplatin Drug Accountability ...............................................................................60 
6.4.9. 
Carboplatin Handling and Disposal ............................................................................61 
6.5. 
Concomitant Medications ...........................................................................................61 
6.6. 
Treatment Compliance ................................................................................................61 
6.7. 
Patient Enrollment ......................................................................................................61 
7. 
ASSESSMENT OF EFFICACY ................................................................................62 
7.1. 
Radiological Tumor Assessment ................................................................................62 
7.1.1. 
Measurability of Tumor Lesions ................................................................................62 
7.1.1.1. 
Recording Tumor Measurements ...............................................................................63 
7.1.2. 
Definitions of Tumor Response ..................................................................................63 
7.1.2.1. 
Target Lesions ............................................................................................................63 
7.1.2.2. 
Non-Target Lesions ....................................................................................................63 
7.1.2.3. 
Determination of Overall Response ............................................................................64 
8. 
ASSESSMENT OF SAFETY .....................................................................................65 
8.1. 
Safety Parameters .......................................................................................................65 
8.1.1. 
Laboratory Safety Assessments ..................................................................................65 
8.1.1.1. 
Hematology, Serum Chemistry, Coagulation, Pregnancy Test ..................................65 
8.1.1.2. 
Urinalysis ....................................................................................................................65 
8.1.1.3. 
Physical Examination .................................................................................................66 
8.1.1.4. 
Vital Signs ..................................................................................................................66 

IND 100522 
 
105LC101 Protocol Amendment #3 
5.3.3.2 Clinical Protocol 
 
7July2015 
Page 16 of 93 
 
8.1.1.5. 
Performance Status .....................................................................................................66 
8.1.1.6. 
ECG ............................................................................................................................66 
8.2. 
Adverse Events ...........................................................................................................66 
8.2.1. 
Definition of Adverse Event .......................................................................................66 
8.2.2. 
Serious Adverse Events ..............................................................................................67 
8.2.2.1. 
Hospitalization ............................................................................................................68 
8.3. 
Reporting Adverse Events ..........................................................................................69 
8.3.1. 
Eliciting Adverse Event Information ..........................................................................69 
8.3.2. 
Adverse Event Reporting Period ................................................................................69 
8.3.3. 
Reporting Requirements .............................................................................................69 
8.3.4. 
Recording Adverse Events in the Case Report Forms ................................................70 
8.3.5. 
Grading of Adverse Event Severity ............................................................................70 
8.3.6. 
Relationship to TRC105 Study Drug, Bevacizumab, Paclitaxel and 
Carboplatin .................................................................................................................71 
8.3.7. 
Expectedness ...............................................................................................................71 
8.3.8. 
Exposure in Utero .......................................................................................................71 
8.3.9. 
Follow-up of Unresolved Adverse Events ..................................................................72 
8.4. 
Safety Monitoring .......................................................................................................72 
9. 
OTHER ASSESSMENTS ..........................................................................................74 
9.1. 
Other Laboratory Assessments ...................................................................................74 
9.1.1. 
Pharmacokinetics ........................................................................................................74 
9.1.1.1. 
TRC105 Trough Concentration ..................................................................................74 
9.1.2. 
TRC105 Immunogenicity ...........................................................................................74 
9.1.3. 
Protein Biomarkers .....................................................................................................74 
9.1.4. 
Archival Tumor Specimens ........................................................................................74 
10. 
STATISTICS ..............................................................................................................75 
10.1. 
Statistical Design/Sample Size ...................................................................................75 
10.1.1. 
Statistical Design/Sample Size ...................................................................................75 
10.1.1.1. 
Definition of Analyzed Study Populations .................................................................75 
10.2. 
Data Analysis ..............................................................................................................76 
10.2.1. 
Analysis of Primary Objective....................................................................................76 
10.2.1.1. 
Analysis of Primary Objective....................................................................................76 
10.2.2. 
Analysis of Pharmacokinetics .....................................................................................76 

IND 100522 
 
105LC101 Protocol Amendment #3 
5.3.3.2 Clinical Protocol 
 
7July2015 
Page 17 of 93 
 
10.2.3. 
Objective Response ....................................................................................................76 
10.2.4. 
Analysis of Protein Biomarkers ..................................................................................77 
10.2.5. 
Analysis of Immunogenicity .......................................................................................77 
10.2.6. 
Analysis of Archival Tumor Tissue ............................................................................77 
11. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................78 
12. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................79 
13. 
ETHICS ......................................................................................................................80 
13.1. 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) ..................80 
13.2. 
Ethical Conduct of the Study ......................................................................................80 
13.3. 
Written Informed Consent ..........................................................................................80 
13.4. 
Patient Compensation .................................................................................................80 
14. 
DATA HANDLING AND RECORDKEEPING .......................................................81 
14.1. 
Inspection of Records .................................................................................................81 
14.2. 
Retention of Records ..................................................................................................81 
15. 
DEFINITION OF END OF TRIAL ...........................................................................82 
15.1. 
End of Trial in all Participating Countries ..................................................................82 
15.2. 
End of Trial in a Member State ..................................................................................82 
15.3. 
TRACON Discontinuation Criteria ............................................................................82 
16. 
PUBLICATION OF TRIAL RESULTS ....................................................................83 
17. 
FINANCING AND INSURANCE .............................................................................84 
18. 
INVESTIGATOR PROTOCOL AGREEMENT: 105LC101 ....................................85 
19. 
REFERENCES ...........................................................................................................86 
20. 
APPENDICES ............................................................................................................92 
20.1. 
Appendix 1:  National Cancer Institute (NCI) Common Terminology 
Criteria for Adverse Events (CTCAE) .......................................................................92 
20.2. 
Appendix 2:  ECOG Performance Status ...................................................................93 
 
LIST OF TABLES 
Table 1: 
Emergency Contact Information ...................................................................................3 
Table 2: 
Abbreviations and Specialist Terms ...........................................................................19 
Table 3: 
Dose Limiting Toxicity Definition and Criteria .........................................................40 
Table 4: 
Schedule of Assessments ............................................................................................45 
Table 5: 
Cycle 1 Premedication Regimen ................................................................................53 

IND 100522 
 
105LC101 Protocol Amendment #3 
5.3.3.2 Clinical Protocol 
 
7July2015 
Page 18 of 93 
 
Table 6: 
Cycle 2 through Cycle 6 Premedication Regimen ......................................................53 
Table 7: 
Cycle 7+ Premedication Regimen (TRC105 + Bevacizumab Maintenance 
Phase of the Protocol) .................................................................................................54 
Table 8: 
Allowable TRC105 Dose Modifications ....................................................................55 
Table 9: 
Management of TRC105 Infusion Reactions .............................................................56 
Table 10: Response Evaluation Criteria in Solid Tumors ..........................................................64 
Table 11: Adverse Event Grading ...............................................................................................70 
Table 12: Probability of Escalation to the Next Dose for Each True Underlying DLT 
Rate at a Dose Level ...................................................................................................75 
Table 13: Probability of Failing to Observe True Underlying DLT Rate at a Dose 
Level ...........................................................................................................................75 
 
LIST OF FIGURES 
Figure 1: Single-Dose and Multiple-Dose Pharmacokinetic Data from Study 105ST101 ............27 
 
 
 
 

IND 100522 
 
105LC101 Protocol Amendment #3 
5.3.3.2 Clinical Protocol 
 
7July2015 
Page 19 of 93 
 
Table 2: 
Abbreviations and Specialist Terms 
Abbreviation or specialist term Explanation 
ADCC 
Antibody-Dependent Cell-mediated Cytotoxicity 
AE 
Adverse Event 
AFP 
Alpha Fetoprotein 
AIDS 
Acquired Immunodeficiency Syndrome 
ALKs 
Activin receptor-Like Kinases 
ALT 
Alanine Aminotransferase 
ANC 
Absolute Neutrophil Count 
APA 
Anti-Product Antibody 
AST 
Aspartate Aminotransferase 
AUC 
Area Under the Curve 
AUClast 
Time of Last Measurable Concentration of Area Under the Curve 
BALB/c mice 
Mouse Strain 
BMP 
Bone Morphogenic Protein 
BUN 
Blood Urea Nitrogen 
CABG 
Coronary Artery Bypass Graft 
CBC 
Complete Blood Count 
CEA 
Carcinoembryonic Antigen 
CHOP 
Cyclophosphamide Hydroxydaunomycin Oncovin® Prednisone 
CL 
Clearance 
Cmax 
Maximum Serum Concentration  
CPA 
Cyclophosphamide 
CR 
Complete Response 
CRF 
Case Report Form 
CT 
Computed Tomography 
CTC 
Common Terminology Criteria 
dL 
Deciliter 
DLT 
Dose Limiting Toxicity 
DVT 
Deep Vein Thrombosis 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
ECM 
Extracellular Matrix 
EGFR 
Epidermal Growth Factor Receptor 
ELISA 
Enzyme-Linked ImmunoSorbent Assay 
EOS 
End of Study 
FDA 
Food and Drug Administration 
FGF 
Fibroblast Growth Factor 
FU 
Fluorouracil 
g 
Gram 
GOG 
Gynecologic Oncology Group 
GCP 
Good Clinical Practice 
GIST 
Gastrointestinal Stromal Tumor 
HACA 
Human Anti-Chimeric Antibodies 
HAMA 
Human Anti-Murine Antibodies 
Her-2 
Human epidermal growth factor receptor 2 

IND 100522 
 
105LC101 Protocol Amendment #3 
5.3.3.2 Clinical Protocol 
 
7July2015 
Page 20 of 93 
 
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 
HRA 
Health Regulatory Authority 
HUVECs 
Human Umbilical Vein Endothelial Cells 
ICH 
International Conference on Harmonization 
ID 
Identification 
IEC 
Independent Ethics Committee 
IgG 
Immunoglobulin G 
IgM 
Immunoglobulin M 
IL 
Interleukin 
INR 
International Normalized Ratio 
IP 
Intraperitoneal 
IRB 
Institutional Review Board 
i.v. 
Intravenous 
Kd 
Avidity Binding Constant 
kg 
Kilogram 
L 
Liter 
LDH 
Lactate Dehydrogenase 
LOQ 
Limit of Quantification 
μL 
Microliter 
Mg 
Milligram 
mL 
Milliliter 
MACA 
Monkey Anti-Chimeric Antibody 
MAMA 
Monkey Anti-Murine Antibody 
MI 
Myocardial Infarction 
mm 
Millimeter 
MRI 
Magnetic Resonance Imaging 
MTD 
Maximum Tolerated Dose 
NCI 
National Cancer Institute 
NCIC 
National Cancer Institute of Canada 
ng 
Nanogram  
NHP 
Nonhuman Primate 
NOAEL 
No Adverse Effect Level 
PBS 
Phosphate-Buffered Saline 
PD 
Progressive Disease 
PDGF 
Platelet Derived Growth Factor 
PDGFR 
Platelet Derived Growth Factor Receptor 
PlGF 
Placental Growth Factor 
pM 
Picomolar 
PR 
Partial Response 
PSA 
Prostate Specific Antigen 
PTCA 
Percutaneous Transluminal Coronary Angioplasty  
PTT 
Partial Thromboplastin Time 
QA 
Quality assurance 
RCC 
Renal cell carcinoma 
RECIST 
Response Evaluation Criteria in Solid Tumors 

IND 100522 
 
105LC101 Protocol Amendment #3 
5.3.3.2 Clinical Protocol 
 
7July2015 
Page 21 of 93 
 
 
 
 
 
 
 
 
SAE 
Serious Adverse Event 
sCD105 
Soluble CD105/endoglin 
SCID 
Severe Combined Immunodeficient 
SD 
Stable Disease 
SGOT 
Serum Glutamic Oxaloacetic Transaminase 
SGPT 
Serum Glutamic Pyruvic Transaminase 
SN6j 
Murine parent antibody of TRC105 
sVEGFR2  
Soluble VEGF Receptor 2 
TGF-β 
Transforming Growth Factor 
TSH 
Thyroid Stimulating Hormone 
ULN 
Upper Limit of Normal 
US 
United States of America 
VEGF 
Vascular Endothelial Growth Factor 
VEGFR 
Vascular Endothelial Growth Factor Receptor 
VEGFR TKI 
Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitor 

IND 100522 
 
105LC101 Protocol Amendment #3 
5.3.3.2 Clinical Protocol 
 
7July2015 
Page 22 of 93 
 
2. 
BACKGROUND 
2.1. 
Angiogenesis and Cancer  
The critical role of angiogenesis in the development, growth, and distant metastasis of solid 
tumors is well described [1,2]  In addition to the delivery of oxygen and nutrients to, and the 
exportation of cellular waste products from tumor cells, the vascular supply provides a 
mechanism by which malignant cells disseminate into distant tissues [3].  As a tumor grows 
beyond 3-4mm, it becomes vitally dependent on angiogenesis to sustain vascular supply. Tumor 
angiogenesis results from the disequilibrium between pro- and anti-angiogenic signaling 
pathways and several targetable regulatory pathways have been identified. In 1971, vascular 
endothelial growth factor (VEGF) was described as a potent factor in inducing tumor 
angiogenesis and was explored as the first target for anti-angiogenic therapy [4]. Further 
characterization of the VEGF/VEGFR signaling pathway led to the identification of VEGF-A as 
the central angiogenesis promoter and subsequently bevacizumab (monoclonal antibody against 
VEGF-A165) was developed [5, 6]. Elevated VEGF levels are thought to cause endothelial leaks 
in tumor vascular supply thereby decreasing the delivery of chemotherapy to tumor [7]. In 
addition arresting the development of new vascular supply to the tumor, bevacizumab is felt to 
increase chemotherapy delivery to tumors through the inhibition of VEGF and stabilization of 
vascular endothelium [8].  
Targeting angiogenesis via VEGF-A antagonists provides clinical benefit in several solid tumor 
types. 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 [9,10].  Bevacizumab is also 
effective therapy for renal cell cancer and malignant glioma [11-13].  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 [14-17].    
2.1.1. 
Angiogenesis and Non-Small Cell Lung Cancer  
Advanced non-small cell lung cancer has been historically difficult to treat, and novel agents are 
in dire need. Prognosis is poor, with 1 year survival rates of 30% to 40%. Two drug platinum-
based chemotherapy regimens have long been the traditional treatment of choice, but a plateau 
effect is inevitably reached and survival is approximately 8 months, regardless of regimen 
chosen [18,19].  Since VEGF over-expression is typical in non-small cell lung cancer, 
bevacizumab was investigated in combination with platinum doublet chemotherapy. A 
randomized phase II study of treatment naïve patients with advanced NSCLC compared 
paclitaxel and carboplatin alone with paclitaxel, carboplatin, and bevacizumab at a dose of 7.5mg 
or 15 mg per kilogram body weight intravenously every three weeks [20]. Improved median time 
to progression was seen in the 15mg bevacizumab group, albeit at an increased risk of pulmonary 
hemorrhage. Based on this study, a landmark phase III study(ECOG 4599) of nearly 900 patients 
with advanced NSCLC was undertaken. Patients in this study were randomized to paclitaxel and 
carboplatin chemotherapy alone or paclitaxel, carboplatin, plus bevacizumab 15mg/kg every 3 
weeks [10]. This study demonstrated an overall survival advantage of 2 months in the 
bevacizumab arm (12.3 months vs 10.3 months). The rates of clinically significant bleeding were 
slightly increased in the bevacizumab group (4.4% vs 0.7%). This trial led to the standardization 

IND 100522 
 
105LC101 Protocol Amendment #3 
5.3.3.2 Clinical Protocol 
 
7July2015 
Page 23 of 93 
 
of paclitaxel, carboplatin, and bevacizumab as preferred first line therapy for patients with 
advanced NSCLC.  
Subsequently, the AVAiL (Avastin in Lung) study confirmed the PFS benefit of adding 
bevacizumab to first-line cisplatin/gemcitabine, though an OS advantage was not demonstrated 
[21].  In an effort to evaluate two agents shown to have activity in the maintenance setting in 
advanced NSCLC patients, the investigators of the AVAPERL trial compared bevacizumab 
monotherapy to bevacizumab plus pemetrexed after induction with bevacizumab, cisplatin, and 
pemetrexed. In an unselected patient population with non-squamous advanced NSCLC who had 
responded to induction chemotherapy, bevacizumab plus pemetrexed maintenance was 
associated with significant PFS benefit (7.4mo vs 3.7 mo) compared to bevacizumab alone [22].  
Given the benefit seen with the combination of bevacizumab and pemetrexed in the maintenance 
setting, there was interest in comparing pemetrexed in combination with bevacizumab and 
platinum with the standard platinum, paclitaxel, and bevacizumab as initial therapy. 
POINTBREAK was randomized phase III trial which compared the efficacy of pemetrexed, 
carboplatin, and bevacizumab followed by pemetrexed plus bevacizumab with paclitaxel, 
carboplatin, and bevacizumab followed by bevacizumab in patients with advanced NSCLC. This 
was a negative study as the primary end point of improved OS in the pemetrexed arm was not 
met. The median OS for both arms in the POINTBREAK trial was similar to the medial OS seen 
in ECOG 4599, at approximately 12.5 months [23].  As such, the regimen of carboplatin, 
paclitaxel, and bevacizumab followed by maintenance bevacizumab remains the standard front 
line therapy for patients with advanced NSCLC. It is the anti-angiogenic agent bevacizumab, 
rather than the addition of more chemotherapy, which seems to confer the greatest benefit 
against disease progression in advance NSCLC. This benefit is conceptually understandable in a 
tumor such as NSCLC in which the majority of cells over express VEGF [24].  Targeting 
angiogenesis, in addition to delivering cytotoxic chemotherapy, has led to the best outcomes for 
patients with advanced NSCLC.   
2.1.2. 
CD105 and Angiogenesis 
However despite the initial enthusiasm for anti-VEGF agents, their clinical effects have proven 
to be generally modest and transient, resulting in limited survival advantage [25, 26].  The 
underlying cause for clinical progression in patients treated with anti-VEGF therapy is the 
acquisition of resistance to therapy via up regulation of alternative pro-angiogenic pathways 
[27].  Surrogate pro-angiogenic signal cascades, including platelet-derived growth factor 
(PDGF), fibroblast growth factor (FGF), and placental growth factor (PlGF) are activated when 
VEGF-mediated angiogenesis is blocked [28].  In addition to these, the transforming growth 
factor β (TGF-β) plays a prominent role in tumor angiogenesis. TGF-β promotes tumor 
development by stimulating cancer cell invasion, immune suppression, and inducing 
angiogenesis [29]. The direct pro-angiogenic effects of TGF-β on endothelial cells are mediated 
by the expression of TGF-β co-receptor endoglin [30]. Also known as CD105, endoglin is highly 
expressed on proliferating endothelial cells and high endoglin expression is associated with sites 
of active angiogenesis [31, 32]. Therefore, endoglin has emerged as an attractive target for both 
anti-angiogenic therapy and response monitoring in patients with disease progression despite 
anti-VEGF therapy. 
CD105 (endoglin) is a homodimeric cell membrane glycoprotein that was initially identified as a 
human leukemia-associated antigen [33] and later also found on endothelial cells [34,35].  

IND 100522 
 
105LC101 Protocol Amendment #3 
5.3.3.2 Clinical Protocol 
 
7July2015 
Page 24 of 93 
 
CD105 is a TGF-β coreceptor that is essential for angiogenesis [36, 37] and CD105 is strongly 
expressed on the proliferating vascular endothelium of solid tumors [35, 38].  All of these 
properties make CD105 an attractive target for the antiangiogenic therapy of cancer [39].  
Vascular targeted therapy may more effectively address large established tumors than 
conventional antiangiogenic therapy such as anti-VEGF therapy [40].  In animal models, CD105 
targeted therapy has demonstrated both vascular targeting effects and antiangiogenic effects by 
inducing regression of established tumors as well as by preventing new tumor formation and 
inhibiting expansion of existing tumors [35,41-44]. Therefore, CD105 offers a novel alternative 
target relative to the VEGF inhibitors currently available for antiangiogenesis therapy.   
CD105 acts to modulate signaling of multiple kinase receptor complexes of the TGF-β 
superfamily, including TGF-β receptors, activin receptor-like kinases (ALKs) and activin 
receptors [45].  In the absence of CD105, activation of TGF-β receptors results in 
phosphorylation of SMAD proteins that inhibit endothelial cell growth.  However, activation of 
CD105 by TGF-β modulates SMAD protein phosphorylation.  The end result is release of the 
growth inhibitory effects of TGF-β receptor activation on endothelium.  Not surprisingly, 
prevention of CD105 activation by anti-CD105 antibody acts synergistically with TGF-β to 
inhibit endothelial cell growth [46].  Similarly, CD105 acts in concert with the bone 
morphogenic protein (BMP) receptor to phosphorylate SMAD 1 and 5 in response to binding 
BMP 9 and 10, to activate endothelium [47]. 
CD105 expression is required for endothelial cell proliferation, and CD105 is upregulated in the 
setting of hypoxia through the induction of hypoxia-inducible factor-1-α (HIF-1-α) [48, 49].  
CD105 has also been shown to protect hypoxic cells from apoptosis [50].  The expression of 
CD105 by endothelial cells is essential for the development of new vasculature.  Targeted 
inactivation (knockout) of murine CD105 results in defective vascular development.  Mice 
lacking CD105 die in utero from defective vascular development by gestational day 11 [37].   
CD105 is critical for normal human blood vessel development [51].  CD105 haplotype 
insufficiency causes a well-described syndrome known as hereditary hemorrhagic telangiectasia 
type 1 (HHT-1 or Osler-Weber-Rendu Syndrome).  HHT-1 is a rare autosomal dominant genetic 
disorder characterized by localized angiodysplasia involving the nasal, buccal, gastrointestinal 
mucosa and skin microvasculature.  Angiodysplasia also occurs in vessels from internal organs 
including the lungs, liver and brain [52].  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 limited to vascular 
effects, indicating the specific role of CD105 in the vasculature [53].   
CD105 is highly expressed on the proliferating endothelial cells of tumor vessels including lung, 
breast, colorectal, gastric, liver, endometrial, renal cell, head and neck, and ovarian cancers.  In 
adults, CD105 expression is limited to vascular endothelial cells and proerythroblasts, a red 
blood cell precursor [54].   
CD105 expression is a prognostic factor in solid tumor patients.  High microvessel density of 
CD105-positive vessels has been correlated with poor prognosis in clinical studies of breast 
cancer [55,56], lung cancer [57], prostate cancer [58,59], colorectal cancer [60,61], ovarian 
cancer  [62,63], gastric cancer [64], endometrial cancer [65], astrocytic brain tumors [66], 
hepatocellular carcinoma [67], esophageal adenocarcinoma [68], and head and neck cancer 
[69,70].   

IND 100522 
 
105LC101 Protocol Amendment #3 
5.3.3.2 Clinical Protocol 
 
7July2015 
Page 25 of 93 
 
Plasma CD105 levels are prognostic in retrospective studies of cancer patients.  In one study, the 
mean plasma CD105 concentration in 76 patients with colorectal cancer was 4-fold higher than 
the mean value in 40 healthy subjects without cancer [60].  In the study, a positive correlation 
was observed between plasma CD105 concentration and stage of disease.   
Importantly, CD105 expression is upregulated in tumor endothelial cells following inhibition of 
the VEGF pathway.  CD105 expression increased more than 2-fold in human pancreatic cancers 
grown in mice treated with an antibody that binds VEGF [71].  As well, treatment of human 
bladder cancers grown in mice with an antibody that blocks activation of the VEGF receptor 
increased CD105 expression within the core tumor vasculature [72].   
TRC105 is a novel IgG1 that binds CD105 with high avidity.  Recent studies at Duke University 
explored the in vitro effects of dual angiogenesis inhibition using bevacizumab and TRC105 in 
human umbilical vein endothelial cells (HUVEC).  Combination therapy was found to be more 
potent in decreasing HUVEC proliferation, migration, and tubular network formation than 
bevacizumab or TRC105 treatment alone [73].  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 FGF [47]. Finally, antibody to 
mouse CD105 potentiates the activity of multitargeted kinase inhibition that targets the VEGFR-
2, in mouse bearing cancer grafts [74].    
2.2. 
TRC105 Background 
 
TRC105 is a genetically engineered human/murine chimeric monoclonal antibody directed 
against human CD105 [66], a growth proliferation receptor found on the surface of normal and 
proliferating endothelial cells [35,41,49].   
The antibody is an IgG1 kappa immunoglobulin containing murine variable region sequences 
and human constant region sequences [75].  TRC105 has an approximate molecular weight of 
148 kDa. TRC105 has a binding avidity for human CD105 of approximately 5 pM. TRC105 is 
formulated as 20 mM L-Histidine/L-Histidine Monohydrochloride, 240 mM Trehalose, 0.01% 
Polysorbate 20 Formulation at a concentration of 25 mg/mL.   
SN6j, the murine parent antibody of TRC105, binds to human umbilical vein endothelial cells 
(HUVECs) with nearly identical avidity as TRC105.  SN6j has been shown to bind the tumor 
vasculature of malignant tissues including breast, colon, rectum, kidney and lung cancers and to 
inhibit the growth of tumor xenografts [42].  Reactivity with tumor tissues is restricted to the 
tumor endothelium, as CD105 is not generally expressed on epithelial tumor cells [41].  TRC105 
induces ADCC on proliferating HUVECs at low conentrations and induces apoptosis and growth 
inhibition at higher concentrations.   
2.2.1. 
Studies with TRC105  
Several studies with TRC105 are underway or have been completed.  An open-label, phase 1, 
multicenter study of TRC105 (Study 105ST101) enrolled fifty patients, who were treated until 
disease progression with TRC105 at 0.01-15 mg/kg/q2wk or 10-15 mg/kg/wk [76].  Studies of 
TRC105 in prostate, bladder, and ovarian cancer and a phase 1b study of TRC105 in 
combination with bevacizumab have also been completed.  Ongoing studies include a phase 1b 
study of TRC105 in combination with sorafenib in liver cancer, a phase 1b study of TRC105 in 

IND 100522 
 
105LC101 Protocol Amendment #3 
5.3.3.2 Clinical Protocol 
 
7July2015 
Page 26 of 93 
 
combination with axitinib in renal cell carcinoma, a phase 1b study of TRC105 in combination 
with pazopanib and a phase 1b study of TRC105 in combination with bevacizumab in 
glioblastoma multiforme.  
2.2.1.1. 
105ST101 Phase 1 Monotherapy 
2.2.1.1.1. 105ST101 Phase 1 Monotherapy Pharmacokinetics 
In Study 105ST101, TRC105 pharmacokinetics were assessed on patients enrolled at doses up to 
15 mg/kg weekly.  Circulating TRC105 was not measurable above the lower limit of quantitation 
of the assay (78 ng/mL) in patients receiving doses below 0.3 mg/kg.  TRC105 was measurable 
above the target concentration based on preclinical data (200 ng/mL) for 4 hours at 0.3 mg/kg, 1 
day at 1 mg/kg, 5 days at 3 mg/kg, and 7 days at 10 mg/kg TRC105 dosed every two weeks.  
Serum concentrations expected to saturate CD105 binding sites (≥ 200 ng/mL) were achieved 
continuously at 15 mg/kg q2wk and 10 mg/kg weekly, and TRC105 accumulated at 15 mg/kg 
weekly (Figure 1). 

IND 100522 
 
105LC101 Protocol Amendment #3 
5.3.3.2 Clinical Protocol 
 
7July2015 
Page 27 of 93 
 
Figure 1: Single-Dose and Multiple-Dose Pharmacokinetic Data from Study 105ST101 
 
 
2.2.1.1.2. 105ST101 Phase 1 Monotherapy Immunogenicity 
In Study 105ST101, serum samples for evaluation of TRC105 immunogenicity, including 
HAMA and HACA, were collected pre-dose on day 1 of each 28 day cycle, at the end of study, 
and then at 4 and 12 weeks after the end of study visit. 
HAMA and HACA data are available from the phase 1 monotherapy TRC105 trial.  Neither 
HAMA nor HACA were detected in patients treated with CHO-produced TRC105, which will be 
used for all future clinical trials, including this study. 

IND 100522 
 
105LC101 Protocol Amendment #3 
5.3.3.2 Clinical Protocol 
 
7July2015 
Page 28 of 93 
 
2.2.1.1.3. 105ST101 Phase 1 Monotherapy Safety  
A total of 50 patients were treated on Study 105ST101 with escalating doses of TRC105 at 0.01, 
0.03, 0.1, 0.3, 1, 3, 10 and 15 mg/kg every two weeks and then 10 and 15 mg/kg weekly.  Dose 
escalation proceeded stepwise until the top dose was reached.  The maximum tolerated dose was 
exceeded at 15 mg/kg weekly and the recommended phase 2 dose of TRC105 was therefore 
determined to be 10 mg/kg weekly.  Three of 4 patients at 15 mg/kg weekly developed grade 3 
hypoproliferative anemia (without leucopenia or thrombocytopenia) in cycle 2, and one of the 
three progressed to grade 4 in cycle 3.  Anemia was associated with accumulation of TRC105 
and characterized by a low reticulocyte production index.  Additional laboratory and clinical 
evaluations excluded common causes of anemia including blood loss, hemolysis, plasma volume 
expansion, inadequate erythropoietin, iron deficiency, and vitamin B-12 or folate deficiency.  
The anemia is believed to result from TRC105-mediated suppression of  proerythroblasts, the 
only cells in the bone marrow known to express substantial levels of CD105 [47].  Anemia was 
reversible and manageable with dose reduction and standard supportive measures including 
erythropoietin and blood transfusion.   
Infusion reactions, anemia, fatigue, epistaxis and headache were the most frequently observed 
adverse events considered related to TRC105.  The majority of treatment-related adverse events 
were grade 1 or 2. 
Infusion reactions, among the most common adverse events, were usually with the initial 
TRC105 dose and included one or more of the following signs or symptoms: rigors, 
bronchospasm, urticaria, hypertension, hypotension, tachycardia or bradycardia.  Infusion 
reactions were initially reported at 1 mg/kg every 2 weeks for patients receiving TRC105 
produced in NS0 cells without premedication.  TRC105 produced in CHO cells was known to 
more potently engage ADCC in vitro than TRC105 produced in NS0 cells.  Because of this, the 
initial dose level for patients receiving CHO-produced TRC105 was de-escalated to 0.3 mg/kg.  
Despite dose de-escalation, the first two patients at 0.3 mg/kg treated with CHO-produced 
TRC105 experienced grade 2 and grade 3 infusion reactions with the first dose in the absence of 
premedication.  The protocol was therefore amended to require a glucocorticoids -based 
premedication regimen and extend the initial infusion duration from 1 to 4 hours.   
The amendment mandating premedication and extended initial infusion duration successfully 
reduced the frequency and severity of infusion reactions and allowed dose escalation to continue. 
One additional patient who received CHO-produced TRC105 at 1 mg/kg developed a grade 3 
infusion reaction with the third dose given over 2 hours.  This patient had experienced a grade 2 
infusion reaction when the dose was administered over 4 hours.  In all three patients with grade 3 
infusion reactions, TRC105 was not detectable in serum at the time of dosing, which allowed de 
novo binding of TRC105 to CD105 expressing endothelium within the vasculature.  Grade 3 
infusion reactions were not observed in patients dosed at 10 or 15 mg/kg who maintained 
TRC105 serum levels known to saturate CD105 binding sites for the full dosing interval.  At 
dose levels where continuous TRC105 serum levels were achieved, glucocorticoids were safely 
discontinued and the infusion duration reduced to 1 hour. 
Three patients developed grade 1 cutaneous telangiectasia on the trunk early in the course of 
therapy, all at dose levels of 10 or 15 mg/kg weekly that resulted in continuous serum levels of 
TRC105 known to saturate CD105 sites on human endothelium.  Grade 1 or 2 hemorrhage was 

IND 100522 
 
105LC101 Protocol Amendment #3 
5.3.3.2 Clinical Protocol 
 
7July2015 
Page 29 of 93 
 
reported, including intermittent postcoital vaginal bleeding (that also occurred prior to TRC105 
treatment), epistaxis, and superficial gingival bleeding.    
Grade 1 or 2 headaches were observed, mainly in patients treated at doses of TRC105 above 3 
mg/kg.  Headaches began the day following infusion and were generally manageable with 
acetaminophen.  However, grade 2 headache in one patient at 15 mg/kg weekly prompted 
discontinuation prior to completion of the dose-limiting toxicity evaluation period.  Fatigue was 
one of the more common adverse events attributable to TRC105 and was more prevalent at doses 
above 3 mg/kg.   
One patient developed dose-limiting toxicity of grade 4 hemorrhage presenting as melena from a 
gastric ulcer within 5 days of the initial TRC105 infusion at 0.1 mg/kg.  He discontinued 
TRC105 treatment, was transfused 2 units of packed red blood cells and the bleeding resolved 
with nonsurgical management by the time of upper endoscopy.  Serious bleeding was not 
observed following protocol amendment to exclude patients with a history of peptic ulcer disease 
(unless healing was documented) and patients on ulcerogenic medications including non-
steroidal anti-inflammatory drugs.  
Classic toxicities associated with VEGF inhibition, including hypertension, proteinuria and 
thrombosis were not prominent.  One patient with recurrent anal cancer treated at 0.1 mg/kg 
developed proteinuria considered possibly related to TRC105, but proteinuria was also noted 
prior to TRC105 dosing.  Transient hypertension (156/112) without QT changes occurred in a 
single patient one day following infusion of 15 mg/kg, and was controlled by a single dose of 
oral antihypertensive medication. There were no arterial or venous thromboembolic events, nor 
gastrointestinal or other perforations in these patients.    
2.2.1.1.4. 105ST101 Phase 1 Monotherapy Efficacy 
In study 105ST101 stable disease ≥ 2 months was observed in 21 of 45 patients (47%) and stable 
disease ≥ 4 months in 6 of 44 patients (14%).  Decreases in CEA, PSA, or CA-125 were noted in 
7 of 21 patients (33%) and a global decrease in key angiogenic biomarkers was observed with 
treatment.  One patient with castrate-refractory prostate cancer remains on TRC105 treatment 
after 6 years at a TRC105 dose of 0.01 mg/kg every 2 weeks.  He has an ongoing complete PSA 
response, with resolution of bone pain and bone scan normalization. One patient with metastatic 
carcinosarcoma, manifested decreased tumor burden on computerized tomographic scanning and 
maintained stable disease for 20 months on therapy. The latter is especially notable when one 
considers that this patient had received three prior treatments -- carboplatin + paclitaxel for 4 
months, anastrozole for 8 months, and ifosfamide for 2 months -- and had manifested tumor 
progression on each.  In effect, TRC105 provided the most favorable clinical outcome and did so 
as a fourth-line therapy.   
2.2.1.2. 
Phase 1b 105ST102 Study with Bevacizumab 
TRC105 was studied in combination with bevacizumab in a Phase 1/2 trial that enrolled 38 
patients [77]. 
2.2.1.2.1. 105ST102 Summary of Safety 
Administration of TRC105 at a dose of 3 mg/kg weekly in combination with bevacizumab was 
well tolerated by three patients without the development of dose limiting toxicity (DLT) and 

IND 100522 
 
105LC101 Protocol Amendment #3 
5.3.3.2 Clinical Protocol 
 
7July2015 
Page 30 of 93 
 
dose escalation occurred per the protocol to cohort 2 (6 mg/kg TR105 weekly).  However, the 
concurrent administration of 6 mg/kg TRC105 and bevacizumab on day 1 resulted in the 
development of moderate or severe headaches (including two grade 3 headaches) in four of five 
treated patients.  The 6 mg/kg dose of TRC105 was tolerated when the initial TRC105 dose was 
delayed one week following bevacizumab dosing at 10 mg/kg every two weeks.  Tolerability 
was further improved when the initial dose of TRC105 was given over two days during the first 
week of TRC105 dosing, and dose escalation proceeded to the recommended phase 2 dose of 10 
mg/kg TRC105 weekly.  At the recommended phase 2 dose of both drugs (10 mg/kg), TRC105 
serum concentration were present above target concentration continuously and immunogenicity 
was rarely observed. 
A total of 38 patients were dosed on study across six cohorts and four dose levels. Other than 
headaches that were mitigated by adjusting the dosing schedule of TRC105, the combination of 
TRC105 and bevacizumab was well tolerated.  Two patients experienced grade 3 serious adverse 
suspected events as described below. Most adverse events were graded as 1 or 2 and Grade 4 and 
5 suspected adverse events were not observed. Grade 3 suspected adverse reactions included 
anemia (the dose limiting toxicity of TRC105 established as a single agent; 9 patients), headache 
(4 patients; three of which occurred prior to adjusting the schedule of TRC105), fatigue (2 
patients), brain abscess (1 patient), infusion reaction (in a patient dosed at 6 mg/kg), and 
decreased appetite (1 patient). Headache was the most common suspected adverse event and 
occurred in 31 patients (86.1%); three patients (7.9%) experienced migraine headaches (two of 
grade 1 and one of grade 2 severity). Headaches were treated with triptans and NSAIDs. 
Two patients experienced serious adverse suspected events as described below.  One of the grade 
3 headaches (in a patient dosed at 8 mg/kg without splitting the initial TRC105 dose over two 
days) resulted in hospitalization and patient discontinuation.  One patient dosed at 10 mg/kg of 
TRC105 experienced a serious suspected event of grade 3 brain abscess.  Serious adverse events, 
considered unrelated to TRC105 treatment, included: grade 3 pneumonia and subsequent grade 4 
MRSA sepsis that was complicated by a non Q-wave myocardial infarction during a period of 
hemodynamic instability while hospitalized; grade 3 ileus at the time of symptomatic disease 
progression; grade 5 disease progression; grade 3 left foot cellulitis; grade 3 recurrent 
pneumothorax; grade 3 small bowel obstruction; grade 4 urosepsis. 
At least one sign of the triad of epistaxis, gingival bleeding and telangiectasia, reflecting vascular 
ectasia characteristic of the Osler-Weber-Rendu syndrome of endoglin haplotype insufficiency 
(i.e., an autosomal dominant genetic disorder of heterozygous endoglin expression) was observed 
frequently.  One of these signs or symptoms (of grade 1 or 2 severity) was noted in one of three 
patients treated at 3 mg/kg, four of eight patients treated at 6 mg/kg, four of eight patients treated 
at 8 mg/kg and in all nineteen patients treated at 10 mg/kg of TRC105, generally within the first 
month of dosing.  These signs and symptoms are an expected pharmacologic effects of TRC105 
binding to the endoglin receptor (i.e., they are characteristic of the Rendu-Osler-Weber 
syndrome, that is caused by endoglin haploinsufficiency), and were also observed routinely 
within the first month of dosing of 10 mg/kg weekly in the single agent TRC105 dose escalation 
study.   
Infusion reactions were, as expected, more notable at lower doses, and were rare at the MTD of 
TRC105 of 10 mg/kg, when TRC105 serum concentrations were maintained continuously.  Two 
of nineteen patients (10%) dosed with 10 mg/kg of TRC105 each experienced a single infusion 

IND 100522 
 
105LC101 Protocol Amendment #3 
5.3.3.2 Clinical Protocol 
 
7July2015 
Page 31 of 93 
 
reaction of grade 2 severity, both with the initial dose of TRC105, that required a brief 
interruption of the infusion prior to completion of the scheduled dose. 
Clinically significant anemia was not reported in patients dosed with 3 mg/kg or 6 mg/kg of 
TRC105, was reported in three of seven patients (43%; all grade 3) dosed with 8 mg/kg of 
TRC105, and was observed in nine of 19 (47%; three of grade 2 and six of grade 3 severity) of 
patients dosed with 10 mg/kg of TRC105.  Anemia prompted transfusion of packed red blood 
cells in 10 patients and growth factors were used in five patients. 
Other, less frequent, suspected adverse reactions included hypothyroidism, periorbital edema 
(which was generally noted prior to splitting the initial dose of TRC105), gingival pain, nausea, 
oral pain, vomiting, edema, decreased appetite, dyspnea, nasal congestion, rash and flushing. 
Other adverse events characteristic of each individual drug were not increased in frequency or 
severity when the two drugs were administered together.  Of note, the concurrent administration 
of bevacizumab and TRC105 did not potentiate the known toxicities of bevacizumab of 
hypertension, hemorrhage (including tumor-associated hemorrhage, and pulmonary hemorrhage 
or hemoptysis), or proteinuria.  Reversible posterior leukoencephalopathy syndrome (RPLS), 
congestive heart failure, fistulae, gastrointestinal perforation impaired wound healing, and 
arterial thromboembolic events, were not observed. 
Notably, hypertension and proteinuria, known adverse events of bevacizumab, were rarely 
observed when bevacizumab was given with TRC105.  Mild and transient clinically significant 
hypertension or blood pressure increases were observed in five patients (13%; grade 3 in one 
case (prior to dosing with study drugs) and grade 2 in four cases) and mild transient proteinuria 
was observed in two patients (5%; both grade 2). 
2.2.1.2.2. 105ST102 Summary of Efficacy 
The combination of TRC105 and bevacizumab was active in patients with advanced refractory 
cancer who had progressed on prior bevacizumab or other VEGF inhibitor treatment.  Thirty-
three patients had measurable disease (31 patients) or evaluable disease (2 patients) at baseline 
and received at least one follow up scan and were evaluable for the primary efficacy outcome of 
ORR by RECIST 1.1.  Eighteen patients with measureable disease (58%) had a best response of 
stable disease or partial response.  Two patients (6%), both of whom had been treated with 
bevacizumab and chemotherapy prior to study entry and were then treated at the top dose level of 
TRC105 and bevacizumab, had RECIST 1.1- defined partial responses, including one patient 
with colorectal cancer who continues on treatment for more than 24 months.  A total of 14 
patients (45%) had decreases in overall tumor burden, of whom 10 received prior VEGF 
inhibitor treatment (usually bevacizumab with chemotherapy).  Notably, the duration of 
treatment with TRC105 and bevacizumab of six patients (19% of those with measureable 
disease) exceeded the duration of treatment of the most recent treatment regimen containing a 
VEGF inhibitor (i.e., VEGFR TKI or bevacizumab), received prior to study entry.  These six 
patients had decreases in tumor burden and several were responders by Choi criteria or RECIST.  
Time to progression ranged from 0 to 437+ days.  Reductions in tumor markers ranging from 5% 
to 85% were observed in 15 of 28 (54%) patients with relevant tumor markers.  Three patients 
demonstrated clinical benefit throughout the study (patient 10038102 at cycle 12 day 22, patient 
10018106 at cycle 7 day 22 and patient 10028101 at cycle 17 day 1); two of them continue to 
receive treatment under a continuation protocol (105CON101).  

IND 100522 
 
105LC101 Protocol Amendment #3 
5.3.3.2 Clinical Protocol 
 
7July2015 
Page 32 of 93 
 
2.3. 
Study Rationale 
Given the critical role of anti-angiogenic therapy in the treatment of advanced NSCLC and the 
tendency of the tumor to develop escape pathways of angiogenesis when challenged with an anti-
VEGF agent, investigation of dual anti-angiogenic therapy in advanced NSCLC is indicated.  
Pre-clinical studies of CD105 targeted therapy have demonstrated both vascular targeting effects 
and anti-angiogenic effects by inducing regression of established tumors in addition to 
preventing new tumor growth [78-80].  TRC 105 is a genetically engineered human/murine 
chimeric monoclonal antibody directed against human CD-105 (endoglin) [75]. TRC-105 has 
been shown to enhance the anti-angiogenic effect of bevacizumab in pre-clinical models of 
human angiogenesis [73]. A phase I trial of TRC 105 in the advanced solid tumors demonstrated 
tolerability and efficacy of TRC-105 as monotherapy in the salvage setting (NCT00582985). 
Subsequently, several other early phase trials in patients with prostate, bladder, hepatocellular, 
glioblastoma, and ovarian cancer are either underway or have completed.  
Most recently, a phase 1b study, the combination of TRC105 and bevacizumab produced 
radiographic reductions in tumor volume in bevacizumab-refractory patients, and was well 
tolerated. TRC105 was also well tolerated with chemotherapy in a trial with capecitabine in 
breast cancer patients [81].  By targeting an essential non-VEGF pathway that is upregulated 
following VEGF inhibition, the combination of TRC105 and bevacizumab has the potential to 
provide clinical benefit through the inhibition of two major driving pathways of tumor 
angiogenesis.  
This trial is a phase 1b dose escalation study of TRC105 in combination with standard dose 
bevacizumab, paclitaxel and carboplatin for treatment-naive patients with stage IV non-
squamous NSCLC in order to assess the safety and efficacy of CD105 blockade combined with 
bevacizumab, paclitaxel and carboplatin.  A standard “3+3” dose- escalation design of patients 
with advanced solid tumors will be employed, followed by an expanded cohort to further assess 
the  safety and tolerability of the recommended phase 2 dose (RPTD) of TRC105.  The purpose 
of the dose escalation portion is to determine the maximum tolerated dose (MTD) of TRC105 
when given in combination with bevacizumab, paclitaxel and carboplatin and to determine the 
dose limiting toxicities.    
Patients will be treated with induction therapy with carboplatin, paclitaxel, bevacizumab, and 
TRC105 for a maximum of 6 cycles of therapy. Patients who demonstrate a response of CR, PR 
or SD, after the end of the induction therapy are eligible for maintenance therapy with 
bevacizumab and TRC105 until disease progression, unacceptable toxicity or withdrawal of 
consent, or other reasons. Patients who are not able to receive more than 4 cycles of induction 
therapy because significant and persistent > grade 2 neurotoxicity related to paclitaxel may be 
eligible for maintenance therapy (i.e., TRC105 + bevacizumab alone) if there is no evidence of 
progressive disease after 4 cycles of induction therapy. Patients may be scanned early at the end 
of cycle 4 to determine disease status. 
2.4. 
Population to be Studied 
Patients with stage 4 Non-Squamous Cell Lung Cancer who have not been treated previously 
with systemic chemotherapy or bevacizumab but may have received prior targeted treatment 
(e.g., alk1 inhibitor). 

IND 100522 
 
105LC101 Protocol Amendment #3 
5.3.3.2 Clinical Protocol 
 
7July2015 
Page 33 of 93 
 
2.5. 
Potential Risks and Benefits to Human Patients 
2.5.1. 
Potential Risks 
TRC105 
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 reductions.  Anemia may be caused by correctable 
mineral or vitamin deficiency. The anemia related to TRC105 is hypoproductive in nature and is 
reversible with interruption of treatment, transfusion, erythropoietin, and other interventions as 
appropriate. 
Gastrointestinal hemorrhage has occurred with TRC105 therapy.  Patients with active ulcer 
disease or risk factors for ulcer disease are excluded from this study.    
Grade 1 and 2 cutaneous telangiectasia related to TRC105 occur early in the course of therapy 
and have been the source of gingival bleeding and epistaxis.  Telangiectasia are also seen in 
patients with hereditary hemorrhagic telangiectasia (HHT), a disease of CD105 haplotype 
insufficiency.  Patients with HHT are at risk of hemorrhage from abnormal blood vessels and this 
could be exacerbated by treatment with TRC105.  Other contraindications to TRC105 therapy 
include a history of significant hemorrhage or tumors located in the central chest or another 
location where bleeding is associated with high morbidity.  All patients treated with TRC105 
should be monitored for signs of hemorrhage and the risks and benefits of drug treatment 
reevaluated in any patient with hemorrhage. 
Premedication including the use of glucocorticoids is required prior to infusion of TRC105 to 
reduce the frequency and severity of infusion reactions.  Infusion reactions following TRC105 
dosing generally occur with the first TRC105 dose and include a grade 4 vasovagal reaction that 
resolved without sequelae.  Signs and symptoms of TRC105 infusion reactions include 
hypertension, hypotension, dyspnea, bronchospasm, chills/rigors, chills, sweats, fever, nausea, 
tachycardia, bradycardia, EKG changes, flushing, urticaria, pruritus, and headache, generally of 
grade 1 and 2 severity. Potential infusion reactions seen with other therapeutic antibodies include 
angioedema, asthenia, throat irritation, rhinitis, vomiting, joint pain, fatigue and neurologic 
disorders including inflammation of the spine and/or brain.  
Hypersensitivity reactions with infusions are a potential risk for sensitized patients, and TRC105 
should be used with caution in patients with known hypersensitivity to any component of the 
drug product.  Host anti-TRC105 antibodies to the murine or human portions of CHO-produced 
TRC105 are rare.  In general, the risk of immunogenicity to therapeutic chimeric antibodies is 
small (<10%) and the clinical significance of immunogenicity is not well defined.  The current 
trial will collect serial blood samples for anti-product antibody concentrations to further 
characterize the immunogenicity of TRC105 and potential clinical implications. 
Grade 3 cerebrovascular hemorrhage resulting in hemiparesis occurred in one patient with 
hepatocellular cancer who was thrombocytopenic (who entered the study with a platelet count of 
60,000/uL) in a study of TRC105 with sorafenib.  Patients must have a platelet count of > 
100,000/uL to enter this study (see inclusion criteria).  A grade 2 transient ischemic attack was 
reported in a study of TRC105 and pazopanib.  Transient Grade 3 hepatic encephalopathy 
occurred in one patient with cirrhosis and hepatocellular carcinoma who received TRC105 in 

IND 100522 
 
105LC101 Protocol Amendment #3 
5.3.3.2 Clinical Protocol 
 
7July2015 
Page 34 of 93 
 
combination with sorafenib.   Additionally, Grade 5 intracranial hemorrhage occurred in one 
glioblastoma patient with markedly abnormal blood clotting parameters in a study of TRC105 
with bevacizumab. A patient with glioblastoma developed temporary confusion and slurred 
speech following treatment with TRC105 and bevacizumab that required hospitalization for 
observation. Another patient with glioblastoma, who underwent resection and had a history of an 
abnormal collection of cerebral spinal fluid, developed a grade 2 cerebral spinal fluid leak. 
Grade 3 myocardial infarction (non-Q wave infarct associated with hypertension following an 
infusion reaction) was observed in a patient with hepatocellular cancer following treatment with 
TRC105 that resolved without sequelae.  In addition, a Grade 5 myocardial infarction occurred in 
a patient with coronary artery disease who received TRC105 in combination with sorafenib. 
Patients with evidence of active coronary artery disease are excluded from participation in this 
trial (see exclusion criteria).   
Adult respiratory distress syndrome that required temporary intubation occurred in one patient 
who received TRC105 with pazopanib, from which the patient recovered. Of note, interstitial 
lung disease has been added as an adverse drug reaction and warning/precaution to the core 
safety information for pazopanib.  Pneumothorax (collapsed lung) has been observed in trials of 
TRC105 administered with a VEGFR TKI in patients with lung metastases. 
A patient with renal cell carcinoma treated with TRC105 and axitinib developed grade 3 
localized perforation of the large intestine at the site of an intraabdominal tumor metastasis that 
required percutaneous drainage and diverting colostomy. 
Infections have been observed rarely. Grade 3 infected lipoma/cyst was observed in a Phase 2 
study of TRC105 as a single agent in patients with metastatic bladder cancer. Grade 3 orbital 
cellulitis and grade 3 brain abscess were observed in patients treated with TRC105 and 
bevacizumab and considered possibly related to TRC105.  Grade 1 and 2 gingivitis including 
infection and ulceration has also been observed.  Overall, infections have been observed in fewer 
than 5% of patients and have largely been considered unrelated to treatment with TRC105. 
Grade 1-3 headaches have been observed following TRC105 treatment, generally within hours 
following completion of the initial infusion.  Headaches are throbbing in nature, are not 
associated with radiographic abnormalities, and have responded to treatment with non-steroidal 
anti-inflammatory agents and to triptans. Headaches were particularly common when TRC105 
and bevacizumab were initially dosed on the same day and were ameliorated when TRC105 was 
dosed one week following bevacizumab dosing and given over two days during the initial week 
of dosing. 
Nasal congestion and periorbital edema have been observed with TRC105 dosing, particularly 
when dosed in combination with bevacizumab.  The edema has been transient in nature and 
treated with corticosteroids.  
Fatigue of grade 1- 3 severity has been reported following dosing with TRC105. Maculopapular 
rash and skin flushing of grade 1 and grade 2 severity have also been reported.  A patient 
receiving treatment with TRC105 and sorafenib developed self-limited pancreatitis of grade 2 
severity. 
Paclitaxel 

IND 100522 
 
105LC101 Protocol Amendment #3 
5.3.3.2 Clinical Protocol 
 
7July2015 
Page 35 of 93 
 
Side effects associated with the use of paclitaxel are bone marrow suppression, hypersensitivity 
reactions, hypotension, ECG abnormalities, peripheral neuropathy, arthralgia/myalgia, liver 
function abnormalities, nausea, vomiting, diarrhea, mucositis, alopecia and edema. 
Further details are available in the package insert [82]. 
Carboplatin 
Side effects associated with the use of carboplatin are bone marrow suppression (leukopenia, 
neutropenia, and thrombocytopenia) which is dose-dependent and a dose limiting toxicity. 
Carboplatin can induce emesis, which can be more severe in patients previously receiving 
emetogenic therapy. Allergic reactions to carboplatin have been reported. These may occur 
within minutes of administration and should be managed with appropriate supportive therapy. 
There is increased risk of allergic reactions including anaphylaxis in patients previously exposed 
to platinum therapy. Carboplatin may cause fetal harm when administered to a pregnant woman. 
Carboplatin has been shown to be embryotoxic and teratogenic in rats. There are no adequate and 
well-controlled studies in pregnant women. If this drug is used during pregnancy, or if the patient 
becomes pregnant while receiving this drug, the patient should be apprised of the potential 
hazard to the fetus. Women of childbearing potential should be advised to avoid becoming 
pregnant. 
Further details are available in the package insert [83]. 
Bevacizumab 
Side effects associated with the use of bevacizumab include gastrointestinal perforation, 
hypertension, impaired wound healing, an increased incidence of arterial thromboembolic 
events, venous thromboembolic events (including pulmonary embolism), hemorrhage (including 
tumor-associated hemorrhage, mucocutaneous hemorrhage, and pulmonary hemorrhage or 
hemoptysis), proteinuria, rare reports of Reversible Posterior Leukoencephalopathy Syndrome 
(RPLS), congestive heart failure, fistulae, hypothyroidism, hypersensitivity reactions, headache 
and infusion reactions. Increased rates of severe neutropenia, febrile neutropenia, or infection 
with severe neutropenia (including some fatalities) have been observed in patients treated with 
some myelotoxic chemotherapy regimens plus bevacizumab in comparison to chemotherapy 
alone.  
No specific studies in animals have been performed to evaluate the effect of bevacizumab on 
fertility. There are no adequate and well-controlled studies in pregnant women.  
Immunoglobulins are excreted in milk, although there are no data specifically for bevacizumab 
excretion in milk. Since bevacizumab could harm infant growth and development, women should 
be advised to discontinue breastfeeding during bevacizumab therapy and not to breast feed for at 
least 6 months following the last dose of bevacizumab.   
Further details are available in the package insert [84]. 
Computed Tomography (CT) Scans 
Patients will be exposed to a small amount of radiation as a result of the CT scans required in 
this study.  This degree of exposure has not been associated with harmful health effects. In 
addition, the frequency of CT scans performed in this study is similar to the standard of care 
frequency. Patients with a medical contraindication to CT scans or known Iodinated contrast 

IND 100522 
 
105LC101 Protocol Amendment #3 
5.3.3.2 Clinical Protocol 
 
7July2015 
Page 36 of 93 
 
allergies may undergo MRI.  There is minimal risk of MRI imaging in patients able to undergo 
this type of exam including very rare reports of gadolinium-induce nephrogenic systemic fibrosis 
in patients with poor renal function. 
Venipuncture 
Patients could also experience side effects from venipuncture for tests that will be done as part of 
this study including pain, tenderness or bruising at the site of collection, and rarely infection may 
occur at the spot where the needle is inserted. 
Other Risks 
This study treatment may involve risks to unborn children therefore patients should not become 
pregnant or father a baby while participating in this study.  Patients should not nurse while on 
this study.  Women of childbearing potential must have a negative pregnancy test before taking 
part in this study.  Women must be of non-child bearing potential due to surgical sterilization (at 
least 6 weeks following surgical bilateral oophorectomy with or without hysterectomy or tubal 
ligation) confirmed by medical history or menopause; or must agree to use two methods of 
effective and highly reliable methods of contraception at the same time [i.e., tubal sterilization 
(tubes tied), partner’s vasectomy, intra-uterine device (IUD), male latex condom with or without 
spermicide, diaphragm with spermicide, cervical cap with spermicide, vaginal sponge (contains 
spermicide)] during study treatment (including during temporary breaks from treatment), and for 
at least 180 days after stopping TRC105, bevacizumab, paclitaxel, and/or carboplatin treatment.  
Men must agree to use two effective and highly reliable methods of contraception at the same 
time [i.e., vasectomy, male latex condom with or without spermicide, partner’s tubal sterilization 
(tubes tied), partner’s use of intra-uterine device (IUD), partner’s use of diaphragm with 
spermicide, cervical cap with spermicide, vaginal sponge (contains spermicide)] during study 
treatment (including temporary breaks from treatment), and for at least 180 days after stopping 
TRC105, bevacizumab, paclitaxel, and/or carboplatin.  The long term risk of infertility is 
unknown. Ovarian failure has been observed with other antiangiogenic agents.  
2.5.2. 
Potential Benefits 
TRC105 is an investigational product, and its efficacy has not been established.  It is possible 
that the administration of TRC105 may result in clinical benefit (i.e., tumor response or 
prolonged stable disease). 
2.6. 
Justification of the Dose, Schedule and Route of Administration of 
TRC105 
2.6.1. 
Justification 
The dose and schedule of TRC105 (8 mg/kg weekly up to 10 mg/kg weekly) were selected based 
on safety, pharmacokinetics and early evidence of activity in the phase 1 study of TRC105 for 
patients with solid tumors (Study 105ST101) and in the phase 1b study of TRC105 with 
bevacizumab.  In phase 1, a weekly dose of 10 mg/kg was well tolerated and associated with 
clinical activity.  Dose reduction was possible for treatment of anemia.  Doses of 8 and 10 mg/kg 
were tolerated in combination with bevacizumab without the development of severe toxicity.  

IND 100522 
 
105LC101 Protocol Amendment #3 
5.3.3.2 Clinical Protocol 
 
7July2015 
Page 37 of 93 
 
Notably, while the initial schedule of TRC105 was adjusted to decrease the frequency of 
headaches, there was no potentiation of life threatening toxicities associated with bevacizumab, 
nor potentiation of common VEGF inhibitor toxicities (e.g., hypertension and proteinuria).   
Additionally, doses of 8 and 10 mg/kg of TRC105 were tolerated in combination with standard 
axitinib and pazopanib, without the development of severe toxicity in their respective studies.  
Given the limited experience dosing TRC105 with VEGF inhibitors and chemotherapy, it is 
possible that TRC105 toxicities will potentiate bevacizumab, paclitaxel, and carboplatin 
toxicities, and vice versa.  Therefore a TRC105 starting dose of 8 mg/kg weekly, which is 20% 
lower than the single-agent TRC105 MTD identified in the phase 1 single agent study and phase 
1b studies with bevacizumab, pazopanib and axitinib was selected. In addition a 6 mg/kg (-1) 
dose level has also been included and will be enrolled should 8 mg/kg of TRC105 in 
combination with bevacizumab and paclitaxel and carboplatin exceed the MTD.  As an added 
precaution, the first dose of TRC105 will be delayed by one (1) week following bevacizumab, 
paclitaxel, and carboplatin dosing and administered over 2 days.  This administration schedule 
will limit immediate Cmax effects of the combination of three drugs that could result in toxicity.  
2.7. 
Conduct 
The 105LC101 clinical trial will be conducted in compliance with the protocol, GCP, and the 
applicable regulatory requirements. 

IND 100522 
 
105LC101 Protocol Amendment #3 
5.3.3.2 Clinical Protocol 
 
7July2015 
Page 38 of 93 
 
3. 
TRIAL OBJECTIVES AND PURPOSE 
3.1. 
Objectives 
3.1.1. 
Purpose 
The purpose of this study is to evaluate the safety and effectiveness of TRC105 in combination 
with bevacizumab, paclitaxel and carboplatin. 
3.1.2. 
Primary objectives  
• To evaluate safety and tolerability and determine a  recommended phase 2 dose for 
TRC105 when added to standard dose bevacizumab and paclitaxel/carboplatin in 
treatment-naive patients with stage IV non-squamous NSCLC  
3.1.3. 
Secondary objectives 
• To assess preliminary evidence of antitumor activity when TRC105 is added to 
bevacizumab and paclitaxel/carboplatin, by assessing objective response rate, median 
progression-free survival, the proportion (%) of patients progression-free at 6 months, 
and the overall survival 
• To characterize the pharmacokinetic profile of TRC105 when given with bevacizumab 
and paclitaxel/carboplatin 
• To evaluate TRC105 Anti-Product Antibodies  
• To explore pharmacodynamic effects on circulating angiogenic biomarkers  

IND 100522 
 
105LC101 Protocol Amendment #3 
5.3.3.2 Clinical Protocol 
 
7July2015 
Page 39 of 93 
 
4. 
INVESTIGATIONAL PLAN 
4.1. 
Overall Study Design and Plan 
4.1.1. 
Overview 
All patients must sign a consent form prior to undertaking any study-related procedures.  
Prospective patients will be screened to determine if they qualify for the study within 28 days of 
enrollment. Toxicities will be graded according to the NCI CTCAE Version 4.0.   
4.1.1.1. 
Overview 
This is a single center, open-label, nonrandomized, phase 1b, and dose-finding study of TRC105 
in combination with standard dose bevacizumab, paclitaxel and carboplatin in treatment-naive 
patients with stage IV non-squamous NSCLC. Patients will be treated with induction therapy 
with carboplatin, paclitaxel, bevacizumab, and TRC105 for a maximum of 6 cycles of therapy. 
Patients who demonstrate a response of CR, PR or SD, after the end of the induction therapy are 
eligible for maintenance therapy with bevacizumab and TRC105 until disease progression, 
unacceptable toxicity or withdrawal of consent, or other reasons.   
Escalating doses of i.v. TRC105 will be administered weekly beginning with Dose Level 1 in 
combination with bevacizumab 15 mg/kg intravenously every 3 weeks and paclitaxel 200 mg/m2 
and Carboplatin 6 AUC administered intravenously on day 1 of each 21 day cycle  (see TRC105 
Administration Section 6.1.6, Bevacizumab Dosing see Section 6.2.6 and Paclitaxel Dosing see 
Section 6.3.6 and Carboplatin Dosing  see Section 6.4.6 ).  Intermediate TRC105 doses (below 
the MTD established during the trial) may be explored based upon clinical, PK, and/or biomarker 
data.  
Level 
Number of 
Evaluable 
Subjects 
Bevacizumab 
mg/kg IV every 
3 weeks 
Paclitaxel  
mg/m2 IV 
every 3 
weeks 
Carboplatin  
AUC IV every 
3 weeks 
TRC105 
mg/kg 
IV, weekly 
(beginning 
cycle 1 day 8)a 
-1 
3-6 
15 
200 
6 
6 
1  
(starting dose) 
3-6 
15 
200 
6 
8  
2 
3-6 
15 
200 
6 
10  
Expanded 
Cohort  
9-12 
(up to 15 
total at the 
MTD) 
15 
200 
6 
MTD 
aThe first weekly TRC105 dose will be split into two doses whereby 3 mg/kg is administered on cycle 1 day 8 and 
the balance is administered on cycle 1 day 11. 
Patients will receive 200 mg/m2 of paclitaxel every 3 weeks beginning with cycle 1 day 1 for 6 
cycles, AUC of 6 of carboplatin every 3 weeks beginning with cycle 1 day 1 for 6 cycles and 15 
mg/kg of bevacizumab every 3 weeks beginning with cycle 1 day 1 until progression. TRC105 

IND 100522 
 
105LC101 Protocol Amendment #3 
5.3.3.2 Clinical Protocol 
 
7July2015 
Page 40 of 93 
 
dosing will begin at 8 mg/kg (Dose Level 1) on cycle 1 day 8 and weekly thereafter until 
progression.  A -1 Dose Level has also been included (6 mg/kg) and will be enrolled if 8 mg/kg 
TRC105 dosed with bevacizumab, paclitaxel and carboplatin exceeds the MTD.  The DLT 
evaluation period, for purposes of dose expansion, will be the first 6 weeks (42 days) of dosing 
bevacizumab, paclitaxel, carboplatin and TRC105 (e.g., from cycle 1 day 1 through cycle 2 day 
21).  Each cycle will be 3 weeks (21 days) in duration.  
Three patients will be initially enrolled and treated at each dose level.  If none of these 3 patients 
experiences a dose-limiting toxicity (DLT) during the initial 42-day evaluation period when all 
drugs are dosed together (extending from cycle 1 day 1 through cycle 2 day 21), dose escalation 
will proceed following review of safety data with site staff including the principal investigator at 
the clinical site. 
If 1 of 3 patients experiences DLT, the dose level will be expanded to 6 patients.  The maximum 
tolerated dose (MTD) will have been exceeded if ≥ 33% of patients experience DLT at a given 
dose level.  DLT will have occurred when a patient has 1 or more toxicity listed in the table 
below that is at least possibly related to the combination of bevacizumab, paclitaxel, carboplatin 
and TRC105 during the first 42 days of concomitant dosing.  Patients who exit the study for 
reasons other than DLT prior to completion of the 42-day DLT evaluation period will be 
replaced to ensure an adequate safety assessment in each cohort. Patients who experience DLT 
who receive less than the prescribed dose of TRC105 or bevacizumab, paclitaxel or carboplatin 
due to documented toxicity during the DLT evaluation period will be considered evaluable for 
dose escalation purposes.  A given TRC105 dose level may be reenrolled at an intermediate dose 
level upon agreement of study investigators. 
Up to 15 treatment-naive patients with stage IV non-squamous NSCLC will be treated at the 
MTD (or top dose level if a MTD is not determined) to further characterize safety and 
tolerability. 
Table 3: 
Dose Limiting Toxicity Definition and Criteria 
Toxicity Category 
Drug-Related Toxicity/Grade 
Hematologic 
Any Grade 4 toxicity 
Neutropenic infection: grade ≥ 3 neutropenia with grade ≥ 3 
infection 
Grade ≥ 3 thrombocytopenia and grade ≥ 3 hemorrhage 
Nonhematologic 
Grade 3 toxicity with the following exceptions: 
• 
Nausea, vomiting or diarrhea for < 48 hoursa 
• 
Asymptomatic electrolyte abnormalities that are corrected 
to grade 1 or better in < 72 hoursb 
Any Grade 4 toxicity 
aPatients with related grade 3 or 4 diarrhea, nausea or vomiting for ≥ 48 hours despite optimal medical 
therapy will require a one-level dose-reduction of TRC105. 

IND 100522 
 
105LC101 Protocol Amendment #3 
5.3.3.2 Clinical Protocol 
 
7July2015 
Page 41 of 93 
 
Toxicity Category 
Drug-Related Toxicity/Grade 
Hematologic 
Any Grade 4 toxicity 
Neutropenic infection: grade ≥ 3 neutropenia with grade ≥ 3 
infection 
Grade ≥ 3 thrombocytopenia and grade ≥ 3 hemorrhage 
Nonhematologic 
Grade 3 toxicity with the following exceptions: 
• 
Nausea, vomiting or diarrhea for < 48 hoursa 
• 
Asymptomatic electrolyte abnormalities that are corrected 
to grade 1 or better in < 72 hoursb 
Any Grade 4 toxicity 
bPatients with related grade 3 or 4 electrolyte abnormalities that persist for ≥ 72 hours will require a one-
level dose-reduction of TRC105 
4.1.2. 
Trial Procedures 
All on-study procedures are permitted within the time window indicated in the Schedule of 
Assessments (Table 4 ).  
4.1.2.1. 
Screening 
The following screening procedures must be performed within 28 days prior to the first day of 
study therapy.  Qualifying hematology (including Fe studies), serum chemistry (including TSH 
testing), coagulation, physical examination, ECG, pregnancy and urinalysis collected within 7 
days of cycle 1 day 1 do not need to be repeated. The following will be performed according to 
the Schedule of Assessments (Table 4).  
• Patient signature on current Institutional Review Board (IRB) approved informed consent 
form.  Prior to undergoing any study-specific procedure, patients must read and sign the 
current Institutional Review Board (IRB) approved informed consent form.  Patients may 
sign consent prior to the 28 day screening period. 
• Medical history, baseline signs and symptoms, prior cancer therapy, prior cancer surgery, 
prior radiation therapy, drug allergies, primary diagnosis and demographics. 
• Physical examination including examination of all major body systems, ECOG 
performance status, and vital signs. 
• Hematology (including serum iron, ferritin and total iron binding capacity), coagulation 
(INR) and serum chemistry (including thyroid stimulating hormone (TSH)) to be 
performed locally. 
• Serum or urine pregnancy test for all females of childbearing potential to be performed 
locally. 

IND 100522 
 
105LC101 Protocol Amendment #3 
5.3.3.2 Clinical Protocol 
 
7July2015 
Page 42 of 93 
 
• Urinalysis to be performed locally.  Microscopic analysis and/or urine protein-creatinine 
ratio (UPCR) should be performed as clinically indicated. 
• CT or MRI scans of chest, abdomen and pelvis in addition to any other applicable sites of 
disease. Brain and bone scans to be performed if metastasis is suspected prior to starting 
the study. 
• Single tracing 12-Lead ECG (QT, PR and QRS intervals and heart rate will be captured).  
• Assessment of concomitant medications and treatments from 28 days prior to the start of 
study treatment.  
• Archival Tumor Tissue Specimens: Archival specimens (formalin-fixed, paraffin-
embedded) of the primary cancer specimen and/or metastatic cancer specimen for each 
study participant. It is preferable that the entire paraffin block be submitted, but if this is 
not feasible, then at least 20 unstained slides are requested for immunohistochemical 
analysis (sections of ~ 5 microns are preferred).  See separate laboratory guide for further 
collection and shipment information 
4.1.2.2. 
Trial Period 
Qualifying hematology (including Fe studies), blood chemistry (including TSH testing), 
coagulation, urinalysis, physical examination, ECG, and pregnancy test do not need to be 
repeated on cycle 1 day 1 if acceptable screening assessments are performed within 7 days prior 
to the start of study therapy.  On days of dosing, all assessments should be performed prior to 
dosing with TRC105 unless otherwise indicated in the Schedule of Assessments. Patients will 
receive 3 cycles (approximately 9 weeks) of treatment.  Patients will be treated with induction 
therapy with carboplatin, paclitaxel, bevacizumab, and TRC105 for a maximum of 6 cycles of 
therapy. Patients who demonstrate a response of CR, PR or SD, after the end of the induction 
therapy are eligible for maintenance therapy with bevacizumab and TRC105 until disease 
progression, unacceptable toxicity or withdrawal of consent, or other reasons.  Each cycle is 3 
weeks in duration. The following will be performed according to the Schedule of Assessments 
(Table 4). 
• Physical examination including examination of all major body systems, ECOG 
performance status, weight and vital signs (heart rate, temperature, blood pressure, 
respiratory rate).  
o Assessment of vital signs during TRC105 infusion: Vital signs are to be assessed 
pre-infusion (i.e., within 30 minutes of starting the infusion), every 30 minutes 
during the infusion (+/- 15 minutes), and at the end of the infusion (i.e., within 30 
minutes after completing the infusion).  Vital signs should be monitored more 
frequently and/or beyond the completion of the infusion if medically indicated 
(e.g. if the patient experiences an infusion reaction that has not yet resolved).  
• Hematology, coagulation (INR) and serum chemistry (including TSH) to be performed 
locally. 
• Single tracing 12-Lead ECG (QT, PR and QRS intervals and heart rate will be captured). 

IND 100522 
 
105LC101 Protocol Amendment #3 
5.3.3.2 Clinical Protocol 
 
7July2015 
Page 43 of 93 
 
• Urinalysis to be performed locally. Microscopic analysis and/or urine protein-creatinine 
ratio (UPCR) should be performed as clinically indicated. 
• Blood sampling for TRC105 pharmacokinetics will include a pre-infusion trough sample 
to be analyzed by a third party laboratory (see laboratory manual for specific instructions 
regarding collection times, procedures, processing, storage and shipment). 
• Blood sampling for immunogenicity to be analyzed by a third party laboratory (see 
laboratory manual for specific instructions regarding collection, processing, storage and 
shipment). 
• Blood sampling for protein biomarker analysis by a third party laboratory (see laboratory 
manual for specific instructions regarding collection processing, storage and shipment) 
• CT or MRI scans of chest, abdomen and/or pelvis in addition to any other applicable sites 
of disease. Scan of the chest, abdomen, and pelvis to be performed on-study as outlined 
in the assessment table. Known areas of disease should be consistently followed 
throughout the study.  Assessments should be performed whenever disease progression is 
suspected.  Allowable window for tumor imaging studies is +/- 7 days. Brain and bone 
scans to be performed if metastasis is suspected prior to starting the study and during 
study conduct. 
• Administration of TRC105. TRC105 diluted in normal saline will be administered as a 1 
to 4 hour infusion (+/- 15 minutes) on day 1, day 8, day 15 of each 21 day cycle 
following premedication (see Section 6.1.6) for all cycles except cycle 1. The first 
TRC105 dose will be split into two doses such that 3 mg/kg is administered on cycle 1 
day 8, and the balance is administered on cycle 1 day 11.  The entire weekly dose of 
TRC105 (6, 8 or 10 mg/kg) is then given on cycle 1 day 15 and weekly thereafter (e.g., if 
TRC105 is given at 3 mg/kg on cycle 1 day 8 and at 5 mg/kg on cycle 1 day 11, then 8 
mg/kg is given on cycle 1 day 15). TRC105 will be administered intravenously utilizing 
an infusion pump.  TRC105 has been demonstrated to be compatible with polyethylene 
lined, non-DEHP infusion sets and polyvinyl chloride, non-DEHP infusion sets.  TRC105 
is required to be administered with a 0.2 micron downstream filter.   Duration of infusion 
administration may be increased as medically necessary. 
• Bevacizumab dosing. Administer 15 mg/kg as an intravenous infusion on day 1 of every 3 
week cycle until disease progression, as described in the package insert.  
• Paclitaxel dosing. Administer 200 mg/m² as an intravenous infusion, on day 1 of every 3 
week cycle for 6 cycles, as described in the package insert.  
• Carboplatin dosing: Administer AUC of 6 as intravenous infusion, on day 1 of every 3 
week cycle for 6 cycles, as described in the package insert.  
• Assessment of adverse events. 
• Assessment of concomitant medications and concomitant treatments. 
4.1.3. 
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 

IND 100522 
 
105LC101 Protocol Amendment #3 
5.3.3.2 Clinical Protocol 
 
7July2015 
Page 44 of 93 
 
the last 8 weeks on study for radiologic tumor assessments).  The following will be performed 
according to the Schedule of Assessments (Table 4). 
• Physical examination including examination of all major body systems, ECOG 
performance status, and vital signs. 
• Single tracing 12-Lead ECG (QT, PR and QRS intervals and heart rate will be captured). 
• Hematology, and serum chemistry (including TSH) to be performed locally. 
• Urinalysis to be performed locally.  Microscopic analysis and/or urine protein-creatinine 
ratio (UPCR) should be performed as clinically indicated. 
• Blood sampling for TRC105 pharmacokinetics to be analyzed by a third party laboratory 
(see laboratory manual for specific instructions regarding collection times, procedures, 
processing, storage and shipment). 
• Blood sampling for immunogenicity to be analyzed by a third party laboratory (see 
laboratory manual for specific instructions regarding collection, processing, storage and 
shipment). 
• Blood sampling for protein biomarker analysis by a third party laboratory (see laboratory 
manual for specific instructions regarding collection processing, storage and shipment) 
• CT or MRI scans of chest, abdomen and pelvis in addition to any other applicable sites of 
disease. 
• Assessment of adverse events. 
• Assessment of concomitant medications and concomitant treatments. 
4.1.4. 
 Post Treatment Follow-up 
The following will be performed according to the Schedule of Assessments (Table 4). Samples 
should be collected and assessments performed even if new anti-cancer therapy commences 
during the follow-up period.  
• Assessment of adverse events. The Investigator should continue to report any related or 
possibly related adverse events that occur beyond the adverse event reporting period. 
• Blood sampling for TRC105 pharmacokinetics to be analyzed by a third party laboratory 
(see laboratory manual for specific instructions regarding collection, processing, storage 
and shipment). 
• Blood sampling for immunogenicity to be analyzed by a third party laboratory (see 
laboratory manual for specific instructions regarding collection, processing, storage and 
shipment). 
• Assessment of concomitant medications and concomitant treatments. 
• Serum or urine pregnancy test for all females of childbearing potential to be performed 
locally. 

IND 100522 
 
105LC101 Protocol Amendment #3 
5.3.3.2 Clinical Protocol 
 
7July2015 
Page 45 of 93 
 
Table 4: 
Schedule of Assessments  
Protocol Activities 
Screening 
Cycle 1 [25] 
Cycles 2 & 3 [26] 
Cycle 4+  
Responding Patients[23] [25] 
End 
of 
Study 
[3] 
28 Day 
Follow-up 
[24] 
Day -28 
Day 1  
[1] 
Day 8 
[1] 
Day 11 
[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+Fe 
  
  
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 
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  
  
  
Bevacizumab [12] 
 
X 
 
 
 
X 
 
 
X  
 
 
 
 
Paclitaxel [13] 
 
X 
 
 
 
X 
 
 
X 
 
 
 
 
Carboplatin [14] 
 
X 
 
 
 
X 
 
 
X  
 
 
 
 
Tumor Assessments 
  
  
  
  
  
 
 
 
  
  
  
  
  
CT or MRI Scans [15] 
X 
  
  
  
  
 
 
Cycle 3 
  
  
Cycles 6. 9. 
12. Etc. 
X 
  
Other Clinical Assessments 
  
  
  
  
  
 
 
 
  
  
  
  
  
12-Lead ECG [16] 
X 
X  
  
  
 X  
 
 
 
 
  
  
X  
  
Concomitant 
Medications/Treatments [17] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events [18] 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Special Laboratory Assessments 
  
  
  
  
  
 
 
 
  
  
  
  
  
APA [19] 
 
X 
 
 
 
Cycle 3 
 
 
Cycles 6. 
9. 12. Etc. 
 
 
X 
X 
Protein Biomarkers [20] 
 
X 
 
 
 
Cycle 3 
 
 
Cycles 6. 
9. 12. Etc. 
 
 
X 
 
TRC105 PK Pre-Dose [21] 
 
 
X 
 
 
Cycle 3 
 
 
Cycles 6. 
9. 12. Etc. 
 
 
 
 
Archival Tumor Tissue [22] 
X 
 
 
 
 
 
 
 
 
 
 
 
 

IND 100522 
 
105LC101 Protocol Amendment #3 
5.3.3.2 Clinical Protocol 
 
7July2015 
Page 46 of 93 
 
 
 
Schedule of Assessments Footnotes 
1. Days of Treatment with TRC105: All assessments should be performed prior to the TRC105 infusion unless otherwise indicated.  Each cycle is 21 days in 
duration.  
2. Cycle 1 day 1: Hematology (including iron studies), blood chemistry (including TSH testing), urinalysis, physical examination, ECG and pregnancy test not 
required if acceptable screening assessment is performed within 7 days prior to the start of treatment on cycle 1 day 1.  
3. End of Study: The end of study visit should generally occur within 7 days (+/- 1 day) of the last dose of TRC105. Assessments other than PK, 
immunogenicity and protein biomarkers do not need to be repeated if performed within the previous 2 weeks (previous 8 weeks for radiologic tumor 
assessments). Follow-up visits should occur 28 days following the last dose of TRC105 study drug as outlined in the Schedule of Assessments.  
4. Informed Consent: Must be obtained prior to undergoing any study specific procedure and may occur prior to the 28-day screening period. 
5. Medical and Oncologic History, Demographics and Baseline Signs and Symptoms: All information related to prior anticancer treatment should be 
recorded. Significant medical history and baseline signs and symptoms should be captured from the date of informed consent.  
6. Physical Examination: Examination of major body systems and ECOG performance status.  
7. Vital Signs: Heart rate, temperature, blood pressure, respiratory rate, weight. Assessment during TRC105 Infusions: Vital signs are to be assessed pre-
infusion (i.e., within 30 minutes of starting the infusion) every 30 minutes during the infusion (+/- 15 minutes) and at the end of the infusion (i.e. within 30 
minutes after completing the infusion). Vital signs should be monitored more frequently and/or beyond the completion of the infusion if medically indicated 
(e.g. if the patient experiences an infusion reaction that has not yet resolved).   
8. Hematology, Chemistry & Coagulation:  Testing to be performed locally.  Thyroid stimulating hormone to be tested at screening, day 1 of each cycle and 
at the end of study visit.  Cycle 1 day 1 assessments only need to be performed if screening assessments were performed more than 7 days prior to cycle 1 
day 1.  Iron studies (FE) to be performed according to the schedule of assessments and as clinically indicated during the study. Lab assessments can be may 
be performed within 3 days prior to TRC105 dosing. In addition to the assessments scheduled for the clinical trial, patients should undergo assessment as 
appropriate to ensure safe treatment. See Section 8.1.1.1 for specific panel collection requirements.  
9. Pregnancy Test: Testing to be performed locally. All female patients of childbearing potential must have a negative serum or urine pregnancy test within 7 
days of cycle 1 day 1 and 28 days following the last dose of TRC105 
10. Urinalysis: To be performed locally. Cycle 1 day 1 urinalysis only needs to be performed if screening urinalysis was performed more than 7 days prior to 
cycle 1 day 1.  Microscopic analysis and/or urine protein creatinine ratio or 24-hour urine protein collection should be performed as clinically indicated. 
11. TRC105 Administration: Intravenous TRC105 diluted in normal saline will be administered every 7 days.  The first weekly TRC105 dose will be given on 
cycle 1 day 8 and split into two doses whereby 3 mg/kg is administered on cycle 1 day 8 and the balance is administered on cycle 1 day 11.  The entire 
weekly dose of TRC105 (6, 8 or 10 mg/kg) is then given on cycle 1 day 15 and weekly thereafter. See Section 6.1.6 for specific TRC105 administration 
guidelines. 
12. Bevacizumab Dosing: Intravenous bevacizumab at a dose of 15 mg/kg diluted in normal saline will be administered on day 1 of every 3 week cycle, starting 
on cycle 1 day 1 as described in the package insert. See Section 6.2  for specific dosing guidelines.    
13. Paclitaxel Dosing: Intravenous paclitaxel at a dose of 200 mg/m² diluted in 0.9% Sodium Chloride Injection, USP, to a final concentration of 0.3 to 1.2 
mg/mL, will be administered on day 1 of each 3 week cycle for 6 cycles, starting on cycle 1 day 1. See Section 6.3.6   for specific dosing guidelines. 
14. Carboplatin Dosing: Intravenous carboplatin a dose of 6 AUC will be administered on day 1 of each 3 week cycle for 6 cycles, starting on cycle 1 day 1. 
See Section 6.4.6 for specific dosing guidelines. 

IND 100522 
 
105LC101 Protocol Amendment #3 
5.3.3.2 Clinical Protocol 
 
7July2015 
Page 47 of 93 
 
15. CT or MRI Tumor Imaging: Images of the chest, abdomen, and pelvis to be performed at screening, and on-study as outlined in the assessment table.  
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 and bone scans are to be performed if metastases are suspected at screening or during study 
therapy. Patients who are not able to receive more than 4 cycles of induction therapy because significant and persistent > grade 2 neurotoxicity related to 
paclitaxel may be scanned early (i.e., at the end of cycle 4) to rule out disease progression and allow for study continuation on maintenance therapy (i.e., 
TRC105 + bevacizumab alone).  
16. 12-Lead ECG: Single tracing 12-lead ECG will be performed at screening and at the time-points indicated in the Schedule of Assessments (pre-dose). If the 
patient develops an arrhythmia, the ECG should be repeated on day 1 of each subsequent cycle. For a QTc >500 ms, the ECG should be evaluated by a 
cardiologist at the site for confirmation.  Additional ECGs may be performed on study as clinically indicated.  
17. Concomitant Medications and Treatments: Concomitant medications and treatments will be recorded from 28 days prior to the start of study treatment 
and up to 28 days following the last dose of study treatment. Required TRC105 premedications should be recorded on TRC105 premedications CRF. 
18. Adverse Events: Patients must be followed for adverse events from the first day of treatment with paclitaxel or carboplatin or bevacizumab or TRC105 
study drug until at least 28 days after the last dose of TRC105 or bevacizumab or paclitaxel or carboplatin study drug treatment, or until all serious or 
TRC105 related toxicities have resolved or are determined to be “chronic” or “stable”, whichever is later.  "Baseline-signs and symptoms” will be recorded 
from the date of informed consent on corresponding case report forms. Any serious AE that is possibly related to TRC105 occurring from the time of first 
TRC105 dose or at any point after the reporting period must be promptly reported to TRACON.  
19. Anti-product antibody: 5 mL blood sample will be collected to assess anti-product antibody at the time-points indicated in the schedule of assessments and 
stored at approximately -70°C to be analysed by a central laboratory. Samples will be batch shipped as indicated in the laboratory manual to a third-party 
laboratory. See separate laboratory guide for further collection and shipment information. Additional samples may also be collected at the time of unexpected 
clinical events. 
20. Protein Biomarkers: One 10 mL purple top (K3EDTA) tube will be collected at the time-points indicated in the schedule of assessments and stored at 
approximately -70°C to be analysed by a central laboratory. See separate laboratory guide for further collection and shipment information. 
21. TRC105 Pharmacokinetics Trough Concentration: A 5 mL blood sample to be collected at the time-points indicated in the Schedule of Assessments, 
prior to starting the TRC105 infusion.  Samples will be stored at approximately -70°C. Samples will be batch shipped as indicated in the laboratory manual 
to a third-party laboratory. See separate laboratory guide for further collection and shipment information. Additional PK samples may also be collected at the 
time of unexpected clinical events.  
22. Archival Tumor Tissue: Archival specimens (formalin-fixed, paraffin-embedded) are required of the primary cancer and/or metastatic cancer specimen for 
each study participant. It is preferable that the entire paraffin block be submitted, but if this is not feasible, then at least 20 unstained slides are requested for 
immunohistochemical analysis (sections of 5 microns are preferred).  See separate laboratory guide for further collection and shipment information. 
23. Cycle 4+ Treatment: Patients who demonstrate a response of CR, PR or SD will be eligible for additional treatment until progression. 
24. Follow-up:  The follow-up visit should occur 28 days following the last dose of TRC105. The allowable visit window is +/- 7 days.  
25. Visit Windows: Allowable window for each visit within the cycle is +/- 2 days unless otherwise stated. 

IND 100522 
 
105LC101 Protocol Amendment #3 
5.3.3.2 Clinical Protocol 
 
7July2015 
Page 48 of 93 
 
5. 
SELECTION AND WITHDRAWAL OF PATIENTS 
5.1. 
Patient Inclusion Criteria 
1. Stage 4 Non-Squamous Cell Lung Cancer that has not been treated previously with 
systemic chemotherapy or bevacizumab, but may have received prior targeted treatment 
(e.g., alk1 inhibitor)  
2. Measurable disease by RECIST  
3. Age of 18 years or older 
4. ECOG performance status ≤ 1 
5. Resolution of all acute adverse events resulting from prior cancer therapies to NCI 
CTCAE grade ≤ 1 or baseline (except alopecia or neuropathy)   
6. 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 times the upper limit of normal 
• Absolute neutrophil count (ANC) ≥ 1500/μL  
• Platelets ≥ 100,000/μL without transfusion support within the past 28 days 
• Hemoglobin ≥ 9.0 g/dL without transfusion support within the past 28 days 
(erythropoietin or darbepoetin permitted) 
• Serum creatinine ≤ 1.5 times the upper limit of normal or creatinine clearance >30 
mL/min by Cockcroft-Gault formula 
• < 1+ proteinuria 
•  INR from 0.8 to 1.2 
7. Willingness and ability to consent for self to participate in study   
8. Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests, 
and other study procedures   
9. Men who are sterile (including vasectomy confirmed by post vasectomy semen analysis) OR 
agree to use at least two forms of a reliable and highly effective method of birth control (refer to 
section 2.5.1) and to not donate sperm and for at least 180 days following last dose of TRC105, 
bevacizumab, paclitaxel, and/or carboplatin 
10. 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, OR woman of child bearing potential who test negative for 
pregnancy at time of enrollment based on serum pregnancy test and agree to use at least 2 forms 

IND 100522 
 
105LC101 Protocol Amendment #3 
5.3.3.2 Clinical Protocol 
 
7July2015 
Page 49 of 93 
 
of a reliable and highly effective method of birth control (refer to Section 2.5.1 ) during the 
study and for at least 180 days after stopping TRC105, bevacizumab, paclitaxel, and/or 
carboplatin 
 
5.2. 
Exclusion Criteria   
1. Non-small cell lung cancer of squamous histology 
2. Prior treatment with TRC105 
3. Current treatment on another therapeutic clinical trial 
4. Receipt of a small molecule anticancer agent, including an investigational anticancer 
small molecule, within 14 days of starting study treatment  
5. Receipt of a large molecule anticancer agent (e.g., antibody), including an  investigational 
anticancer antibody, within 28 days of starting study treatment 
6. No major surgical procedure or significant traumatic injury within 6 weeks prior to study 
registration, and must have fully recovered from any such procedure; date of surgery (if 
applicable) 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 therapy initiation: Thoracentesis, paracentesis, port placement, 
laparoscopy, thoracoscopy, tube thoracostomy, bronchoscopy, endoscopic 
ultrasonographic procedures,  mediastinoscopy, skin biopsies, incisional biopsies, 
imaging-guided biopsy for diagnostic purposes, and routine dental procedures 
7. 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 study registration or those patients who have not recovered adequately from side 
effects of such therapy 
8. Uncontrolled chronic hypertension defined as systolic > 150 or diastolic > 90 despite 
optimal therapy (initiation or adjustment of BP medication prior to study entry is allowed 
provided that the average of 3 BP readings at a visit prior to enrollment is < 140/90 mm 
Hg) 
9. 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  
10. Angina, MI, symptomatic congestive heart failure, cerebrovascular accident, transient 
ischemic attack, arterial embolism, pulmonary embolism, PTCA or CABG within the 
past 6 months. Deep venous thrombosis within 6 months, unless the patient is 
anticoagulated without the use of warfarin for at least 2 weeks. In this situation, low 
molecular weight heparin is preferred.  
11. Active bleeding or pathologic condition that carries a high risk of bleeding (e.g. 
hereditary hemorrhagic telangiectasia).  Patients who have been uneventfully anti-
coagulated with low molecular weight heparin are eligible. 

IND 100522 
 
105LC101 Protocol Amendment #3 
5.3.3.2 Clinical Protocol 
 
7July2015 
Page 50 of 93 
 
12. Thrombolytic use (except to maintain i.v. catheters) or anticoagulant use within 10 days 
prior to first day of study therapy 
13. Cardiac dysrhythmias of NCI CTCAE grade ≥ 2 within the last 28 days 
14. Known active viral or nonviral hepatitis or cirrhosis 
15. History of hemorrhage or hemoptysis (> ½ teaspoon bright red blood) within 3 months of 
starting study treatment 
16. History of peptic ulcer disease or erosive gastritis within the past 3 months, unless treated 
for the condition and complete resolution has been documented by 
esophagogastroduodenoscopy (EGD) within 28 days of starting study treatment 
17. History of gastrointestinal perforation or fistula in the past 6 months, or while previously 
on antiangiogenic therapy, unless underlying risk has been resolved (e.g., through 
surgical resection or repair) 
18. Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome 
(AIDS) related illness 
19. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality 
that may increase the risk associated with study participation or may interfere with the 
interpretation of study results and, in the judgment of the Investigator, would make the 
patient inappropriate for this study 
5.3. 
Patient Withdrawal Criteria 
A patient should be withdrawn from study treatment if, in the opinion of the Investigator, it is 
medically necessary, or if it is the wish of the patient.  If a patient does not return for a scheduled 
visit, every effort should be made to contact the patient.  In any circumstance, every effort should 
be made to document patient outcome.  Data to be collected at the end of study visit are 
described in the Schedule of Assessments (Table 4).  Patients will be followed for at least 28 
days after the last dose of TRC105 study drug for adverse events.  If the patient withdraws 
consent, no further evaluations should be performed, and no attempts should be made to collect 
additional data. In addition, patients will be withdrawn from treatment in the case of: 
1. RECIST 1.1-defined disease progression. In cases where RECIST cannot be applied, 
progression should be based on unequivocal evidence of progressive disease sufficient to 
require a change in therapy. 
2. A need for surgery, radiation, or for other anticancer therapy not specified in the protocol. 
3. Lost to follow-up or noncompliant. 
4. Any TRC105 dose delay > 14 days, other than a dose delay for planned surgery or 
hematologic toxicity, in which case up to 6 weeks is allowed. 
5. Pregnancy.  Pregnant patients should be followed for the duration of the pregnancy and 
the outcome of the pregnancy should be documented. 
 

IND 100522 
 
105LC101 Protocol Amendment #3 
5.3.3.2 Clinical Protocol 
 
7July2015 
Page 51 of 93 
 
6. 
TREATMENT OF PATIENTS 
6.1. 
Description of TRC105 Study Drug 
TRC105 is a genetically engineered human/murine chimeric monoclonal antibody directed 
against human CD105 found on the surface of proliferating endothelial cells.   
6.1.1. 
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.  
6.1.2. 
TRC105 Dose Level 
Each patient will be dosed with 6, 8 or 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.  Eighty-five kg for women and 100 kg for men represent accepted maximum lean body 
masses for the two genders. The first weekly dose will be split into two doses whereby 3 mg/kg 
will be administered on cycle 1 day 8 and the balance will be administered on cycle 1 day 11.  
The entire weekly dose of TRC105 (6, 8 or 10 mg/kg) is then given on cycle 1 day 15 and 
weekly thereafter (until progression) in combination with intravenous 15 mg/kg bevacizumab 
every three weeks starting on cycle 1 day 1 (until progression) and intravenous 200 mg/m2 
paclitaxel every three weeks starting on cycle 1 day 1 (for 6 cycles) and intravenous carboplatin 
6 AUC every three weeks starting on cycle 1 day 1 (for 6 cycles). The DLT evaluation period, 
for purposes of dose escalation, will be the first 42 days of dosing with all drugs (i.e., cycle 1 day 
1 through cycle 2 day 21).  
Each cycle will be 21 days in duration. 
6.1.3. 
TRC105 Packaging and Labeling 
TRC105 will be provided in the following presentations. 
20 mM L-Histidine/L-Histidine Monohydrochloride, 240 mM Trehalose,  
0.01% Polysorbate 20 Formulation (25 mg TRC105/mL) 
100 mg TRC105/4mL single-use vial 
400 mg TRC105/16mL single-use vial 
 
 
 
6.1.4. 
TRC105 Storage and Shipping 
TRC105 must be stored upright between 2 °C and 8 °C (36 °F to 46 °F). 

IND 100522 
 
105LC101 Protocol Amendment #3 
5.3.3.2 Clinical Protocol 
 
7July2015 
Page 52 of 93 
 
6.1.5. 
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 
observed.  Multiple vials will be required for a single dose.  The following formulae should be 
used to calculate the volume of TRC105 to be added to normal saline: 
• Patient weight (kg) × dose level (mg/kg) divided by TRC105 concentration (mg/mL) = 
volume of TRC105 (mL) to be administered. 
The volume of TRC105 that is to be administered can be rounded up or down to the nearest 1.0 
mL; in the case of an increment of 0.5 mL the volume should be rounded up. The maximum 
weight that should be used for dose calculation in this study is 85 kg for women and 100 kg 
for men (note: there is not a weight restriction for enrollment purposes).  If the patient’s 
weight changes by > 10% during the study, the dose of TRC105 will be recalculated.  At that 
time a new baseline weight will be established such that subsequent weight changes by >10% 
from the new baseline weight would require further recalculation of the TRC105 dose. The 
calculated volume of TRC105 will be diluted with normal saline.  Appropriate judgment should 
be exercised in withdrawing an adequate amount of saline necessary to permit injection of the 
appropriate volume of antibody into a normal saline bag in accordance with the dose needed.  
The final TRC105 concentration must be between 0.3 mg/mL and 10 mg/mL.  The prepared 
TRC105 must be gently inverted several times in order to ensure a homogeneous solution. The 
diluted infusion solution of TRC105 should be used within 8 hours of preparation if stored at 
room temperature, or within 24 hours of dilution if stored at 2 ° to 8 °C (36 to 46 ºF). The 
expiration time should be labeled on the bag.  If the diluted infusion solution of TRC105 cannot 
be infused within 8 hours of preparation (i.e.: the prepared infusion is at room temperature for 
more than 8 hours), a second bag will be prepared that contains the balance of the planned dose 
that was not already delivered. The prepared solution should not be frozen. 
6.1.6. 
TRC105 Administration 
Dosing will occur in the following order on day 1 of each cycle (Note: TRC105 is NOT dosed on cycle 1 
day 1): 
• Pre-medications 
• Paclitaxel 200 mg/kg (3 hour IV infusion) (for 6 cycles) 
• Carboplatin AUC of 6 (30  to 60 minutes IV infusion) (for 6 cycles) 
• Bevacizumab 15 mg/kg (30 minute IV infusion) (until progression) 
• TRC105 10 mg/kg – (1 to 4 hour IV infusion) (until progression) 
 
TRC105 infusions will be given weekly until progression. TRC105 will be dosed alone on days 8 
and 15 of each cycle following appropriate pre-medication (note: TRC105 will be held on cycle 
1 day 1, the first dose will be given on cycle 1 day 8 and split over two days whereby 3 mg/kg is 
given on cycle 1 day 8 and the remainder is give on cycle 1 day 11).  
Patients should be encouraged to drink abundant fluid (e.g., two eight 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. 

IND 100522 
 
105LC101 Protocol Amendment #3 
5.3.3.2 Clinical Protocol 
 
7July2015 
Page 53 of 93 
 
The following TRC105 premedications, including the dexamethasone infusion, should be 
completed 2 hours to 30 minutes prior to initiating Paclitaxel infusions (on days of 
Paclitaxel dosing) or TRC105 infusions (all other dosing days where TRC105 is given): 
Table 5: 
Cycle 1 Premedication Regimen 
 
Day 1 
Day 8 
Day 11 
Day 15 
Acetaminophen 650 mg 
p.o. x 1 
Yes 
Yes 
Yes 
Yes 
Dexamethasone 20 mg 
i.v. x 1 
Yes 
Yes 
Yes 
Given if the 
patient develops 
an infusion 
reaction > grade 
2 during the 
immediate prior 
TRC105 
infusion 
Famotidine 20 mg i.v. 
or p.o. (or similar H2 
blocker) x 1 
Yes 
Yes 
Yes 
Yes 
Cetirizine 10 mg i.v. or 
p.o. x 1 (or similar oral 
or intravenous 
antihistamine) 
Yes 
Yes 
Yes 
Yes 
Table 6: 
Cycle 2 through Cycle 6 Premedication Regimen 
 
Day 1 
Day 8 
Day 15 
Acetaminophen 
650 mg p.o. x 1 
Yes 
Yes 
Yes 
Dexamethasone 
20 mg i.v. x 1 
Yes 
Given in the case of a delay of > 
10 days between any two 
TRC105 doses or if the patient 
develops an infusion reaction > 
grade 2 during the immediate 
prior TRC105 infusion 
Given in the case of a delay of > 
10 days between any two 
TRC105 doses or if the patient 
develops an infusion reaction > 
grade 2 during the immediate 
prior TRC105 infusion 
Famotidine 20 mg 
i.v. or p.o. (or 
similar H2 
blocker) x 1 
Yes 
Does not need to be given prior 
to TRC105 infusions starting 
with Cycle 2 in the absence of 
TRC105 infusion reactions with 
the prior dose. 
Does not need to be given prior 
to TRC105 infusions starting 
with Cycle 2 in the absence of 
TRC105 infusion reactions with 
the prior dose. 
Cetirizine 10 mg 
i.v. or p.o. x 1 (or 
similar oral or 
intravenous 
antihistamine) 
Yes 
Does not need to be given prior 
to TRC105 infusions starting 
with Cycle 2 in the absence of 
TRC105 infusion reactions with 
the prior dose. 
Does not need to be given prior 
to TRC105 infusions starting 
with Cycle 2 in the absence of 
TRC105 infusion reactions with 
the prior dose. 

IND 100522 
 
105LC101 Protocol Amendment #3 
5.3.3.2 Clinical Protocol 
 
7July2015 
Page 54 of 93 
 
Table 7: 
Cycle 7+ Premedication Regimen (TRC105 + Bevacizumab Maintenance 
Phase of the Protocol) 
 
Day 1 
Day 8 
Day 15 
Acetaminophen 
650 mg p.o. x 1 
Yes 
Yes 
Yes 
Dexamethason
e 20 mg i.v. x 1 
Given in the case of a 
delay of > 10 days 
between any two 
TRC105 doses or if the 
patient develops an 
infusion reaction > grade 
2 during the immediate 
prior TRC105 infusion 
Given in the case of a 
delay of > 10 days 
between any two 
TRC105 doses or if the 
patient develops an 
infusion reaction > 
grade 2 during the 
immediate prior 
TRC105 infusion 
Given in the case of a 
delay of > 10 days 
between any two TRC105 
doses or if the patient 
develops an infusion 
reaction > grade 2 during 
the immediate prior 
TRC105 infusion 
Famotidine 20 
mg i.v. or p.o. 
(or similar H2 
blocker) x 1 
Does not need to be 
given prior to TRC105 
infusions starting with 
Cycle 2 in the absence 
of TRC105 infusion 
reactions with the prior 
dose. 
Does not need to be 
given prior to TRC105 
infusions starting with 
Cycle 2 in the absence 
of TRC105 infusion 
reactions with the prior 
dose. 
Does not need to be given 
prior to TRC105 infusions 
starting with Cycle 2 in the 
absence of TRC105 
infusion reactions with the 
prior dose. 
Cetirizine 10 
mg i.v. or p.o. 
x 1 (or similar 
oral or 
intravenous 
antihistamine) 
Does not need to be 
given prior to TRC105 
infusions starting with 
Cycle 2 in the absence 
of TRC105 infusion 
reactions with the prior 
dose. 
Does not need to be 
given prior to TRC105 
infusions starting with 
Cycle 2 in the absence 
of TRC105 infusion 
reactions with the prior 
dose. 
Does not need to be given 
prior to TRC105 infusions 
starting with Cycle 2 in the 
absence of TRC105 
infusion reactions with the 
prior dose. 
 
TRC105 premedication, including the dexamethasone infusion, should be completed 2 
hours to 30 minutes prior to initiating Paclitaxel infusions (on days of Paclitaxel dosing) or 
TRC105 infusions (all other dosing days where TRC105 is given).  TRC105 will be 
administered intravenously utilizing an infusion pump.  TRC105 has been demonstrated to be 
compatible with polyethylene lined, non-DEHP infusion sets and polyvinyl chloride, non-DEHP 
infusion sets.  TRC105 is required to be administered with a 0.2 micron downstream filter.  The 
attachment of the infusion pump administration set to the i.v. bag and transport of the TRC105 
study drug to the patient will be performed as per standard study site procedures.   
The first weekly TRC105 dose will be split into two doses whereby 3 mg/kg is administered on 
cycle 1 day 8 over 4 hours (+/- 15 minutes). Do not increase the infusion rate above 25 mg/min 
during the Cycle 1 Day 8 dose. The remainder of the Cycle 1 Day 8 dose will be administered on 
Cycle 1 Day 11 (e.g., 7 mg/kg) over 2 hours (+/- 15 minutes).  The full TRC105 dose (e.g., 8 
mg/kg for Dose Level 1) will be administered on Cycle 1 Day 15, and weekly thereafter, over 1 
hour (+/- 15 minutes). Patients must complete at least one 4 hour infusion without the 
development of any infusion reactions, in order to reduce the subsequent TRC105 infusion to 2 
hours (+/- 15 minutes) and complete a 2 hour infusion without the development of any infusion 

IND 100522 
 
105LC101 Protocol Amendment #3 
5.3.3.2 Clinical Protocol 
 
7July2015 
Page 55 of 93 
 
reactions in order to reduce subsequent TRC105 infusions to 1 hour (+/- 15 minutes).  Patients 
with infusion reactions of any kind should be managed appropriately (see Section 6.1.8) 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 20 mL normal saline.  The dose level, time of transfer to i.v. bag, 
and the infusion start and stop times must be recorded in the source documents. 
If a patient misses a weekly TRC105 dose (i.e., ≥ 10 days between doses), the dexamethasone 
dose should be reinstituted as per the initial infusion and first TRC105 dose should be 
administered over two days as was done for the initial dose.   
6.1.7. 
TRC105 Dose Modification/Dose Interruptions 
TRC105 dose reductions and interruptions should be avoided in cycle 1.  In cycle 2 and beyond, 
TRC105 dose reductions are allowed for grade 3 or 4 related adverse events that resolve to grade 
1 or baseline (including anemia).  Any TRC105 dose delay > 14 days will require 
discontinuation of TRC105 treatment, other than a dose delay for planned surgery or recovery 
from hematologic toxicity, in which case up to 6 weeks is allowed. Treatment dose delays cannot 
exceed 6 consecutive weeks (i.e., dosing with all drugs held).  
TRC105, bevacizumab, paclitaxel and carboplatin should be held for two weeks prior and for 
two weeks following surgical procedures.  
Table 8: 
Allowable TRC105 Dose Modifications 
Toxicity Attributed to 
TRC105 
Dose Adjustment for Next Dose of TRC105 (% of Starting 
Dose) 
Grade 1 or 2 
Maintain Dose Level 
Grade 3 or 4 
 
• 
1st appearance 
80% 
• 
2nd appearance 
60% 
• 
3rd appearance 
Discontinue treatment permanently 
Patients with arterial thrombosis or grade 3 or 4 venous thrombosis should discontinue TRC105 
and bevacizumab therapy but may remain on study on carboplatin and paclitaxel. Patients with 
grade 1 or 2 venous thrombosis who require anticoagulation will have their TRC105 therapy 
interrupted.  TRC105 therapy may resume once the following criteria are met:   
• The patient is on a stable dose of heparin or low molecular weight heparin.  
• 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 (no evidence of disease progression). 

IND 100522 
 
105LC101 Protocol Amendment #3 
5.3.3.2 Clinical Protocol 
 
7July2015 
Page 56 of 93 
 
6.1.8. 
Management of TRC105 Infusion Reactions 
If a patient experiences a grade 2 or higher adverse reaction during infusion, the infusion should 
be interrupted and the patient treated accordingly.  Antipyretic, antihistamine, antiemetic, anti-
inflammatory, or other symptomatic medications including epinephrine may be administered as 
indicated.  For grade 2 and certain grade 3 infusion reactions, the infusion may be restarted at 
half of the previous rate if and when the infusion reaction has resolved and then increased per 
patient tolerance to a maximum of 25 mg/min.  For grade 4 infusion reactions, the infusion 
should not be restarted and the patient should be discontinued from study treatment.  Infusion 
reactions will be recorded as AEs in the case report form.  Interventions should be documented 
as concomitant medications or concomitant treatments as appropriate.   
Table 9: 
Management of TRC105 Infusion Reactions 
Infusion 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. Withdraw patient from study unless other factors that contributed to the 
infusion reaction are identified and corrected 
Grade 4 (life-
threatening) 
1. Discontinue infusion 
2. Treat with symptomatic medicationsa 
3. Hospitalize patient 
4. Withdraw from study 
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). 
6.1.9. 
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 

IND 100522 
 
105LC101 Protocol Amendment #3 
5.3.3.2 Clinical Protocol 
 
7July2015 
Page 57 of 93 
 
• 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. 
6.1.10. 
TRC105 Study Drug Handling and Disposal 
TRC105 must be stored upright between 2 °C and 8 °C (36 °F to 46 °F). The Investigator should 
not return clinical study materials to TRACON unless specifically instructed to do so by 
TRACON.  Used vials do not need to be maintained.  All expired vials of TRC105 should be 
retained until destruction is authorized by a TRACON representative.  The Site Pharmacist will 
be responsible for documenting the destruction (according to institutional requirements) of used 
or expired vials. 
6.2. 
Description of Bevacizumab 
See bevacizumab package insert [84].   
6.2.1. 
Composition of Bevacizumab 
See bevacizumab package insert [84].    
6.2.2. 
Bevacizumab Dose Level 
Fifteen mg/kg will be dosed every 3 weeks, starting on cycle 1 day 1, until disease progression or 
unacceptable toxicity [84].   
6.2.3. 
Bevacizumab Packaging and Labeling 
See bevacizumab package insert [84].    
6.2.4. 
Bevacizumab Storage  
See bevacizumab package insert [84].   
6.2.5. 
Bevacizumab Preparation 
Commercially available bevacizumab will be utilized in this study. Patients will receive 15 
mg/kg on day 1 of each 3 week cycle until progression.  Bevacizumab should be prepared 
according to the package insert [84]. 
6.2.6. 
Bevacizumab Dosing 
Dosing will occur in the following order on day 1 of each cycle (Note: TRC105 is NOT dosed on 
cycle 1 day 1): 
• Pre-medications 
• Paclitaxel 200 mg/kg (3 hour IV infusion) (for 6 cycles) 
• Carboplatin AUC of 6 (30  to 60 minutes IV infusion) (for 6 cycles) 
• Bevacizumab 15 mg/kg (30 minute IV infusion) (until progression) 
• TRC105 10 mg/kg (1 to 4 hour IV infusion) (until progression) 

IND 100522 
 
105LC101 Protocol Amendment #3 
5.3.3.2 Clinical Protocol 
 
7July2015 
Page 58 of 93 
 
Do not administer as an intravenous push or bolus. Administer only as an intravenous (IV) 
infusion. 
• Administered over 30 minutes per institutional guidelines 
Do not initiate bevacizumab until at least 28 days following major surgery. Administer 
bevacizumab after the surgical incision has fully healed. 
6.2.7. 
Bevacizumab Dose Modification 
Dose reduction of bevacizumab for adverse reactions is not recommended. Patients with arterial 
thrombosis or grade 3 or 4 venous thrombosis should discontinue TRC105 and bevacizumab 
therapy but may remain on study on carboplatin and paclitaxel alone.  If indicated, bevacizumab 
should either be discontinued or temporarily suspended, see bevacizumab package insert for 
specific information related to different adverse events [84].   
6.2.8. 
Bevacizumab Drug Accountability 
The investigator must maintain an accurate accounting of bevacizumab product that is used. 
During the study, the following information must be maintained: 
• ID number of the patient to whom the product is dispensed 
• Lot number dispensed 
• The date(s) and quantity of the product dispensed  
6.2.9. 
Bevacizumab Drug Handling and Disposal 
The Site Pharmacist will be responsible for documenting the destruction (according to 
institutional requirements) of used or expired vials. 
6.3. 
Description of Paclitaxel 
Commercially available paclitaxel will be used in this study. See paclitaxel package insert for 
additional information [82].  
6.3.1. 
Composition of Paclitaxel 
See paclitaxel package insert [82]. 
6.3.2. 
Paclitaxel Dose Level 
Each patient will be dosed with 200 mg/m2 paclitaxel on day 1 of each 3 week cycle, starting on 
cycle 1 day1 for 6 cycles.   
6.3.3. 
Paclitaxel Packaging and Labeling 
See paclitaxel package insert [82].   
6.3.4. 
Paclitaxel Storage  
See paclitaxel package insert [82]. 

IND 100522 
 
105LC101 Protocol Amendment #3 
5.3.3.2 Clinical Protocol 
 
7July2015 
Page 59 of 93 
 
6.3.5. 
Paclitaxel Preparation 
Commercially available paclitaxel will be used in this study.  See paclitaxel package insert for 
specific preparation instructions [82].  
6.3.6. 
Paclitaxel Dosing 
Dosing will occur in the following order on day 1 of each cycle (Note: TRC105 is NOT dosed on cycle 1 
day 1): 
• Pre-medications 
• Paclitaxel 200 mg/kg (3 hour IV infusion) (for 6 cycles) 
• Carboplatin AUC of 6 (30  to 60 minutes IV infusion) (for 6 cycles) 
• Bevacizumab 15 mg/kg (30 minute IV infusion) (until progression) 
• TRC105 10 mg/kg (1 to 4 hour IV infusion) (until progression) 
Patients will be dosed with 200 mg/m2 paclitaxel on day 1 of each 3 week cycle, starting on 
cycle 1 day1 for 6 cycles. Paclitaxel is to be administered as an intravenous infusion over 3 
hours.  
All patients should be premedicated prior to paclitaxel administration in order to prevent severe 
hypersensitivity reactions – see Table 5, Table 6, and Table 7 for details. 
See paclitaxel package insert for additional dosing information [82].  
6.3.7. 
Paclitaxel Dose Modification 
See paclitaxel package insert [82]. Patients with arterial thrombosis or grade 3 or 4 venous 
thrombosis should discontinue TRC105 and bevacizumab therapy but may remain on study on 
carboplatin and paclitaxel alone. 
6.3.8. 
Paclitaxel Drug Accountability 
The investigator must maintain an accurate accounting of paclitaxel product that is used. During 
the study, the following information must be maintained: 
• ID number of the patient to whom the product is dispensed 
• Lot number dispensed 
• The date(s) and quantity of the product dispensed  
6.3.9. 
Paclitaxel Handling and Disposal 
See paclitaxel package insert [82].  
The Site Pharmacist will be responsible for the destruction, according to institutional 
requirements, of used or partially used vials. 
6.4. 
Description of Carboplatin 
Commercially available carboplatin will be used in this study. See carboplatin package insert 
[83].  

IND 100522 
 
105LC101 Protocol Amendment #3 
5.3.3.2 Clinical Protocol 
 
7July2015 
Page 60 of 93 
 
6.4.1. 
Composition of Carboplatin 
See carboplatin package insert [83]. 
6.4.2. 
Carboplatin Dose Level 
Each patient will be dosed with an AUC of 6 carboplatin on day 1 of each 3 week cycle, starting 
on cycle 1 day1 for 6 cycles.  
6.4.3. 
Carboplatin Packaging and Labeling 
See carboplatin package insert [83]. 
6.4.4. 
Carboplatin Storage 
See carboplatin package insert [83].  
6.4.5. 
Carboplatin Preparation 
See carboplatin package insert [83].  
6.4.6. 
Carboplatin Dosing 
Dosing will occur in the following order on day 1 of each cycle (Note: TRC105 is NOT dosed on cycle 1 
day 1): 
• Pre-medications 
• Paclitaxel 200 mg/kg (3 hour IV infusion) (for 6 cycles) 
• Carboplatin AUC of 6 (30  to 60 minutes IV infusion) (for 6 cycles) 
• Bevacizumab 15 mg/kg (30 minute IV infusion) (until progression) 
• TRC105 10 mg/kg (1 to 4 hour IV infusion) (until progression) 
Patients will be dosed with an AUC of 6 carboplatin on day 1 of each 3 week cycle, starting on 
cycle 1 day1 for 6 cycles. Carboplatin is to be administered as an intravenous infusion over 30 to 
60 minutes.  
6.4.7. 
Carboplatin Dose Modification 
See carboplatin package insert [83]. Patients with arterial thrombosis or grade 3 or 4 venous 
thrombosis should discontinue TRC105 and bevacizumab therapy but may remain on study on 
carboplatin and paclitaxel alone. 
6.4.8. 
Carboplatin Drug Accountability 
The investigator must maintain an accurate accounting of carboplatin product that is used. 
During the study, the following information must be maintained: 
• ID number of the patient to whom the product is dispensed 
• Lot number dispensed 
• The date(s) and quantity of the product dispensed  

IND 100522 
 
105LC101 Protocol Amendment #3 
5.3.3.2 Clinical Protocol 
 
7July2015 
Page 61 of 93 
 
6.4.9. 
Carboplatin Handling and Disposal 
The site pharmacist will be responsible for the destruction, according to institutional 
requirements, of used or partially used vials. 
6.5. 
Concomitant Medications 
No other approved or investigational anticancer treatment will be permitted during the study 
period.  No other investigational drug may be used during treatment on this protocol, and 
concurrent participation in another clinical trial is not allowed. 
Patients who receive NSAIDs on study should also receive peptic ulcer disease (PUD) 
prophylaxis with an H2 or proton pump blocker. 
Narcotic analgesics, nonsteroidal anti-inflammatory drugs, and triptans (e.g. sumatriptan) may be 
offered as needed for relief of pain or headaches.  Antihistamines and decongestants may be 
offered for the treatment of sinus congestion. 
Packed red blood cell, colony stimulating factors, and platelet transfusions should be 
administered as clinically indicated.  
The metabolism of paclitaxel is catalyzed by cytochrome P450 isoenzymes CYP2C8 and 
CYP3A4. Caution should be exercised when paclitaxel is concomitantly administered with 
known substrates (e.g., midazolam, buspirone, felodipine, lovastatin, eletriptan, sildenafil, 
simvastatin, and triazolam), inhibitors (e.g., atazanavir, clarithromycin, indinavir, itraconazole, 
ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin), and inducers 
(e.g., rifampin and carbamazepine) of CYP3A4.  
Caution should also be exercised when paclitaxel is concomitantly administered with known 
substrates (e.g., repaglinide and rosiglitazone), inhibitors (e.g., gemfibrozil), and inducers (e.g., 
rifampin) of CYP2C8.  
Potential interactions between paclitaxel, a substrate of CYP3A4, and protease inhibitors 
(ritonavir, saquinavir, indinavir, and nelfinavir), which are substrates and/or inhibitors of 
CYP3A4, have not been evaluated in clinical trials. 
The renal effects of nephrotoxic compounds may be potentiated by carboplatin.  
6.6. 
Treatment Compliance 
All TRC105, bevacizumab, paclitaxel and carboplatin infusions will occur at the trial site under 
the direct supervision of the treating physician or his or her designee.  
6.7. 
Patient Enrollment 
Patients will be manually enrolled by TRACON Pharmaceuticals and assigned an eight digit 
patient number. This eight digit number will be used to identify patients throughout their 
participation in the trial.  A regulatory binder will be provided and will include detailed 
instructions for the manual enrollment process.  

IND 100522 
 
105LC101 Protocol Amendment #3 
5.3.3.2 Clinical Protocol 
 
7July2015 
Page 62 of 93 
 
7. 
ASSESSMENT OF EFFICACY 
7.1. 
Radiological Tumor Assessment 
The primary efficacy assessment will be best overall response as defined in Section 7.1.2.  The 
determination of antitumor efficacy will be based on objective tumor assessments made by the 
Investigator according to RECIST version 1.1 [85].  Investigators will make treatment decisions 
based on these assessments.  All lesions will be classified as target or non-target lesions at the 
Screening visit.  Each lesion designation will be maintained through the course of the study.  
The same method and technique should be used to characterize each identified and reported 
lesion at Screening, during the study treatment period, and at the End of Study visit. Imaging-
based evaluation over clinical examination is the required technique when both could be used to 
assess the antitumor effect of the treatment.  Clinical Oncology review of all tumor 
measurements is desired. 
Whenever possible, clinical evaluation of superficial lesions should not be used as the sole form 
of measurement.  However, when necessary, color photograph with metric caliber is acceptable.  
Tumor evaluation by positron emission tomography (PET) scan or by ultrasound may not 
substitute for CT or MRI scans.  
Radiological tumor assessments will be performed at screening, as outlined in the Schedule of 
Assessments (Table 4), and whenever disease progression is suspected.  Another tumor 
assessment will be performed at the End of Study Visit if an assessment has not been performed 
within the prior 8 weeks.  All patient files and radiological images must be available for CRF 
source verification.     
7.1.1. 
Measurability of Tumor Lesions 
At Screening, individual tumor lesions will be categorized by the Investigator as either target or 
non-target according to RECIST 1.1 as described below. 
• Measurable:  Lesions that can be accurately measured in at least one dimension (longest 
diameter to be recorded) as ≥ 10 mm with spiral CT scan. Lytic bone lesions, with an 
identifiable soft tissue component, evaluated by CT or MRI, can be considered 
measurable lesions if the soft tissue component otherwise meets the definition of 
measurability previously described.  Blastic bone lesions are non-measurable. Lesions in 
previously irradiated areas (or areas treated with local therapy) should not be selected as 
target lesions, unless there has been demonstrated progression in the lesion. Clinical 
lesions will only be considered measurable when they are superficial (e.g. skin nodules, 
palpable lymph nodes) and ≥ 10 mm.  Clinical lesions must be measured with calipers. 
• Non-Measurable:  All other lesions, including small lesions and bone lesions other than 
lytic bone lesions, leptomeningeal disease, ascites, pleural or pericardial effusions, 
lymphangitis of the skin or lung, abdominal masses that are not confirmed and followed 
by imaging techniques, previously irradiated lesions (unless there has been demonstrated 
progression in the lesion), and disease documented by indirect evidence only (e.g. by 
laboratory tests such as alkaline phosphatase).  

IND 100522 
 
105LC101 Protocol Amendment #3 
5.3.3.2 Clinical Protocol 
 
7July2015 
Page 63 of 93 
 
7.1.1.1. 
Recording Tumor Measurements 
Measurable lesions up to a maximum of 5 lesions representative of all involved organs (with a 
maximum of 2 lesions per organ) should be identified as target lesions and measured and 
recorded at Screening and at the stipulated intervals during treatment.  Target lesions should be 
selected on the basis of their size (lesion with the longest diameters) and their suitability for 
accurate repetitive measurements (either by imaging techniques or clinically).  Target lesions 
may include lymph nodes with a short axis > 15 mm.  
The longest diameter will be recorded for each target lesion (with the exception of lymph nodes, 
where the short axis will be used). The sum of the diameter for all target lesions at Screening will 
be calculated and recorded as the baseline sum diameter to be used as reference to further 
characterize the objective tumor response of the measurable dimension of the disease during 
treatment.  All measurements should be performed using a caliper or ruler and should be 
recorded in metric notation in millimeters. 
All other lesions (or sites of disease) should be identified as non-target lesions and should also be 
recorded at baseline.  Measurements are not required and these lesions should be followed as 
“present”, “stable”, “absent”, “increased” or “decreased”. 
7.1.2. 
Definitions of Tumor Response 
7.1.2.1. 
Target Lesions 
• Complete response (CR) is defined as the disappearance of all target lesions. 
• Partial response (PR) is defined as a ≥ 30% decrease in the sum of the dimensions of 
the target lesions taking as a reference the baseline sum dimensions. 
• Progressive disease (PD) is defined as a ≥ 20% relative increase and ≥ 5 mm absolute 
increase in the sum of the dimensions of the target lesions taking as a reference the 
smallest sum of the dimensions recorded since the treatment started, or the appearance of 
one or more new lesions. 
• Stable disease (SD) is defined as neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD taking as a reference the smallest sum of the 
dimensions since the treatment started.  
7.1.2.2. 
Non-Target Lesions 
• Complete response (CR) is defined as the disappearance of all non-target lesions. 
• non-CR/non-PD is defined as a persistence of ≥ 1 non-target lesions. 
• Progressive disease (PD) is defined as unequivocal progression of existing non-target 
lesions, or the appearance of ≥ 1 new lesions. 
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment when the measurable tumor has met criteria for response or stable disease is 
mandatory to differentiate between response or stable disease and progressive disease. 

IND 100522 
 
105LC101 Protocol Amendment #3 
5.3.3.2 Clinical Protocol 
 
7July2015 
Page 64 of 93 
 
7.1.2.3. 
Determination of Overall Response  
7.1.2.3.1. By RECIST  
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 
10.  Per RECIST 1.1, in non-randomized trials with response as a primary endpoint, confirmation 
of PR or CR is required.  Per RECIST 1.1, a modest increase in the size of one or more non-
target lesions is usually not sufficient to qualify for unequivocal progression status.  
Table 10: 
Response Evaluation Criteria in Solid Tumors 
Target Lesionsa 
Non-target Lesionsb 
New Lesionsc 
Overall Response 
CR 
CR 
No 
CR 
CR 
non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all 
evaluated 
No 
PR 
SD 
Non-PD or not all 
evaluated 
No 
SD 
Not all evaluated 
Any Response 
Yes or No 
Not Evaluable 
PD 
Any Response 
Yes or No 
PD 
Any Response 
PD 
Yes or No 
PD 
Any Response 
Any Response 
Yes 
PD 
aMeasurable lesions only. 
bMay include measurable lesions not followed as target lesions or non-measurable lesions. 
cMeasurable or nonmeasurable lesions.  
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started).  The patient’s best response assignment will 
depend on the achievement of both measurement and confirmation criteria. 
NOTE:  Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be reported as 
“Need for additional anti-cancer therapy/surgery”.  Every effort should be made to document the 
objective progression even after discontinuation of treatment.   
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. 

IND 100522 
 
105LC101 Protocol Amendment #3 
5.3.3.2 Clinical Protocol 
 
7July2015 
Page 65 of 93 
 
8. 
ASSESSMENT OF SAFETY 
8.1. 
Safety Parameters 
Safety will be characterized in terms of the incidence, timing, severity (graded by the National 
Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE], Version 
4.0), seriousness, and relatedness of adverse events and laboratory abnormalities.  In addition, 
physical examination, vital signs, and ECOG performance status will be serially monitored.  
Laboratory safety analyses will be based on the local laboratory data, and will include 
hematology, serum chemistry (including liver and kidney function), urinalysis, serum or urine 
pregnancy testing, and coagulation profile. Serum will also be assessed for immunogenicity to 
TRC105 (including anti-product antibody titers).  In addition, single tracing 12-lead ECGs will 
be performed at the time-points indicated in the Schedule of Assessments (Table 4).  QT, PR and 
QRS intervals and heart rate will be captured. ECGs will also be collected as clinically indicated 
throughout the study.   
8.1.1. 
Laboratory Safety Assessments 
Abnormal and clinically significant laboratory tests should be recorded as adverse events.  To 
meet the definition of clinically significant, the test result generally requires a change in medical 
management (e.g. new medication, unplanned treatment, additional tests, etc.). 
8.1.1.1. 
Hematology, Serum Chemistry, Coagulation, Pregnancy Test  
Assessments will be performed at the time points indicated in the Schedule of Assessments 
(Table 4) and analyzed at local laboratories.  Investigators may have additional blood tests 
performed for the purpose of planning treatment administration, or for following adverse events 
as clinically indicated.  
• Hematology: CBC with differential and platelet count. Iron studies (serum iron, ferritin 
and total iron binding capacity). 
• Coagulation: International Normalized Ratio (INR) will be assessed 
• Serum Chemistry: Total bilirubin, alanine transaminase (ALT), aspartate transaminase 
(AST), alkaline phosphatase, lipase, amylase, total protein, albumin, sodium, potassium, 
bicarbonate, chloride, calcium, phosphorus, blood urea nitrogen, creatinine, magnesium, 
thyroid stimulating hormone and glucose 
• Pregnancy Test: Serum or urine pregnancy tests will be performed locally on all female 
patients of childbearing potential. Patients must be surgically sterile (i.e.: hysterectomy) 
or be postmenopausal, or must agree to use effective contraception during the study and 
for 90 days following last dose of TRC105.  The definition of effective contraception will 
be based on the judgment of the Principal Investigator or a designated associate. 
8.1.1.2. 
Urinalysis  
Urinalysis (without microscopic analysis, unless indicated) will be performed at time points 
indicated in the Schedule of Assessments (Table 4) and analyzed by local laboratories.  

IND 100522 
 
105LC101 Protocol Amendment #3 
5.3.3.2 Clinical Protocol 
 
7July2015 
Page 66 of 93 
 
Microscopic analysis, urine protein-creatinine ratio (UPCR), and 24 urine collection for protein 
should be performed as clinically indicated. 
8.1.1.3. 
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 4).  The physical examination will 
include examination of known and suspected sites of disease.   
8.1.1.4. 
Vital Signs  
Heart rate, temperature, blood pressure, respiratory rate and weight will be assessed at time 
points indicated within the Schedule of Assessments (Table 4).  Heart rate, temperature, blood 
pressure, and respiratory rate will also be assessed during TRC105 infusions as described in 
Section 4.1.2.2 and the footnotes of the Schedule of Assessments (Table 4).  
8.1.1.5. 
Performance Status  
The ECOG scale will be used to assess performance status at Screening.  
8.1.1.6. 
ECG  
A single 12-lead (with a 10–second rhythm strip) tracing will be used for all ECGs.  It is 
preferable that the machine used has a capacity to calculate standard intervals automatically. 
ECG will be performed at the time-points indicated in the Schedule of Assessments (Table 4) 
and as clinically indicated throughout the study.  
8.2. 
Adverse Events 
All observed or volunteered adverse events regardless of suspected causal relationship to 
TRC105 study drug will be reported as described below.  
8.2.1. 
Definition of Adverse Event 
An adverse event is any untoward medical occurrence in a trial patient who is administered a 
drug or biologic (medicinal product); the event may or may not have a causal relationship with 
the medicinal product.  Examples of adverse events include, but are not limited to the following: 
• Clinically significant symptoms and signs including:  
o Worsening of signs and symptoms of the malignancy under trial (disease 
progression without worsening of signs and symptoms assessed by measurement 
of malignant lesions on radiographs or other methods should not be reported as 
adverse events). 
o Signs and symptoms resulting from drug overdose, abuse, misuse, withdrawal, 
sensitivity, dependency, interaction or toxicity.   
o All possibly related and unrelated illnesses, including the worsening of a 
preexisting illness.  

IND 100522 
 
105LC101 Protocol Amendment #3 
5.3.3.2 Clinical Protocol 
 
7July2015 
Page 67 of 93 
 
o Injury or accidents.  Note that if a medical condition is known to have caused the 
injury or accident (hip fracture from a fall secondary to dizziness), the medical 
condition (dizziness) and the outcome of the accident (hip fracture from a fall) 
should be reported as 2 separate adverse events.   
o Symptoms or signs resulting from exposure in utero. 
• Abnormalities in physiological testing or physical examination findings that require 
clinical intervention or further investigation (beyond ordering a repeat confirmatory test). 
• Laboratory abnormalities that meet any of the following (Note: merely repeating an 
abnormal test, in the absence of any of the below conditions, does not constitute an 
adverse event.  Any abnormal test result that is determined to be an error does not require 
reporting as an adverse event.): 
o Test result that is associated with accompanying symptoms 
o Test result that requires additional diagnostic testing or medical/surgical 
intervention 
o Test result that leads to a change in TRC105 study drug dosing outside of 
protocol-stipulated dose adjustments or discontinuation from the trial, significant 
additional concomitant drug treatment, or other therapy 
o Test result that is considered to be an adverse event by the Investigator or 
TRACON 
8.2.2. 
Serious Adverse Events 
An adverse event that meets one or more of the following criteria/outcomes is classified as 
serious: 
• Results in death 
• Is life-threatening (i.e., at immediate risk of death) 
• Requires in patient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability/incapacity  
• Results in congenital anomaly/birth defect 
• Other important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the patient or may require medical or surgical intervention 
to prevent one of the outcomes listed above.  Examples of such events are intensive 
treatment in an emergency room for allergic bronchospasm; blood dyscrasias or 
convulsions that do not result in hospitalization; or the development of drug dependence 
or drug abuse.  
Serious also includes any other event that the Investigator or sponsor judges to be serious, or 
which is defined as serious by the HRA in the country in which the event occurred.   
Progression of the malignancy under study (including signs and symptoms of progression) 
should not be reported as SAEs unless the outcome is fatal during the trial or within the safety 

IND 100522 
 
105LC101 Protocol Amendment #3 
5.3.3.2 Clinical Protocol 
 
7July2015 
Page 68 of 93 
 
reporting period. Hospitalizations due to signs and symptoms of disease progression should not 
be reported as SAEs.  If the malignancy has a fatal outcome during the trial or within the safety 
reporting period, then the event leading to death must be recorded as an adverse event and as an 
SAE with 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).  
8.2.2.1. 
Hospitalization 
Adverse events 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 hospitalizations 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 
adverse events as follows: 
o Admission for treatment of preexisting condition not associated  with the 
development of a new adverse event or with a worsening of the preexisting 
condition  
o Social admission 
o Administrative admission (e.g. for yearly physical exam) 
o Protocol-specified admission during a clinical trial 
o Optional admission not associated with a precipitating clinical adverse event (e.g. 
for elective cosmetic surgery) 
o Preplanned treatments or surgical procedures that are not related to an SAE 
o Hospitalization for observation without an AE 
• Diagnostic and therapeutic noninvasive and invasive procedures, such as surgery, should 
not be reported as adverse events.  The medical condition for which the procedure was 
performed should be reported if it meets the definition of an adverse event (e.g. acute 

IND 100522 
 
105LC101 Protocol Amendment #3 
5.3.3.2 Clinical Protocol 
 
7July2015 
Page 69 of 93 
 
appendicitis that begins during the adverse event reporting period should be reported as 
an adverse event and the appendectomy should be recorded as a concomitant treatment). 
8.3. 
Reporting Adverse Events 
8.3.1. 
Eliciting Adverse Event Information 
The Investigator is to report all directly observed adverse events and all adverse events 
spontaneously reported by the trial patient using concise medical terminology.  In addition, each 
trial patient will be questioned about adverse events at each clinic visit following initiation of 
treatment.  The question asked will be, “Since your last clinic visit have you had any health 
problems?” 
8.3.2. 
Adverse Event Reporting Period 
Safety information for each patient will be collected from the date of informed consent.  Adverse 
events occurring prior to the initiation of the study treatment with bevacizumab and/or paclitaxel 
and/or carboplatin and/or TRC105 study drug will be considered "baseline-signs and symptoms”, 
will be recorded on corresponding case report forms and will not be retained for patients who fail 
screening. The adverse event reporting period for this trial begins when the patient has received 
even a portion of the first dose of bevacizumab and/or paclitaxel and/or carboplatin and/or 
TRC105 study drug and ends 28 days after the last dose of the latest study treatment (i.e. 
bevacizumab and/or paclitaxel and/or carboplatin and/or TRC105 study drug) is administered.  
All adverse events that occur in trial patients during the adverse event 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 adverse event 
reporting period that the Investigator assesses as possibly related to the investigational 
medication/product should also be reported as an adverse event. 
8.3.3. 
Reporting Requirements 
Each adverse event is to be classified by the Investigator as SERIOUS or NONSERIOUS.  This 
classification of the gravity 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 event 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 suspected TRC105 adverse drug reactions (e.g.,: change in grade etc.), 
including a change in attribution to TRC105 study drug from “not related” to “suspected adverse 
drug reaction” should also be communicated to TRACON immediately. This notification should 
be made to: 
Charles Theuer, MD PhD 
TRACON Pharmaceuticals Inc. 
8910 University Center Lane, Suite 700 
San Diego, California 92122 
Email: ctheuer@traconpharma.com 
Cell Phone:  (858) 344-9400 
Office Phone:  (858) 550-0780 x233 

IND 100522 
 
105LC101 Protocol Amendment #3 
5.3.3.2 Clinical Protocol 
 
7July2015 
Page 70 of 93 
 
Following notification, the Investigator will report the SAE via the AE CRF via the data 
management system.  The initial AE CRF is to be updated with more detailed adverse event 
information within 5 calendar days of the event. 
In the rare event that the Investigator is not immediately aware of an SAE (for example, if the 
study subject seeks urgent medical attention elsewhere), the Investigator is to notify the Sponsor 
immediately upon learning of it and document his/her first awareness. 
Each SAE should be followed until resolution, or until such time as the Investigator determines 
its cause or determines that it has become stable.  Information pertaining to follow-up of SAEs 
should also be sent to the TRACON Pharmaceuticals Inc. 
Serious adverse events that are unexpected and associated with use of the study medication will 
be reported to the US Food and Drug Administration (FDA) and all participating clinical sites by 
TRACON via MedWatch forms.  For events which are fatal or life-threatening, unexpected, and 
associated with use of the investigational product, a 7-Day Alert Report will be submitted to the 
FDA within 7 calendar days of receipt of the SAE information.  For all other events that are 
serious, unexpected, and associated with use of the investigational product, 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 adverse events, including SAEs, are to be reported on the adverse event CRFs.  
8.3.4. 
Recording Adverse Events in the Case Report Forms 
The Investigator is to report all directly observed adverse events and all adverse events 
spontaneously reported by the trial patient.  In addition, each trial patient will be questioned 
about adverse events.  All adverse events that meet the criteria specified in Section 8.2.1 are to 
be recorded on patient source documents and on the CRFs. Adverse events should be reported 
using concise medical terminology on the CRFs.  
8.3.5. 
Grading of Adverse Event Severity 
To report adverse events on the CRFs, the Investigator will use the severity grading as described 
in NCI CTCAE (Version 4.0).   
Every effort should be made by the Investigator to assess the adverse event according to CTCAE 
criteria. If the Investigator is unable to assess severity because the term is not described in NCI 
(Version 4.0), severity of MILD, MODERATE, SEVERE, LIFE-THREATENING, or FATAL 
may be used to describe the maximum intensity of the adverse event. For purposes of 
consistency, these intensity grades are defined as follows:  
Table 11: 
Adverse Event Grading 
Grade 
Non-CTCAE Severity 
Definition 
1 
Mild  
Does not interfere with patient’s usual function 
2 
Moderate 
Interferes to some extent with patient’s usual function 
3 
Severe 
Interferes significantly with patient’s usual function 
4 
Life-Threatening 
Results in immediate risk of patient’s death 

IND 100522 
 
105LC101 Protocol Amendment #3 
5.3.3.2 Clinical Protocol 
 
7July2015 
Page 71 of 93 
 
Grade 
Non-CTCAE Severity 
Definition 
5 
Fatal 
Results in patient’s death 
Note the distinction between the severity and the seriousness of an adverse event.  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 
one of the criteria for serious events.     
8.3.6. 
Relationship to TRC105 Study Drug, Bevacizumab, Paclitaxel and Carboplatin 
In this study, TRC105 study drug is given in combination with bevacizumab, paclitaxel and 
carboplatin.  The relationship of an adverse event to TRC105 study drug and/or bevacizumab 
and/or paclitaxel and/or carboplatin should be classified by the Investigator using the following 
guidelines: 
• Suspected Adverse Reaction: There is a reasonable possibility that TRC105 study drug 
and/or bevacizumab and/or paclitaxel and/or carboplatin caused the adverse event (i.e.: 
there is evidence to suggest a causal relationship between TRC105 and/or ramucirumab 
and/or paclitaxel and the adverse event). 
• Not Related: There is no reasonable possibility that the adverse event is associated with 
TRC105 study drug and/or bevacizumab and/or paclitaxel and/or carboplatin.  
AE’s related to TRC105 study drug or bevacizumab or paclitaxel or carboplatin are considered 
Adverse Drug Reactions (ADR). 
8.3.7. 
Expectedness  
All TRC105 adverse events and adverse drug reactions are considered “unexpected” if it’s not 
listed in the investigator brochure or not listed at the specificity or severity that has been 
observed.  For example, under this definition, hepatic necrosis would be unexpected (by virtue of 
greater severity) if the investigator brochure referred only to elevated hepatic enzymes or 
hepatitis.  Similarly, cerebral thromboembolism and cerebral vasculitis would be unexpected (by 
virtue of greater specificity) if the investigator brochure listed only cerebral vascular accidents.  
"Unexpected," as used in this definition, also refers to adverse events or suspected adverse 
reactions that are mentioned in the investigator brochure as occurring with a class of drugs or as 
anticipated from the pharmacological properties of the drug, but are not specifically mentioned 
as occurring with the particular drug under investigation. 
All bevacizumab or paclitaxel or carboplatin adverse events and adverse drug reactions are 
considered “unexpected” if it’s not listed in the package insert or not listed at the specificity or 
severity that has been observed. "Unexpected," as used in this definition, also refers to adverse 
events or suspected adverse reactions that are mentioned in the package insert as occurring with 
a class of drugs or as anticipated from the pharmacological properties of the drug, but are not 
specifically mentioned as occurring with bevacizumab or paclitaxel or carboplatin. 
8.3.8. 
Exposure in Utero 
If any trial patient (or partner of a trial patient) becomes or is found to be pregnant during the 
study or within 90 days of discontinuing the investigational medication/product, the Investigator 

IND 100522 
 
105LC101 Protocol Amendment #3 
5.3.3.2 Clinical Protocol 
 
7July2015 
Page 72 of 93 
 
must report the information to TRACON, or designee via the Pregnancy Notification Report 
Form.  This must be done irrespective of whether an adverse event has occurred and within 24 
hours of awareness of the pregnancy.  The information submitted should include the anticipated 
date of delivery.   
The Investigator will follow the patient (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. 
The Investigator should follow procedures for reporting an SAE if pregnancy outcome meets 
criteria for an SAE (i.e., spontaneous abortion, stillbirth, neonatal death, or congenital anomaly 
[including that in an aborted fetus]). 
In the case of a live birth, the “normality” of the newborn can be assessed at the time of birth and 
the Pregnancy Outcome Report Form should be completed (i.e., no minimum follow-up period 
of a presumably normal infant must pass before a Pregnancy Outcome Report Form can be 
completed).  The “normality” of an aborted fetus can be assessed by gross visual inspection 
unless pre-abortion laboratory findings are suggestive of a congenital anomaly. 
Additional information about pregnancy outcomes that are classified as SAEs follows:  
• “Spontaneous abortion” includes miscarriage and missed abortion. 
• All neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs.  In addition, any infant death after 1 month that the Investigator 
assesses as possibly related to the in utero exposure to the investigational medication 
should also be reported. 
8.3.9. 
Follow-up of Unresolved Adverse Events  
All adverse events should be followed until they are resolved or the Investigator assesses them as 
chronic or stable.  Any increase or decrease in adverse event grade should be recorded as a new 
adverse event.  
All serious and those non-serious events assessed by the Investigator as possibly related to the 
investigational medication/product should continue to be followed even after the patient’s 
participation in the trial is over.  Such events should be followed until they resolve or until the 
Investigator assesses them as “chronic” or “stable.”  The event should also be documented on the 
adverse event CRF.  
8.4. 
Safety Monitoring 
The TRACON Clinical Team will monitor safety throughout the study via the following 
activities:  
• Surveillance for SAEs according to regulatory guidelines 
• Routine monitoring of non-serious adverse experiences as they are recorded in the case 
report forms and the source documents at study sites 

IND 100522 
 
105LC101 Protocol Amendment #3 
5.3.3.2 Clinical Protocol 
 
7July2015 
Page 73 of 93 
 
• A formally chartered TRACON in-house Safety Review Team that includes, among other 
staff, two physicians 
• Periodic teleconferences with the Principal Investigators to share experiences and ensure 
communication 
• Toxicity information that may affect the treatment of patients on this study will be 
promptly communicated in writing to all participating clinical sites and institutions 
participating in this clinical trial.      

IND 100522 
 
105LC101 Protocol Amendment #3 
5.3.3.2 Clinical Protocol 
 
7July2015 
Page 74 of 93 
 
9. 
OTHER ASSESSMENTS 
9.1. 
Other Laboratory Assessments  
9.1.1. 
Pharmacokinetics  
Samples will be sent to Fisher BioServices for storage See separate laboratory manual for 
specific collection, storage and shipping information.  
9.1.1.1. 
TRC105 Trough Concentration  
A 5 mL blood sample will be collected prior to dosing with TRC105 on the days indicated within 
the Schedule of Assessments (Table 4).  Samples will be separated and stored at approximately -
70 °C for shipment to third party laboratory. See separate laboratory guide for further collection 
and shipment information. 
9.1.2. 
TRC105 Immunogenicity 
Samples will be sent to Fisher BioServices for storage. See separate laboratory manual for 
specific collection, storage and shipping information. 
Anti-product antibody concentrations will be measured using validated ELISA methods at the 
time points specified in the Schedule of Assessments (Table 4) in all patients.  Anti-product 
antibody concentrations will be evaluated in the context of pharmacokinetic parameters and AE 
profiles. Samples will be separated and stored at approximately -70 °C for shipment to Fisher 
BioServices.  See separate laboratory guide for further collection and shipment information.  
9.1.3. 
Protein Biomarkers 
One 10mL purple top (K2EDTA) tube of blood will be collected on the days indicated within the 
Schedule of Assessments (Table 4).  Samples will be stored at approximately -70 °C and shipped 
to Fisher BioServices Inc for storage until the time of analysis. Duke University Medical Center 
will analyze plasma for several biomarkers including but not limited to VEGF, VEGF-R2, PIGF 
and sCD105.  Please see the separate laboratory guide for further collection and shipment 
information.  
9.1.4. 
Archival Tumor Specimens 
Archival specimens (formalin-fixed, paraffin-embedded) of the primary cancer and/or metastatic 
cancer specimen for each study participant will be obtained.  It is preferable that the entire 
paraffin block be submitted, but if this is not feasible, then at least 20 unstained slides are 
requested for immunohistochemical analysis (sections of ~ 5 microns are preferred).  Samples 
will be stored at room temperature and shipped to Fisher BioServices Inc for storage until the 
time of analysis. See separate laboratory guide for further collection and shipment information. 

IND 100522 
 
105LC101 Protocol Amendment #3 
5.3.3.2 Clinical Protocol 
 
7July2015 
Page 75 of 93 
 
10. 
STATISTICS 
10.1. 
Statistical Design/Sample Size 
10.1.1. 
Statistical Design/Sample Size 
The number of patients to be enrolled in this study will depend upon the observed safety profile, 
which will determine the number of patients per dose level and the number of dose escalations.  
It is anticipated that up to 18 patients will be enrolled in the study. 
The probability of escalation to the next higher dose for each underlying true DLT rate is shown 
in Table 12.  For example, at a dose level with a true DLT rate of 5%, there is a greater than 95% 
probability of escalating.  Conversely, for a dose level with a true DLT rate of 70%, the 
probability of escalating is < 5%. 
Table 12: 
Probability of Escalation to the Next Dose for Each True Underlying DLT 
Rate at a Dose Level 
True Underlying DLT Rate 
5% 
10% 
20% 
30% 
40% 
50% 
60% 
70% 
80% 
90% 
Probability of Escalating Dose 
0.97 
0.91 
0.71 
0.49 
0.31 
0.17 
0.08 
0.03 
0.01 
0.001 
The probability of failing to observe DLT in a sample size of 3 or 6 patients given various true 
underlying DLT rates in shown in Table 13.  For example, with 6 patients, the probability of 
failing to observe DLT occurring at least 40% of the time is less than 5%. The enrollment of 15 
patients at a given dose level will reduce the probability of failing to observe toxicity occurring 
at least 30% of the time to < 5%. 
Table 13: 
Probability of Failing to Observe True Underlying DLT Rate at a Dose Level 
True Underlying DLT 
Rate 
5% 
10% 
20% 
30% 
40% 
50% 
60% 
70% 
80% 
90% 
Probability of Failing to 
Observe Toxicity if N = 
3 
0.86 
0.73 
0.51 
0.34 
0.22 
0.13 
.0064 
0.027 
0.008 
0.001 
Probability of Failing to 
Observe Toxicity if N = 
6 
0.74 
0.53 
0.26 
0.12 
0.047 
0.016 
0.0041 
<0.001 
<0.001 
<0.001 
10.1.1.1. 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 TRC105.   
• The study population for PK includes also subjects with adequate data for PK 
modeling of TRC105.   
• The study population for efficacy will include all safety population patients who have 
baseline and follow-up tumor measurements as required for assessment by RECIST 
1.1. 

IND 100522 
 
105LC101 Protocol Amendment #3 
5.3.3.2 Clinical Protocol 
 
7July2015 
Page 76 of 93 
 
Patients who experience DLT who receive less than the prescribed dose of TRC105 or 
bevacizumab, carboplatin or paclitaxel due to documented toxicity in cycle 1 will be considered 
evaluable for dose escalation purposes. 
Only those patients who are deemed "ineligible" or who receive no therapy (i.e., no TRC105 or 
bevacizumab, carboplatin or paclitaxel) will be eliminated from the analysis.  Ineligible patients 
who receive therapy will not be included in the assessment of efficacy endpoints, but their data 
will be included in the assessment of all adverse event reporting.  
10.2. 
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, efficacy, pharmacokinetic parameters, 
protein biomarkers, and archival tumor tissue.  Data will also be displayed graphically, where 
appropriate. 
10.2.1. 
Analysis of Primary Objective  
10.2.1.1. Analysis of Primary Objective 
For each cohort, DLTs will be summarized by category (hematologic and non-hematologic) and 
by MedDRA preferred term.  
All AEs with an onset after initiation of treatment will be considered as treatment-emergent AEs.  
A preexisting condition that worsens during the treatment period will also be considered as a 
treatment emergent AE.  All AEs will be coded by system organ class (SOC) and preferred term 
using NCI CTCAE (MedDRA) version 4.0.  
The number and percentage of patients with the following types of treatment-emergent AEs will 
be summarized: common and serious AEs, AEs related to study medication, AEs resulting in 
study discontinuation, and clinically significant laboratory abnormalities. Non-treatment-
emergent serious AEs will be described separately.  Deaths will be reported with demographic 
information. 
10.2.2. 
Analysis of Pharmacokinetics  
Trough serum TRC105 concentrations will be measured using validated ELISA methods.   The 
TRC105 pharmacokinetic data will be assessed for potential correlations with response, PFS, 
survival, adverse events, and baseline characteristics using descriptive statistics and models as 
appropriate. 
10.2.3. 
Objective Response 
The best response (CR, PR, SD or PD according to RECIST 1.1) for each patient with 
measurable disease who received at least one dose of TRC105 study drug will be listed by 
cohort.  Stable disease will be defined as lack of tumor progression lasting for 3 cycles or longer. 

IND 100522 
 
105LC101 Protocol Amendment #3 
5.3.3.2 Clinical Protocol 
 
7July2015 
Page 77 of 93 
 
10.2.4. 
Analysis of Protein Biomarkers 
Angiogenic protein biomarker data for each patient who received at least one dose of TRC105 
study drug will be listed. 
10.2.5. 
Analysis of Immunogenicity 
Anti-product antibody concentrations will be measured using validated ELISA methods at the 
time points specified in the Schedule of Assessments (Table 4).  Anti-product antibody 
concentrations will be evaluated in the context of pharmacokinetic parameters and AE profiles. 
10.2.6. 
Analysis of Archival Tumor Tissue 
CD105 expression within the tumor vasculature and on sarcoma tissue will be quantified for each 
patient who received at least one dose of TRC105 study drug and will be listed by cohort.  
Expression will be determined by immunohistochemistry (IHC).  Other markers that may relate 
to efficacy or toxicity of TRC105 may also be explored. 
 

IND 100522 
 
105LC101 Protocol Amendment #3 
5.3.3.2 Clinical Protocol 
 
7July2015 
Page 78 of 93 
 
11. 
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. 

IND 100522 
 
105LC101 Protocol Amendment #3 
5.3.3.2 Clinical Protocol 
 
7July2015 
Page 79 of 93 
 
12. 
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 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. 
 

IND 100522 
 
105LC101 Protocol Amendment #3 
5.3.3.2 Clinical Protocol 
 
7July2015 
Page 80 of 93 
 
13. 
ETHICS 
13.1. 
Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) 
It is the responsibility of the Investigator to have approval of the trial protocol, protocol 
amendments, informed consent forms, and advertisements from the IRB/IEC before potential 
patients are consented for participation on the trial. All correspondence and other evidence of 
appropriate and timely communications with the IRB/IEC should be retained in the 
Investigator/site files. Copies of all IRB/IEC approvals should also be forwarded to TRACON. 
The only circumstance in which an amendment may be initiated prior to IRB/IEC approval is 
where the change is necessary to eliminate apparent immediate hazards to the patients.  In that 
event, the Investigator must notify the IRB/IEC and TRACON in writing within 5 business days 
after the implementation. 
13.2. 
Ethical Conduct of the Study 
The trial will be performed in accordance with the protocol, applicable local regulatory 
requirements and laws, and the International Conference on Harmonization Guideline on Good 
Clinical Practice, which supports the application of ethical principles that have their origin in the 
Declaration of Helsinki (see ICH E6, § 2.1).  
13.3. 
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. 
13.4. 
Patient Compensation 
Patients will not be compensated for participation in this trial; this will be outlined in the patient 
informed consent form. 

IND 100522 
 
105LC101 Protocol Amendment #3 
5.3.3.2 Clinical Protocol 
 
7July2015 
Page 81 of 93 
 
14. 
DATA HANDLING AND RECORDKEEPING 
14.1. 
Inspection of Records 
CRF’s are required and should be completed for each patient who receives treatment with 
pazopanib or TRC105.  Screen failure CRF’s will not be collected.    Nevertheless, records of 
potential patients identified and screened shall be retained on site screening logs.  The completed 
original CRFs are the sole property of TRACON and should not be made available in any form 
to third parties without written permission from TRACON (except for authorized representatives 
of the HRA and in accordance with HIPAA regulations). 
It is the Investigator’s responsibility to ensure completion and to review and approve all CRF 
data.    The investigator will sign off on his/her data per patient.  These signatures serve to attest 
that the investigator has reviewed and approved the information contained on the case report 
forms and that the information is complete, accurate, and true.  At all times, the Investigator has 
final personal responsibility for the accuracy and authenticity of all clinical and laboratory data 
entered on the CRFs.    
The use of electronic CRFs (eCRFs) to capture study data using automated computerized data 
capture systems does not change the principles and requirements for collecting study data.  The 
investigator still retains final personal responsibility for eCRF data and any associated data 
pertaining to it (e.g. metadata including any record of change to the originally recorded data).  
The investigator’s signed approval of the eCRF data serves to attest that the electronic data and 
all of its associated metadata (including changes) has been reviewed and accepted as complete, 
accurate, and true for each patient in the study. 
14.2. 
Retention of Records 
To allow for appropriate evaluations and/or audits by regulatory authorities or TRACON, the 
Investigator agrees to keep records, including the identity of all participating patients (sufficient 
information to link records, CRFs and hospital records), all original signed informed consent 
forms, copies of all CRFs, source documents, and detailed records of treatment disposition.  The 
Investigator should retain these records according to local regulations or as specified in the 
Clinical Trial Agreement, whichever is longer.   
If the Investigator relocates, retires, or for any reason withdraws from the study, then TRACON 
should be prospectively notified.  The study records must be transferred to an acceptable 
designee, such as another Investigator, another institution.  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.  
 

IND 100522 
 
105LC101 Protocol Amendment #3 
5.3.3.2 Clinical Protocol 
 
7July2015 
Page 82 of 93 
 
15. 
DEFINITION OF END OF TRIAL 
15.1. 
End of Trial in all Participating Countries 
End of trial in all participating countries is defined as the time at which all patients enrolled in 
the study have completed treatment on study. 
15.2. 
End of Trial in a Member State 
End of trial in a Member State of the European Union is defined as the time at which it is 
deemed that sufficient patients have been recruited and completed the trial as stated in the 
regulatory application (e.g. the Clinical Trials Agreement (CTA)) and ethics application in the 
Member State.  Poor recruitment is not a reason for premature termination but is considered a 
normal conclusion to the trial in that Member State.  
15.3. 
TRACON Discontinuation Criteria 
Premature termination of this trial may occur because of a regulatory authority decision, change 
in opinion of the IRB/IEC, drug safety problems, or at the discretion of TRACON.  In addition, 
TRACON retains the right to discontinue development of TRC105 at any time.  
TRACON reserves the right to discontinue the trial prior to inclusion of the intended number of 
patients, but intends only to exercise this right for valid scientific or administrative reasons. If a 
trial is prematurely terminated or discontinued, TRACON will promptly notify the Investigator.  
After notification, the Investigator must contact all participating patients within a 28 day time 
period.  As directed by TRACON, all trial materials must be collected and all CRF data must be 
completed to the greatest extent possible.  

IND 100522 
 
105LC101 Protocol Amendment #3 
5.3.3.2 Clinical Protocol 
 
7July2015 
Page 83 of 93 
 
16. 
PUBLICATION OF TRIAL RESULTS 
Publication of trial results is discussed in the Clinical Trial Agreement.  

IND 100522 
 
105LC101 Protocol Amendment #3 
5.3.3.2 Clinical Protocol 
 
7July2015 
Page 84 of 93 
 
17. 
FINANCING AND INSURANCE 
Financing and Insurance are discussed in the Clinical Trial Agreement.  

IND 100522 
 
105LC101 Protocol Amendment #3 
5.3.3.2 Clinical Protocol 
 
7July2015 
Page 85 of 93 
 
18. 
INVESTIGATOR PROTOCOL AGREEMENT: 105LC101 
I understand that all information concerning this study supplied to me by TRACON 
Pharmaceuticals, Inc. is confidential information.  I have read this protocol and agree to conduct 
the study according to all applicable regulations, Good Clinical Practice Guidelines, and in 
accordance with the Clinical Trial Agreement. 
I understand that this protocol and all amendments must be submitted to the appropriate 
IRB/IEC. 
 
 
Investigator Name (PLEASE PRINT):  ______________________________________________ 
 
 
 
Signature: _________________________________________________Date: _______________ 
 
 
Please sign and return this agreement to: 
TRACON Pharmaceuticals, Inc.  
Attn: Clinical Operations  
8910 University Center Lane, Suite 700 
San Diego, CA  92122 
 
Please keep a copy for your records. 
 

IND 100522 
 
105LC101 Protocol Amendment #3 
5.3.3.2 Clinical Protocol 
 
7July2015 
Page 86 of 93 
 
19. 
REFERENCES 
 
1. 
Folkman J. Tumor angiogenesis: therapeutic implications. New Eng J Med 
1971;285(21):1182-1186. 
2. 
Potente M, Gerhardt H, Carmeliet P. Basic and therapeutic aspects of angiogenesis. Cell 
2011;146(6):873-887. 
3. 
Carmeliet P, Jain RK. Angiogenesis in cancer and other diseases. Nature 
2000;407(6801):249-257. 
4. 
Folkman J, Merler E, Abernathy C, et al. Isolation of a tumor factor responsible for 
angiogenesis. J Exp Med 1971;133(2):275-288. 
5. 
Hu DE, Fan TP. Suppression of VEGF-induced angiogenesis by the protein tyrosine 
kinase inhibitor, lavendustin A. British J Pharm 1995; 114(2):262-268. 
6. 
Rosen LS. Clinical experience with angiogenesis signaling inhibitors: focus on vascular 
endothelial growth factor (VEGF) blockers. Cancer control: journal of the Moffitt Cancer 
Center 2002;9(2 Suppl):36-44. 
7. 
Jain RK. Normalizing tumor vasculature with anti-angiogenic therapy: a new paradigm 
for combination therapy. Nat Med 2001;7(9):987-989. 
8. 
Willett CG, Boucher Y, di Tomaso E, et al. Direct evidence that the VEGF-specific 
antibody bevacizumab has antivascular effects in human rectal cancer. Nat Med 
2004;10(2):145-147. 
9. 
Hurwitz, H., et al., Bevacizumab plus irinotecan, fluorouracil, and leucovorin for 
metastatic colorectal cancer. N Engl J Med, 2004. 350(23): p. 2335-42. 
10. 
Sandler, A., et al., Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell 
lung cancer. N Engl J Med, 2006. 355(24): p. 2542-50. 
11. 
Miller, K.D., et al., Randomized phase III trial of capecitabine compared with 
bevacizumab plus capecitabine in patients with previously treated metastatic breast 
cancer. J Clin Oncol, 2005. 23(4): p. 792-9. 
12. 
Friedman, H.S., et al., Bevacizumab alone and in combination with irinotecan in 
recurrent glioblastoma. J Clin Oncol, 2009. 27(28): p. 4733-40. 
13. 
Escudier, B., et al., Phase III trial of bevacizumab plus interferon alfa-2a in patients with 
metastatic renal cell carcinoma (AVOREN): final analysis of overall survival. J Clin 
Oncol, 2010. 28(13): p. 2144-50. 
14. 
Escudier, B., et al., Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med, 
2007. 356(2): p. 125-34. 
15. 
Llovet, J.M., et al., Sorafenib in advanced hepatocellular carcinoma. N Engl J Med, 2008. 
359(4): p. 378-90. 
16. 
Motzer, R.J., et al., Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N 
Engl J Med, 2007. 356(2): p. 115-24. 

IND 100522 
 
105LC101 Protocol Amendment #3 
5.3.3.2 Clinical Protocol 
 
7July2015 
Page 87 of 93 
 
17. 
Rini, B.I., Vascular endothelial growth factor-targeted therapy in metastatic renal cell 
carcinoma. Cancer, 2009. 115(10 Suppl): p. 2306-12. 
 
18. 
Schiller JH, Harrington D, Belani CP, et al. Comparison of four chemotherapy regimens 
for advanced non-small-cell lung cancer. The New England journal of medicine 
2002;346(2):92-98. 
19. 
Breathnach OS, Freidlin B, Conley B, et al. Twenty-two years of phase III trials for 
patients with advanced non-small-cell lung cancer: sobering results. Journal of clinical 
oncology : official journal of the American Society of Clinical Oncology 
2001;19(6):1734-1742. 
20. 
Johnson DH, Fehrenbacher L, Novotny WF, et al. Randomized phase II trial comparing 
bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in 
previously untreated locally advanced or metastatic non-small-cell lung cancer. Journal 
of clinical oncology : official journal of the American Society of Clinical Oncology 
2004;22(11):2184-2191. 
21. 
Ciuleanu T, Brodowicz T, Zielinski C, et al. Maintenance pemetrexed plus best 
supportive care versus placebo plus best supportive care for non-small-cell lung cancer: a 
randomised, double-blind, phase 3 study. Lancet 2009;374(9699):1432-1440. 
22. 
Barlesi F, Scherpereel A, Rittmeyer A, et al. Randomized phase III trial of maintenance 
bevacizumab with or without pemetrexed after first-line induction with bevacizumab, 
cisplatin, and pemetrexed in advanced nonsquamous non-small-cell lung cancer: 
AVAPERL (MO22089). Journal of clinical oncology : official journal of the American 
Society of Clinical Oncology 2013;31(24):3004-3011. 
23. 
Patel JD, Socinski MA, Garon EB, et al. PointBreak: a randomized phase III study of 
pemetrexed plus carboplatin and bevacizumab followed by maintenance pemetrexed and 
bevacizumab versus paclitaxel plus carboplatin and bevacizumab followed by 
maintenance bevacizumab in patients with stage IIIB or IV nonsquamous non-small-cell 
lung cancer. Journal of clinical oncology : official journal of the American Society of 
Clinical Oncology 2013;31(34):4349-4357. 
24. 
Mattern J, Koomagi R, Volm M. Association of vascular endothelial growth factor 
expression with intratumoral microvessel density and tumour cell proliferation in human 
epidermoid lung carcinoma. British journal of cancer 1996;73(7):931-934. 
25. 
Eskander RN, Randall LM. Bevacizumab in the treatment of ovarian cancer. Biologics : 
targets & therapy 2011;5:1-5. 
26. 
Beal K, Abrey LE, Gutin PH. Antiangiogenic agents in the treatment of recurrent or 
newly diagnosed glioblastoma: analysis of single-agent and combined modality 
approaches. Radiation oncology 2011;6:2. 
27. 
Bergers G, Hanahan D. Modes of resistance to anti-angiogenic therapy. Nature reviews 
Cancer 2008;8(8):592-603. 
28. 
Bottsford-Miller JN, Coleman RL, Sood AK. Resistance and escape from 
antiangiogenesis therapy: clinical implications and future strategies. Journal of clinical 

IND 100522 
 
105LC101 Protocol Amendment #3 
5.3.3.2 Clinical Protocol 
 
7July2015 
Page 88 of 93 
 
oncology : official journal of the American Society of Clinical Oncology 
2012;30(32):4026-4034. 
29. 
Meulmeester E, Ten Dijke P. The dynamic roles of TGF-beta in cancer. The Journal of 
pathology 2011;223(2):205-218. 
30. 
Burrows FJ, Derbyshire EJ, Tazzari PL, et al. Up-regulation of endoglin on vascular 
endothelial cells in human solid tumors: implications for diagnosis and therapy. Clinical 
cancer research : an official journal of the American Association for Cancer Research 
1995;1(12):1623-1634. 
31. 
Miller DW, Graulich W, Karges B, et al. Elevated expression of endoglin, a component 
of the TGF-beta-receptor complex, correlates with proliferation of tumor endothelial 
cells. International journal of cancer Journal international du cancer 1999;81(4):568-572. 
32. 
Paauwe M, ten Dijke P, Hawinkels LJ. Endoglin for tumor imaging and targeted cancer 
therapy. Expert opinion on therapeutic targets 2013;17(4):421-435. 
33. 
Haruta, Y. and B.K. Seon, Distinct human leukemia-associated cell surface glycoprotein 
GP160 defined by monoclonal antibody SN6. Proc Natl Acad Sci U S A, 1986. 83(20): p. 
7898-902. 
34. 
Gougos, A. and M. Letarte, Identification of a human endothelial cell antigen with 
monoclonal antibody 44G4 produced against a pre-B leukemic cell line. J Immunol, 
1988. 141(6): p. 1925-33. 
35. 
Seon, B.K., et al., Long-lasting complete inhibition of human solid tumors in SCID mice 
by targeting endothelial cells of tumor vasculature with antihuman endoglin 
immunotoxin. Clin Cancer Res, 1997. 3(7): p. 1031-44. 
36. 
Cheifetz, S., et al., Endoglin is a component of the transforming growth factor-beta 
receptor system in human endothelial cells. J Biol Chem, 1992. 267(27): p. 19027-30. 
37. 
Li, D.Y., et al., Defective angiogenesis in mice lacking endoglin. Science, 1999. 
284(5419): p. 1534-7. 
38. 
Burrows, F.J., et al., Up-regulation of endoglin on vascular endothelial cells in human 
solid tumors: implications for diagnosis and therapy. Clin Cancer Res, 1995. 1(12): p. 
1623-34. 
39. 
Seon, B.K., Expression of endoglin (CD105) in tumor blood vessels. Int J Cancer, 2002. 
99(2): p. 310-1; author reply 312. 
40. 
Horsman, M.R. and D.W. Siemann, Pathophysiologic effects of vascular-targeting agents 
and the implications for combination with conventional therapies. Cancer Res, 2006. 
66(24): p. 11520-39. 
41. 
Matsuno, F., et al., Induction of lasting complete regression of preformed distinct solid 
tumors by targeting the tumor vasculature using two new anti-endoglin monoclonal 
antibodies. Clin Cancer Res, 1999. 5(2): p. 371-82. 
42. 
Takahashi, N., et al., Antiangiogenic therapy of established tumors in human skin/severe 
combined immunodeficiency mouse chimeras by anti-endoglin (CD105) monoclonal 

IND 100522 
 
105LC101 Protocol Amendment #3 
5.3.3.2 Clinical Protocol 
 
7July2015 
Page 89 of 93 
 
antibodies, and synergy between anti-endoglin antibody and cyclophosphamide. Cancer 
Res, 2001. 61(21): p. 7846-54. 
43. 
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. 
44. 
Uneda, S., H. Toi, and B.K. Seon, Anti-endoglin monoclonal antibodies are effective for 
suppressing metastasis and the primary tumors by targeting tumor vasculature. Int J 
Cancer, 2009. 125: p. 1446. 
45. 
Barbara, N.P., J.L. Wrana, and M. Letarte, Endoglin is an accessory protein that interacts 
with the signaling receptor complex of multiple members of the transforming growth 
factor-beta superfamily. J Biol Chem, 1999. 274(2): p. 584-94. 
46. 
She, X., et al., Synergy between anti-endoglin (CD105) monoclonal antibodies and TGF-
beta in suppression of growth of human endothelial cells. Int J Cancer, 2004. 108(2): p. 
251-7. 
47. 
Olivier Nolan-Stevaux, W.Z., Stacey Culp, Kathy Shaffer, Joseph Hoover, Dineli 
Wickramasinghe, Astrid Ruefli-Brasse, Endoglin Requirement for BMP9 Signaling in 
Endothelial Cells Reveals New Mechanism of Action for Selective Anti-Endoglin 
Antibodies. PLOS ONE, 2012. 7(12): p. e50920. 
48. 
Guo, B., et al., CD105 inhibits transforming growth factor-beta-Smad3 signalling. 
Anticancer Res, 2004. 24(3a): p. 1337-45. 
49. 
Warrington, K., et al., Functional role of CD105 in TGF-beta1 signalling in murine and 
human endothelial cells. Anticancer Res, 2005. 25(3B): p. 1851-64. 
50. 
Sanchez-Elsner, T., et al., Endoglin expression is regulated by transcriptional cooperation 
between the hypoxia and transforming growth factor-beta pathways. J Biol Chem, 2002. 
277(46): p. 43799-808. 
51. 
van Laake, L.W., et al., Endoglin has a crucial role in blood cell-mediated vascular 
repair. Circulation, 2006. 114(21): p. 2288-97. 
52. 
Lenato, G.M. and G. Guanti, Hereditary Haemorrhagic Telangiectasia (HHT): genetic 
and molecular aspects. Curr Pharm Des, 2006. 12(10): p. 1173-93. 
53. 
Sabba, C., et al., Life expectancy in patients with hereditary haemorrhagic telangiectasia. 
Qjm, 2006. 99(5): p. 327-34. 
54. 
Rokhlin, O.W., et al., Differential expression of endoglin on fetal and adult hematopoietic 
cells in human bone marrow. J Immunol, 1995. 154(9): p. 4456-65. 
55. 
Kumar, S., et al., Breast carcinoma: vascular density determined using CD105 antibody 
correlates with tumor prognosis. Cancer Res, 1999. 59(4): p. 856-61. 
56. 
Vo, M.N., et al., Elevated plasma endoglin (CD105) predicts decreased response and 
survival in a metastatic breast cancer trial of hormone therapy. Breast Cancer Res Treat, 
2008. 
57. 
Tanaka, F., et al., Evaluation of angiogenesis in non-small cell lung cancer: comparison 
between anti-CD34 antibody and anti-CD105 antibody. Clin Cancer Res, 2001. 7(11): p. 
3410-5. 

IND 100522 
 
105LC101 Protocol Amendment #3 
5.3.3.2 Clinical Protocol 
 
7July2015 
Page 90 of 93 
 
58. 
El-Gohary, Y.M., et al., Endoglin (CD105) and vascular endothelial growth factor as 
prognostic markers in prostatic adenocarcinoma. Am J Clin Pathol, 2007. 127(4): p. 572-
9. 
59. 
Svatek, R.S., et al., Preoperative plasma endoglin levels predict biochemical progression 
after radical prostatectomy. Clin Cancer Res, 2008. 14(11): p. 3362-6. 
60. 
Li, C., et al., Both high intratumoral microvessel density determined using CD105 
antibody and elevated plasma levels of CD105 in colorectal cancer patients correlate with 
poor prognosis. Br J Cancer, 2003. 88(9): p. 1424-31. 
61. 
Romani, A.A., et al., The risk of developing metastatic disease in colorectal cancer is 
related to CD105-positive vessel count. J Surg Oncol, 2006. 93(6): p. 446-55. 
62. 
Rubatt, J.M., et al., Independent prognostic relevance of microvessel density in advanced 
epithelial ovarian cancer and associations between CD31, CD105, p53 status, and 
angiogenic marker expression: A Gynecologic Oncology Group study. Gynecol Oncol, 
2009. 112(3): p. 469-74. 
63. 
Taskiran, C., et al., The prognostic value of endoglin (CD105) expression in ovarian 
carcinoma. Int J Gynecol Cancer, 2006. 16(5): p. 1789-93. 
64. 
Ding, S., et al., Comparative evaluation of microvessel density determined by CD34 or 
CD105 in benign and malignant gastric lesions. Hum Pathol, 2006. 37(7): p. 861-6. 
65. 
Erdem, O., et al., CD105 expression is an independent predictor of survival in patients 
with endometrial cancer. Gynecol Oncol, 2006. 103(3): p. 1007-11. 
66. 
Yao, Y., et al., Prognostic significance of microvessel density determined by an anti-
CD105/endoglin monoclonal antibody in astrocytic tumors: comparison with an anti-
CD31 monoclonal antibody. Neuropathology, 2005. 25(3): p. 201-6. 
67. 
Yang, L.Y., et al., Correlation between CD105 expression and postoperative recurrence 
and metastasis of hepatocellular carcinoma. BMC Cancer, 2006. 6: p. 110. 
68. 
Saad, R.S., et al., Endoglin (CD105) and vascular endothelial growth factor as prognostic 
markers in esophageal adenocarcinoma. Hum Pathol, 2005. 36(9): p. 955-61. 
69. 
Kyzas, P.A., N.J. Agnantis, and D. Stefanou, Endoglin (CD105) as a prognostic factor in 
head and neck squamous cell carcinoma. Virchows Arch, 2006. 448(6): p. 768-75. 
70. 
Marioni, G., et al., Endoglin expression is associated with poor oncologic outcome in oral 
and oropharyngeal carcinoma. Acta Otolaryngol, 2006. 126(6): p. 633-9. 
71. 
Bockhorn, M., et al., Differential vascular and transcriptional responses to anti-vascular 
endothelial growth factor antibody in orthotopic human pancreatic cancer xenografts. 
Clin Cancer Res, 2003. 9(11): p. 4221-6. 
72. 
Davis, D.W., et al., Regional effects of an antivascular endothelial growth factor receptor 
monoclonal antibody on receptor phosphorylation and apoptosis in human 253J B-V 
bladder cancer xenografts. Cancer Res, 2004. 64(13): p. 4601-10. 
73.  
Liu Y, Tian H, Blobe GC, Theuer CP, Hurwitz HI, Nixon AB.  Effects of the 
combination of TRC105 and bevacizumab on endothelial cell biology.Invest New Drugs. 
2014 Oct;32(5):851-9.  

IND 100522 
 
105LC101 Protocol Amendment #3 
5.3.3.2 Clinical Protocol 
 
7July2015 
Page 91 of 93 
 
74. 
Duffy A, Ma C, Ulahannan S, Rahma O, Fioravanti S, Venkatesan AM, Turkbey B, 
Choyke P, Trepel J, Figg WD, Greten TF. TRC105 for the treatment of Hepatocellular 
Carcinoma: Preclinical data and preliminary results from two clinical trials evaluating 
monotherapy and combination with sorafenib. Presentation at the ASCO Gastrointestinal 
Cancer 2014 Symposia, San Francisco, CA 
75. 
Shiozaki, K., et al., Antiangiogenic chimeric anti-endoglin (CD105) antibody: 
pharmacokinetics and immunogenicity in nonhuman primates and effects of doxorubicin. 
Cancer Immunol Immunother, 2006. 55(2): p. 140-50 
76.  
Rosen LS, Hurwitz HI, Wong MK, Goldman J, Mendelson DS, Figg WD, Spencer S, 
Adams BJ, Alvarez D, Seon BK, Theuer CP, Leigh BR, Gordon MS. A phase I first-in-
human study of TRC105 (Anti-Endoglin Antibody) in patients with advanced cancer. 
Clin Cancer Res. 2012 Sep 1;18(17):4820-9 
77. 
Gordon MS, Robert F, Matei D, et al. An Open Label Phase 1b Dose Escalation Study of 
TRC105 (Anti-Endoglin Antibody) with Bevacizumab in Patients with Advanced Cancer. 
Clin Cancer Res 2014, in press 
78. 
Seon BK, Matsuno F, Haruta Y, et al. Long-lasting complete inhibition of human solid 
tumors in SCID mice by targeting endothelial cells of tumor vasculature with antihuman 
endoglin immunotoxin. Clinical cancer research : an official journal of the American 
Association for Cancer Research 1997;3(7):1031-1044. 
79. 
Tsujie M, Tsujie T, Toi H, et al. Anti-tumor activity of an anti-endoglin monoclonal 
antibody is enhanced in immunocompetent mice. International journal of cancer Journal 
international du cancer 2008;122(10):2266-2273. 
80. 
Uneda S, Toi H, Tsujie T, et al. Anti-endoglin monoclonal antibodies are effective for 
suppressing metastasis and the primary tumors by targeting tumor vasculature. 
International journal of cancer Journal international du cancer 2009;125(6):1446-1453. 
81.  
Levin EG, Forero A, O'Connor T, Seon BK, Jivani MA, Adams BJ, Theuer CP. A phase 
Ib dose-escalation study of TRC105 (anti-endoglin antibody) in combination with 
capecitabine for advanced solid tumors (including patients with progressive or recurrent 
HER2-negative metastatic breast cancer), Presentation at the ASCO 2013 General 
meeting, Chicago, IL 
82.  
Paclitaxel Package Insert 
83. 
Carboplatin Package Insert 
84. 
Bevacizumab Package Insert 
85. 
Eisenhauer, E.A., et al., New response evaluation criteria in solid tumours: revised 
RECIST guideline (version 1.1). Eur J Cancer, 2009. 45(2): p. 228-47. 
 
 
 

IND 100522 
 
105LC101 Protocol Amendment #3 
5.3.3.2 Clinical Protocol 
 
7July2015 
Page 92 of 93 
 
20. 
APPENDICES 
20.1. 
Appendix 1:  National Cancer Institute (NCI) Common Terminology 
Criteria for Adverse Events (CTCAE) 
The NCI CTCAE (Version 4.0) should be used to assess Adverse Events and may be reviewed 
on-line at the following NCI website: 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf 
 
 

IND 100522 
 
105LC101 Protocol Amendment #3 
5.3.3.2 Clinical Protocol 
 
7July2015 
Page 93 of 93 
 
20.2. 
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.