Conditions: Gestational Trophoblastic Neoplasia Choriocarcinoma Placental Site Trophoblastic Tumor Epithelioid Trophoblastic Tumor
Keywords: TRC105 CD105 Endoglin Angiogenesis inhibitor GTN Bevacizumab Avastin
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 3
Healthy volunteers: no

Brief summary:
The purpose of the study is to determine the overall response rate of single agent TRC105 and the combination of TRC105 and bevacizumab in patients with refractory GTN (including choriocarcinoma, placental site trophoblastic tumor (PSTT), and epithelioid trophoblastic tumor (ETT)). Up to 30 patients will be treated.

Detailed description:
TRC105 is a monoclonal antibody that binds to endoglin, an angiogenic target highly expressed on the tumor vessels and tumor cells in gestational trophoblastic neoplasia (GTN). Bevacizumab is a monoclonal antibody to vascular endothelial growth factor (VEGF) that inhibits angiogenesis and extends survival in patients with a wide variety of solid tumor types. TRC105 has been well tolerated as a single agent and when combined with bevacizumab. These antibodies may be efficacious in refractory GTN, a tumor type that is highly vascular and has been shown to densely express endoglin.

Arms:
arm 1: All subjects will begin by receiving single agent TRC105 weekly. In the case of a complete response to single agent TRC105, subjects will continue to receive single agent TRC105 for at least 3 months following complete response. In the case of a partial response (without a complete response) to single agent TRC105, bevacizumab every two weeks will be added. In the absence of a partial or complete response to single agent TRC105, subjects will receive single agent bevacizumab every two weeks. In the absence of a complete response to single agent bevacizumab, or for subjects who have documented disease progression on a prior bevacizumab containing regimen, subjects will receive TRC105 weekly and bevacizumab every two weeks.

Interventions: intervention 1: TRC105 intervention 2: Bevacizumab
Intervention descriptions: intervention 1: Subjects will begin by receiving TRC105 weekly. Subjects who achieve a complete response on single agent TRC105 may transition to every two week dosing. intervention 2: Bevacizumab will be dosed every two weeks.

Protocol document:
Prot_001.pdf: 


5.3.5.2 Clinical Protocol 
 
105GTN201 Amendment #3 
EudraCT 2015-005475-25 
 
20SEP2016 
Page 2 of 102 
 
PROCEDURES IN CASE OF EMERGENCY 
Table 1: 
Emergency Contact Information 
Role in Study 
Name 
Address and Telephone number 
Primary Medical Monitor 
Richard Yocum, MD 
8910 University Center Lane, Suite 700 
San Diego, CA 92122 
Office: 1.858.550.0780 x230 
Mobile Phone: 1.858.229.8585 
Email: ryocum@traconpharma.com 
Secondary Medical Monitor 
Charles Theuer, MD, PhD 
8910 University Center Lane, Suite 700 
San Diego, CA 92122 
Office: 1.858.550.0780 x233 
Mobile Phone: 1.858.344.9400 
Email: ctheuer@traconpharma.com 
 


5.3.5.2 Clinical Protocol 
 
105GTN201 Amendment #3 
EudraCT 2015-005475-25 
 
20SEP2016 
Page 3 of 102 
 
1. 
SYNOPSIS 
Name of Sponsor/Company: TRACON Pharmaceuticals, Inc.  
Name of Investigational Product: TRC105 
Name of Active Ingredient: TRC105 
Title of Study:  
A PHASE 2A STUDY OF TRC105 (WITH OPTION TO ADD BEVACIZUMAB) IN 
PATIENTS WITH  REFRACTORY GESTATIONAL TROPHOBLASTIC NEOPLASIA 
(GTN) 
Study center(s): This study will be performed at multiple centers globally. 
Investigator: To be determined 
Studied period:  
Estimated date first patient enrolled: October 2016 
Estimated date last patient enrolled: July 2018 
Estimated date last patient completed: December 2018 
Phase of development: 2A 
 
Rationale:  
TRC105 is a monoclonal antibody that binds to endoglin, an angiogenic target highly expressed on 
the tumor vessels and tumor cells in gestational trophoblastic neoplasia (GTN).   Bevacizumab is a 
monoclonal antibody to vascular endothelial growth factor (VEGF) that inhibits angiogenesis and 
extends survival in patients with a wide variety of solid tumor types.  TRC105 has been well tolerated 
as a single agent and when combined with bevacizumab.  These antibodies may be efficacious in 
refractory GTN, a tumor type that is highly vascular and has been shown to densely express endoglin.  
A single patient IND study of TRC105 and bevacizumab demonstrated a complete response to 
treatment as evidenced by normalization of hCG, a reliable marker highly correlated with disease 
burden, in a heavily treated and chemotherapy refractory patient with metastatic choriocarcinoma, an 
aggressive form of GTN.  Given the limited experience treating patients with TRC105 and 
bevacizumab, this trial will limit toxicity and maximize the opportunity of each individual patient to 
respond to treatment with either TRC105 or bevacizumab, and if necessary, both agents, by 
employing a sequential treatment design per Figure 1 - Figure 4. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


5.3.5.2 Clinical Protocol 
 
105GTN201 Amendment #3 
EudraCT 2015-005475-25 
 
20SEP2016 
Page 4 of 102 
 
Figure 1: Sequential Treatment Design 
 
 
Figure 2: 
Treatment Algorithm After Single-Agent TRC105 
 
 
 


5.3.5.2 Clinical Protocol 
 
105GTN201 Amendment #3 
EudraCT 2015-005475-25 
 
20SEP2016 
Page 5 of 102 
 
Figure 3: 
Treatment Algorithm After Single-Agent Bevacizumab 
 
 
Figure 4: 
Treatment Algorithm After Combination Therapy 
(TRC105+Bevacizumab) 
 
 


5.3.5.2 Clinical Protocol 
 
105GTN201 Amendment #3 
EudraCT 2015-005475-25 
 
20SEP2016 
Page 6 of 102 
 
Objectives  
Primary: 
 
To determine the objective response rate (ORR) of single agent TRC105 and of the 
combination of TRC105 and bevacizumab (in bevacizumab refractory patients) in patients 
with refractory GTN (including choriocarcinoma, placental site trophoblastic tumor [PSTT], 
and epithelioid trophoblastic tumor [ETT])   
Secondary:   
 
To determine PFS 
 
To determine ORR of single agent bevacizumab in patients with refractory GTN (including 
choriocarcinoma, PSTT, and ETT) 
 
To evaluate the formation of TRC105 anti-product antibodies 
 
To evaluate PK of TRC105 and bevacizumab 
 
To determine the frequency and severity of adverse events as assessed by NCI CTCAE 
(Version 4.03) 
Exploratory:   
 
To correlate efficacy endpoints with endoglin expression on tumor samples 
 
To explore the effects of TRC105 and bevacizumab on circulating angiogenic protein 
biomarkers 
 
To explore the effects of CD16 genotype on response to TRC105 therapy 


5.3.5.2 Clinical Protocol 
 
105GTN201 Amendment #3 
EudraCT 2015-005475-25 
 
20SEP2016 
Page 7 of 102 
 
Methodology:  
This is a multicenter, open-label, nonrandomized, single-arm phase 2 study to assess the response rate 
to treatment with single agent TRC105 and the combination of TRC105 and bevacizumab (in 
bevacizumab refractory patients) in patients with GTN that has progressed following treatment with 
at least one chemotherapy regimen that included two or more chemotherapy agents.   
As per Figure 1 - Figure 4, all patients will initially receive TRC105 as a single agent.  Patients will 
receive TRC105 for two 28-day cycles at which time formal measurement for response will be made.  
The following scenarios are possible: 
1. Single agent TRC105 
a. Complete response after 2 cycles:  The patient will receive at least 3 cycles of 
consolidation therapy with single agent TRC105. 
b. Partial response after 2 cycles:  The patient will continue single agent TRC105 for an 
additional 2 cycles and re-evaluate the response, unless the patient has clear 
progression any time after completing 2 cycles of treatment then add bevacizumab.  
If there is continued improvement in response after 4 cycles of treatment, continue 
single agent TRC105. If there is no improvement in response, add bevacizumab for 
combination therapy.  If there is a complete response any time after completing 2 
cycles of treatment, the patient will receive at least 3 cycles of consolidation therapy. 
c. Progression after 2 cycles or clear progression before 2 cycles:  Transition to single 
agent bevacizumab after a 2 week washout period.  Patients who have documented 
disease progression on a prior bevacizumab containing regimen will transition 
directly to TRC105 plus bevacizumab combination therapy. 
2. Single agent bevacizumab 
a. Complete response after 2 cycles:  The patient will receive at least 3 cycles of 
consolidation therapy with single agent bevacizumab. 
b. Partial response after 2 cycles:  The patient will continue single agent bevacizumab 
for an additional 2 cycles are re-evaluate the response unless the patient has clear 
progression any time after completing 2 cycles of treatment then add TRC105.  If 
there is continued improvement in response after 4 cycles of treatment, continue 
single agent bevacizumab. If there is no improvement in response, add TRC105 for 
combination therapy.  If there is a complete response any time after completing 2 
cycles of treatment, the patient will receive at least 3 cycles of consolidation therapy. 
c. Progression after 2 cycles or clear progression before 2 cycles:  Add TRC105 and 
treat with combination therapy. 
3. Combination therapy with TRC105 + bevacizumab 
a. Complete response after 2 cycles:  The patient will receive at least 3 cycles of 
consolidation therapy with the combination. 
b. Partial response after 2 cycles:  The patient will continue combination therapy for 
another 2 cycles to confirm partial response.  Combination therapy will be continued 
until remission or progression. 
c. Progression after 2 cycles or clear progression before 2 cycles:  The patient will come 
off study. 
Improvement in response is defined as a continued decline in hCG and/or a continued decrease in 
tumor volume by RECIST 1.1 for patients with measurable disease. For patients with 
choriocarcinoma, efficacy will be assessed using weekly hCG central lab results, starting two weeks 
after initiation of treatment:   


5.3.5.2 Clinical Protocol 
 
105GTN201 Amendment #3 
EudraCT 2015-005475-25 
 
20SEP2016 
Page 8 of 102 
 
 
Disease progression is defined as >20% increase (the absolute increase must be ≥10 IU/L) 
above nadir on consecutive measurements separated by at least two weeks;  
 
Partial response is defined as a hCG decrease of 50% or more from starting value on 
consecutive measurements separated by at least two weeks;  
 
Complete response is defined as normalization of hCG on consecutive measurements 
separated by at least two weeks;  
 
Stable disease is defined as the absence of response or progression on 3 consecutive 
measurements separated by at least two weeks.  
Assessment of patients with PSTT and ETT will use standard RECIST 1.1 radiographic criteria 
integrated with weekly hCG assessment.  Refer to Section 7.3.2.   
Number of patients:  
Up to 30 evaluable patients with refractory GTN 
Diagnosis and main criteria for inclusion:  
Note: If study therapy is resumed > 56 days after last dose of study drug for patients with a CR who 
come off study treatment following consolidation therapy, the investigator must confirm that the 
patient continues to be eligible to receive study therapy.  
Inclusion Criteria: 
1. Willingness and ability to consent for self to participate in study   
2. Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests, and 
other study procedures  
3. Elevated serum hCG (in cases of choriocarcinoma); elevated hCG or measurable disease (in 
cases of PSTT or ETT) 
4. Histologically proven trophoblastic neoplasia, or clinically demonstrated trophoblastic 
neoplasia that has progressed following treatment with at least one chemotherapy regimen 
that included two or more chemotherapy agents.  
5. Female age of 16 years or older 
6. ECOG performance status ≤ 1 
7. Resolution of all acute adverse events resulting from prior cancer therapies to NCI CTCAE 
grade ≤ 1 or baseline (except alopecia or neuropathy) 
8. 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 14 days 
(erythropoietin or darbepoetin permitted) 


5.3.5.2 Clinical Protocol 
 
105GTN201 Amendment #3 
EudraCT 2015-005475-25 
 
20SEP2016 
Page 9 of 102 
 
 
Serum creatinine ≤ 1.5 times the upper limit of normal or creatinine clearance > 30 
mL/min by Cockcroft-Gault formula 
 
INR from 0.8 to 1.2 
9. Woman of non-child bearing potential due to surgical sterilization (at least 6 weeks following 
surgical bilateral oophorectomy with or without hysterectomy or tubal ligation) confirmed by 
medical history or menopause (i.e., no menstrual bleeding for more than 12 months in a 
woman aged 45 years or more), OR woman of child bearing potential who agrees to use at 
least two acceptable methods of birth control, one of which must be highly effective during 
the study and for at least 180 days after stopping TRC105 or bevacizumab (refer to 
Section 2.3.1). Women that enter the study with hCG > 100 IU/L and had maintained that 
level continuously after exclusion of pregnancy by a previous pelvic ultrasound are excluded 
from the birth control requirement unless their hCG decreases to ≤ 100 IU/L. 
10. Women of child bearing potential only: ultrasound of pelvis to exclude pregnancy at 
screening except women that enter the study with a hCG > 100 IU/L and had maintained that 
level continuously after exclusion of pregnancy by a previous pelvic ultrasound.  
Exclusion Criteria:   
1. Males are excluded from the study 
2. Prior treatment with TRC105 
3. Current treatment on another therapeutic clinical trial 
4. 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 < 150/90 mm Hg) 
5. Significant pericardial effusion, pleural effusion, or ascites 
6. Active bleeding or pathologic condition that carries a high risk of bleeding (e.g., hereditary 
hemorrhagic telangiectasia) 
7. Tumors located in the central chest or other location where bleeding is associated with high 
morbidity 
8. Thrombolytic use (except to maintain i.v. catheters) within 10 days prior to first day of study 
therapy 
9. Angina, MI, symptomatic congestive heart failure, cerebrovascular accident, transient 
ischemic attack, arterial embolism, pulmonary embolism, percutaneous transluminal coronary 
angioplasty (PTCA) or coronary artery bypass graft (CABG) within the past 6 months. Deep 
venous thrombosis within 6 months unless the patient is therapeutically anti-coagulated 
without the use of warfarin for at least 2 weeks. In this situation, low molecular weight 
heparin is preferred. 
10. Known active viral or nonviral hepatitis  
11. Pregnant or actively breastfeeding without intention to discontinue prior to initiation of study 
12. Open wounds or unhealed fractures within 28 days of starting study treatment 


5.3.5.2 Clinical Protocol 
 
105GTN201 Amendment #3 
EudraCT 2015-005475-25 
 
20SEP2016 
Page 10 of 102 
 
13. History of peptic ulcer disease or erosive gastritis within the past 6 months, unless treated for 
the condition and complete resolution has been documented by esophagogastroduodenoscopy 
(EGD) within 28 days of starting study treatment 
14. 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) 
15. Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome 
(AIDS) related illness 
16. Other severe acute or chronic medical (including bone marrow suppressive diseases) or 
psychiatric condition or laboratory abnormality that may increase the risk associated with 
study participation or may interfere with the interpretation of study results and, in the 
judgment of the Investigator, would make the patient inappropriate for this study 
17. 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 brain edema for at least 28 days 
18. Receipt of systemic anticancer therapy, or any investigational agents, within 28 days of 
starting study treatment. If anticancer therapy was given within 28 days of starting study 
treatment, patients may be included if 5 times the elimination half-life of the drug has passed 
19. 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 starting 
study treatment or those patients who have not recovered adequately from side effects of such 
therapy 
20. Major surgical procedure or significant traumatic injury within 6 weeks prior to study 
registration or not 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 
21. Patients with known hypersensitivity to the active substance or any of the excipients, or 
Chinese hamster ovary products or other recombinant human, chimeric, or humanized 
antibodies 
22. Patients with active infection that requires systemic therapy 
Investigational products dose and mode of administration:  
Following the appropriate premedication regimen, TRC105 will be dosed weekly with the first 
weekly dose of TRC105 split, with 3 mg/kg administered on cycle 1 day 1 and 7 mg/kg administered 
on cycle 1 day 4, and then the full dose of 10 mg/kg given on cycle 1 day 8 and weekly thereafter.  
 
Patients who achieve CR on single-agent TRC105 and have received at least 2 cycles of weekly 
TRC105 may transition to TRC105 15 mg/kg administered every two weeks. 


5.3.5.2 Clinical Protocol 
 
105GTN201 Amendment #3 
EudraCT 2015-005475-25 
 
20SEP2016 
Page 11 of 102 
 
Bevacizumab will be dosed at 5 mg/kg every 2 weeks and will be administered according to the 
package insert. On days of combination dosing with TRC105 and bevacizumab, there will be at least 
60 minutes between the completion of the bevacizumab infusion and the initiation of the TRC105 
infusion. 
 
Withdrawal Criteria:  
Patients may continue on treatment until disease progression, unacceptable toxicity or withdrawal of 
consent, or other reasons.   
Patients 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. Disease Progression while receiving TRC105 and bevacizumab as combination therapy.   
2. There is a need for anticancer therapy not specified in the protocol including cancer surgery 
or radiation therapy. 
3. Lost to follow-up or noncompliant. 
4. Arterial thrombosis of any grade (including cerebrovascular ischemia, cardiac 
ischemia/infarction, or peripheral or visceral arterial ischemia) or grade 4 thromboembolism. 
For grade 3 venous thromboembolism hold TRC105 and/or bevacizumab treatment.  If the 
planned duration of full dose anticoagulation is < 2 weeks, TRC105 and/or bevacizumab 
should be held until the full dose anticoagulation period is over.  If the planned duration of 
full dose anticoagulation is > 2 weeks, TRC105 and/or bevacizumab may be resumed during 
full dose anticoagulation IF all the following criteria are met.  1.  Subject does not have a 
pathologic condition that carries high risk of bleeding (i.e. tumor involving major vessels).  2.  
Subject has not had any hemorrhagic events > grade 1 on study.  3.  The subject has a stable 
dose of heparin or a Factor X inhibitor or has an in-range INR (usually 2-3) on a stable dose 
of warfarin prior to restarting TRC105 and/or bevacizumab.  4.  If thromboembolism 
worsens/recurs upon resumption of TRC105 and/or bevacizumab, despite anticoagulation, 
study drugs (TRC105 and/or bevacizumab) should be discontinued.  
5. Missed study drug treatment (i.e., single agent TRC105, single agent bevacizumab, or BOTH 
TRC105 and bevacizumab if dosing with the combination regimen) for > 8 consecutive 
weeks without CR as defined in Section 7 OR discontinuation of study therapy (i.e., single 
agent TRC105, single agent bevacizumab or BOTH TRC105 and bevacizumab if dosing with 
the combination regimen) for > 6 months following CR. 
6. Pregnancy. Pregnant patients should be followed for the duration of the pregnancy and the 
outcome of the pregnancy should be documented. 
7. Discontinuation of bevacizumab treatment for other toxicities is at the discretion of the 
investigator, after considering the individual risk and benefit to the patient of continued 
treatment and per appropriate product labeling. 
Criteria for evaluation: 
Safety: 
A formally chartered in-house TRACON Safety Review Team will review safety data. Safety 
assessments include adverse events (AEs), physical exams, performance status, laboratory results 


5.3.5.2 Clinical Protocol 
 
105GTN201 Amendment #3 
EudraCT 2015-005475-25 
 
20SEP2016 
Page 12 of 102 
 
(complete blood counts and serum chemistry) and 12-lead ECGs (if the patient develops an 
arrhythmia).   
Efficacy: 
The co-primary objectives are to determine the objective response rates (ORR) of single agent 
TRC105 and of the combination of TRC105 and bevacizumab (in bevacizumab refractory patients) in 
patients with refractory GTN. ORR will be assessed by hCG response and/or radiologic criteria in 
patients with measurable disease. Treatment decisions will be based on hCG testing in patients with 
choriocarcinoma and on radiographic criteria integrated with serum hCG assessment in patients with 
PSTT and ETT. 
Statistical methods: 
Efficacy analysis: 
Point estimates and two-sided exact binomial 95% confidence intervals will be provided for the co-
primary endpoints (ORR), as well as for all secondary endpoints defined as proportions.  The 
estimates and confidence intervals for ORR will be calculated twice – once for each of the two co-
primary populations.  PFS will be estimated using the Kaplan-Meier method. 
Sample size justification: 
The sample size of 30 patients is not based on statistical considerations.  If five or more responses to 
TRC105 given as a single agent or when combined with bevacizumab (in a bevacizumab refractory 
patient) are detected among 30 patients, then the lower limit of the two-sided exact binomial 95% 
confidence interval will be greater than 5%.  For example, with five responses, the 95% confidence 
interval would be (5.64%, 34.72%). 


5.3.5.2 Clinical Protocol 
 
105GTN201 Amendment #3 
EudraCT 2015-005475-25 
 
20SEP2016 
Page 13 of 102 
 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES  
TABLE OF CONTENTS 
1. 
SYNOPSIS ...................................................................................................................3 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ..................................13 
2. 
INTRODUCTION ......................................................................................................21 
2.1. 
Background .................................................................................................................21 
2.1.1. 
Angiogenesis and Cancer ...........................................................................................21 
2.1.2. 
CD105 and Angiogenesis ...........................................................................................21 
2.2. 
TRC105 Background ..................................................................................................23 
2.2.1. 
Studies with TRC105 ..................................................................................................23 
2.2.1.1. 
105ST101 Phase 1 Monotherapy ................................................................................24 
2.2.1.2. 
Phase 1b 105ST102 Study with Bevacizumab ...........................................................27 
2.2.2. 
Gestational Trophoblastic Neoplasia ..........................................................................29 
2.2.3. 
Rationale for Sequential Single Agent Treatment and Combination 
Treatment with TRC105 and Bevacizumab ...............................................................30 
2.2.4. 
Complete Response in a Single Patient Study of TRC105 and Bevacizumab 
in Metastatic and Refractory Choriocarcinoma ..........................................................31 
2.3. 
Potential Risks and Benefits to Human Patients .........................................................31 
2.3.1. 
Potential Risks ............................................................................................................31 
2.3.2. 
Potential Benefits ........................................................................................................35 
2.4. 
Conduct .......................................................................................................................35 
3. 
TRIAL OBJECTIVES ................................................................................................36 
3.1. 
Primary: ......................................................................................................................36 
3.2. 
Secondary: ..................................................................................................................36 
3.3. 
Exploratory: ................................................................................................................36 
4. 
INVESTIGATIONAL PLAN .....................................................................................37 
4.1. 
Overall Study Design and Plan: Description ..............................................................37 
4.1.1. 
Trial Overview ............................................................................................................37 
4.1.2. 
Trial Procedures ..........................................................................................................38 
4.1.2.1. 
Screening ....................................................................................................................38 
4.1.2.2. 
Trial Period .................................................................................................................40 
4.1.3. 
Complete Response Discontinuation of Therapy Visit and/or Change in 
Therapy Visit ..............................................................................................................41 
4.1.4. 
End of Study Visit Assessments .................................................................................42 


5.3.5.2 Clinical Protocol 
 
105GTN201 Amendment #3 
EudraCT 2015-005475-25 
 
20SEP2016 
Page 14 of 102 
 
4.1.5. 
Post Treatment Follow-up ..........................................................................................43 
5. 
SELECTION AND WITHDRAWAL OF PATIENTS ..............................................56 
5.1. 
Patient Inclusion Criteria ............................................................................................56 
5.2. 
Patient Exclusion Criteria ...........................................................................................57 
5.3. 
Patient Withdrawal Criteria ........................................................................................58 
6. 
TREATMENT OF PATIENTS ..................................................................................60 
6.1. 
Description of TRC105 Study Drug ...........................................................................60 
6.2. 
Composition of TRC105 .............................................................................................60 
6.3. 
TRC105 Dose Level ...................................................................................................60 
6.4. 
TRC105 Packaging and Labeling ...............................................................................60 
6.5. 
TRC105 Storage and Shipping ...................................................................................60 
6.6. 
TRC105 Preparation ...................................................................................................60 
6.7. 
TRC105 Administration .............................................................................................61 
6.7.1. 
TRC105 15 mg/kg Every 2 Week Dosing ..................................................................63 
6.7.2. 
TRC105 Dose Modification/Dose Interruptions ........................................................64 
6.7.3. 
Management of TRC105 Infusion Reactions .............................................................65 
6.7.4. 
TRC105 Study Drug Accountability ..........................................................................66 
6.7.5. 
TRC105 Study Drug Handling and Disposal .............................................................66 
6.8. 
Bevacizumab Packaging .............................................................................................67 
6.9. 
Bevacizumab Preparation ...........................................................................................67 
6.10. 
Bevacizumab Administration .....................................................................................67 
6.10.1. 
Bevacizumab Dose Modification ...............................................................................67 
6.11. 
Bevacizumab Drug Accountability .............................................................................68 
6.12. 
Bevacizumab Handling and Disposal .........................................................................68 
6.13. 
Concomitant Medications ...........................................................................................68 
6.14. 
Treatment Compliance ................................................................................................69 
6.14.1. 
TRC105 .......................................................................................................................69 
6.14.2. 
Bevacizumab ...............................................................................................................69 
6.15. 
Patient Enrollment ......................................................................................................69 
7. 
ASSESSMENT OF EFFICACY ................................................................................70 
7.1. 
Assessment of Efficacy by Serum hCG ......................................................................70 
7.2. 
Radiologic Tumor Assessment ...................................................................................70 
7.2.1. 
Definitions of Tumor Response by RECIST 1.1 ........................................................71 


5.3.5.2 Clinical Protocol 
 
105GTN201 Amendment #3 
EudraCT 2015-005475-25 
 
20SEP2016 
Page 15 of 102 
 
7.2.1.1  
Target Lesions ............................................................................................................71 
7.2.1.2  
Non-Target Lesions ....................................................................................................72 
7.2.2. 
Determination of Overall Response by RECIST 1.1 ..................................................72 
7.3. 
Determination of Best Overall Response by Histology ..............................................73 
7.3.1. 
Determination of Best Overall Response in Patients with Choriocarcinoma .............73 
7.3.2. 
Determination of Best Overall Response in Patients with PSTT and ETT ................73 
8. 
ASSESSMENT OF SAFETY .....................................................................................75 
8.1. 
Safety Parameters .......................................................................................................75 
8.1.1. 
Laboratory Safety Assessments ..................................................................................75 
8.1.1.1. 
Hematology, Serum Chemistry, Coagulation .............................................................75 
8.1.1.2. 
Urinalysis ....................................................................................................................75 
8.1.2. 
Other Safety Assessments ...........................................................................................75 
8.1.2.1. 
Physical Examination .................................................................................................75 
8.1.2.2. 
Vital Signs ..................................................................................................................76 
8.1.2.3. 
Performance Status .....................................................................................................76 
8.1.2.4. 
ECG ............................................................................................................................76 
8.2. 
Adverse Events ...........................................................................................................76 
8.2.1. 
Definition of Adverse Event .......................................................................................76 
8.2.2. 
Serious Adverse Events ..............................................................................................77 
8.2.2.1. 
Hospitalization ............................................................................................................78 
8.3. 
Reporting Adverse Events ..........................................................................................79 
8.3.1. 
Eliciting Adverse Event Information ..........................................................................79 
8.3.2. 
Adverse Event Reporting Period ................................................................................79 
8.3.3. 
Reporting Requirements .............................................................................................79 
8.3.4. 
Recording Adverse Events in the Case Report Forms ................................................80 
8.3.5. 
Grading of Adverse Event Severity ............................................................................80 
8.3.6. 
Relationship to TRC105 Study Drug/Bevacizumab ...................................................81 
8.3.7. 
Expectedness ...............................................................................................................81 
8.3.8. 
Exposure in Utero .......................................................................................................82 
8.3.9. 
Follow-up of Unresolved Adverse Events ..................................................................82 
8.4. 
Safety Monitoring .......................................................................................................82 
9. 
OTHER ASSESSMENTS ..........................................................................................83 
9.1. 
Other Laboratory Assessments ...................................................................................83 


5.3.5.2 Clinical Protocol 
 
105GTN201 Amendment #3 
EudraCT 2015-005475-25 
 
20SEP2016 
Page 16 of 102 
 
9.1.1. 
TRC105 Trough Concentration ..................................................................................83 
9.1.2. 
TRC105 Peak Concentration ......................................................................................83 
9.1.3. 
Bevacizumab Trough Concentration ..........................................................................83 
9.1.4. 
Bevacizumab Peak Concentration ..............................................................................83 
9.1.5. 
TRC105 Immunogenicity ...........................................................................................83 
9.1.6. 
Protein Biomarker .......................................................................................................83 
9.1.7. 
CD16 Genotype ..........................................................................................................84 
9.1.8. 
Archival Tumor Specimens ........................................................................................84 
10. 
STATISTICS ..............................................................................................................85 
10.1. 
Data Analysis ..............................................................................................................85 
10.1.1. 
Analysis of Co-Primary Objectives ............................................................................85 
10.1.2. 
Analysis of Secondary Objectives ..............................................................................85 
10.1.2.1. 
Analysis for Pharmacokinetics ...................................................................................85 
10.1.2.2. 
Analysis of Protein Biomarkers ..................................................................................85 
10.1.2.3. 
Analysis of CD16 Genotype .......................................................................................86 
10.1.2.4. 
Analysis of Archival Tumor Tissue ............................................................................86 
10.2. 
Sample Size Justification ............................................................................................86 
11. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS .........................................87 
12. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................88 
13. 
ETHICS ......................................................................................................................89 
13.1. 
Health Authorities and Independent Ethics Committees/Institutional Review 
Boards .........................................................................................................................89 
13.2. 
Ethical Conduct of the Study ......................................................................................89 
13.3. 
Written Informed Consent ..........................................................................................89 
13.4. 
Patient Compensation .................................................................................................90 
14. 
DATA HANDLING AND RECORDKEEPING .......................................................91 
14.1. 
Inspection of Records .................................................................................................91 
14.2. 
Retention of Records ..................................................................................................91 
15. 
DEFINITION OF END TRIAL ..................................................................................93 
15.1. 
End of Trial in all Participating Countries ..................................................................93 
15.2. 
TRACON Discontinuation Criteria ............................................................................93 
16. 
PUBLICATION OF TRIAL RESULTS ....................................................................94 
17. 
FINANCING AND INSURANCE .............................................................................95 


5.3.5.2 Clinical Protocol 
 
105GTN201 Amendment #3 
EudraCT 2015-005475-25 
 
20SEP2016 
Page 17 of 102 
 
18. 
INVESTIGATOR PROTOCOL AGREEMENT: 105GTN201 .................................96 
19. 
REFERENCES ...........................................................................................................97 
20. 
APPENDICES ..........................................................................................................100 
Appendix 1:  National Cancer Institute (NCI) Common Terminology Criteria for 
Adverse Events (CTCAE) ........................................................................................100 
Appendix 2:  ECOG Performance Status .....................................................................................101 
Appendix 3:  Avastin Package Insert ...........................................................................................102 
 
LIST OF TABLES 
Table 1: 
Emergency Contact Information ...................................................................................2 
Table 2: 
Abbreviations and Specialist Terms ...........................................................................18 
Table 3: 
FIGO 2000 Scoring System for GTN [59] .................................................................30 
Table 4: 
Single Agent TRC105 Schedule of Assessments .......................................................44 
Table 5: 
Single Agent Bevacizumab Schedule of Assessments ...............................................48 
Table 6: 
Combination Therapy Schedule of Assessments (TRC105 + Bevacizumab) ............52 
Table 7: 
Ideal Cycle 1 TRC105 Dosing Schema ......................................................................63 
Table 8: 
Ideal Monotherapy TRC105 15 mg/kg Dosing Schema .............................................64 
Table 9: 
Allowable TRC105 Dose Modifications ....................................................................65 
Table 10: Management of TRC105 Infusion Reactions .............................................................66 
Table 11: Response Evaluation Criteria in Solid Tumors ..........................................................72 
Table 12: Best overall response in PSTT and ETT patients with measurable disease 
and who are also evaluable by hCG ...........................................................................73 
Table 13: Adverse Event Grading ...............................................................................................81 
 
LIST OF FIGURES 
Figure 1: 
Sequential Treatment Design ........................................................................................4 
Figure 2: 
Treatment Algorithm After Single-Agent TRC105 ......................................................4 
Figure 3: 
Treatment Algorithm After Single-Agent Bevacizumab ..............................................5 
Figure 4: 
Treatment Algorithm After Combination Therapy (TRC105+Bevacizumab) .............5 
Figure 5: 
Single-Dose and Multiple-Dose Pharmacokinetic Data from Study 
105ST101 ....................................................................................................................24 
 
 
 
 


5.3.5.2 Clinical Protocol 
 
105GTN201 Amendment #3 
EudraCT 2015-005475-25 
 
20SEP2016 
Page 18 of 102 
 
Table 2: 
Abbreviations and Specialist Terms 
Abbreviation or specialist term 
Explanation 
5-FU 
Fluorouracil 
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 Antibodies 
AST 
Aspartate Aminotransferase 
AUC 
Area Under the Curve 
AUClast 
Time of Last Measurable Concentration of Area Under the 
Curve 
BALB/c mice 
Mouse Strain 
BUN 
Blood Urea Nitrogen 
CA-125 
Cancer Antigen-125 
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 
EMA-CO 
Etoposide, Methotrexate, Actinomycin D, 
Cyclophosphamide, and Vincristine 
EMA-EP 
Etoposide, Methotrexate, Actinomycin, and Cisplatinum 
EOS 
End of Study 
ETT 
Epithelioid Trophoblastic Tumor 
FIGO 
International Federation of Gynecology and Obstetrics 
FDA 
Food and Drug Administration 
G 
Gram 
GCP 
Good Clinical Practice 


5.3.5.2 Clinical Protocol 
 
105GTN201 Amendment #3 
EudraCT 2015-005475-25 
 
20SEP2016 
Page 19 of 102 
 
GTD 
Gestational Trophoblastic Disease 
GTN 
Gestational Trophoblastic Neoplasia 
hCG 
Human chorionic gonadotropin 
Her-2 
Human epidermal growth factor receptor 2 
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 
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 
ORR 
Overall Response Rate 
PBS 
Phosphate-Buffered Saline 
PD 
Progressive Disease 
PDGF 
Platelet Derived Growth Factor 
PlGF 
Placental Growth Factor 
pM 
Picomolar 
PR 
Partial Response 
PSA 
Prostate Specific Antigen 
PSTT 
Placental Site Trophoblastic Tumor 
PT 
Prothrombin Time 


5.3.5.2 Clinical Protocol 
 
105GTN201 Amendment #3 
EudraCT 2015-005475-25 
 
20SEP2016 
Page 20 of 102 
 
PTCA 
Percutaneous Transluminal Coronary Angioplasty  
PTT 
Partial Thromboplastin Time 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
Serious Adverse Event 
sCD105 
Soluble CD105/endoglin 
SCID 
Severe Combined Immunodeficient 
SD 
Stable Disease 
SGOT 
Serum Glutamic Oxaloacetic Transaminase 
SGPT 
Serum Glutamic Pyruvic Transaminase 
SN6j 
Murine parent antibody of TRC105 
sVEGFR2  
Soluble VEGF Receptor 2 
TGF-β 
Transforming Growth Factor 
TP-TE 
Paclitaxel, Cisplatin – Paclitaxel, Etoposide 
TSH 
Thyroid Stimulating Hormone 
ULN 
Upper Limit of Normal 
US 
United States of America 
VEGF 
Vascular Endothelial Growth Factor 
WHO 
World Health Organization 


5.3.5.2 Clinical Protocol 
 
105GTN201 Amendment #3 
EudraCT 2015-005475-25 
 
20SEP2016 
Page 21 of 102 
 
2. 
INTRODUCTION 
2.1. 
Background 
2.1.1. 
Angiogenesis and Cancer 
 
Angiogenesis is required for the survival and growth of solid cancers [1, 2].  It is generally 
accepted that solid cancers have two phases, an avascular phase and a vascular phase [2].  During 
the initial avascular phase, tumors exist as small aggregates of malignant cells supported by 
simple diffusion of oxygen and nutrients.  The progressive growth of solid cancers beyond 
clinically occult sizes requires the continuous formation of new blood vessels, a process known 
as tumor angiogenesis.  Tumor growth and metastasis require angiogenesis.  Therefore, 
inhibition of tumor angiogenesis and selective inhibition of the tumor vasculature represent 
potentially effective strategies for the prevention and treatment of solid cancers.   
Therapies that are directed against targets implicated in the development of tumor angiogenesis 
are attractive for many reasons.  First, except for female reproduction and wound healing, 
angiogenesis in adults is generally part of a pathologic process such as tumor growth or 
choroidal neovascularization.  Second, treatments that interrupt tumor angiogenesis should apply 
broadly to all solid cancers.  Third, angiogenic targets are present in the plasma or on endothelial 
cells themselves.  These targets are readily accessible to antibody treatments, in contrast to 
targets expressed within tumors that are more difficult for antibodies to access.  Fourth, 
angiogenic targets on vascular endothelial cells are less prone to genetic mutation than targets 
expressed by genetically unstable cancer cells.  As a result, development of resistance may be 
more predictable for agents that target endothelial cell functions than for those targeting cancer 
cells. 
Indeed, agents that target pathways required for tumor angiogenesis have an important role in the 
therapy of cancer patients.  The monoclonal antibody bevacizumab, which binds to the 
angiogenic cytokine VEGF, significantly prolongs overall survival for patients with advanced 
colorectal cancer or non-small cell lung cancer when added to standard chemotherapy regimens 
[3, 4].   Bevacizumab is also indicated for renal cell cancer, breast cancer, ovarian cancer [57], 
cervical cancer [58] and malignant glioma [5-7] with published evidence of clinical benefit in 
other solid tumor types.  Orally available small molecule VEGF inhibitors include sunitinib, 
sorafenib, pazopanib and axitinib, all of which have been shown to prolong survival in patients 
with metastatic renal cell cancer and/or hepatocellular cancer [8-11].   
2.1.2. 
CD105 and Angiogenesis 
CD105 (endoglin) is a homodimeric cell membrane glycoprotein that was initially identified as a 
human leukemia-associated antigen [12] and later also found on endothelial cells [13, 14].  The 
expression pattern of CD105 is relatively restricted and CD105 is mainly expressed on immature 
B-lineage/myeloid leukemia cells and proliferating endothelial cells [12, 13]. CD105 is a TGF-β 
coreceptor that is essential for angiogenesis [15, 16].  CD105 is strongly expressed on the 
proliferating vascular endothelium of solid tumors [14, 17]. All of these properties make CD105 
a good target for the antiangiogenic therapy of cancer [18]. Vascular targeted therapy may be 
more effective for destroying large established tumors than conventional antiangiogenic therapy 
such as anti-VEGF therapy [19].  In animal models, CD105 targeted therapy has demonstrated 
both vascular targeting effects and antiangiogenic effects by inducing regression of established 


5.3.5.2 Clinical Protocol 
 
105GTN201 Amendment #3 
EudraCT 2015-005475-25 
 
20SEP2016 
Page 22 of 102 
 
tumors as well as by preventing new tumor formation and inhibiting expansion of existing 
tumors [14, 20-23]. Therefore, CD105 offers a novel alternative target relative to the VEGF 
inhibitors currently available for antiangiogenesis therapy.  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) [24, 25].  CD105 has also been show to 
protect hypoxic cells from apoptosis [26].   
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 [27].  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 endothelial.  Not surprisingly, 
prevention of CD105 activation by anti-CD105 antibody acts synergistically with TGF-β to 
inhibit endothelial cell growth [28].   
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 [16].   
CD105 is critical for normal human blood vessel development [29].  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 [30].  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 [31].   
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 can be measured on activated monocytes and endothelial cells, and 
expression levels on endothelial cells exceed those on activated monocytes by approximately 10-
fold [32, 33].   
Importantly, CD105 expression is increased following inhibition of the VEGF pathway.  CD105 
expression increased more than two-fold in human pancreatic cancers grown in mice treated with 
an antibody that binds VEGF [34].  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 [35].   
CD105 expression is a prognostic factor in solid tumor patients.  Higher numbers of tumor 
vessels expressing CD105 have been correlated with poor prognosis in clinical studies of breast 
cancer [36, 37], lung cancer [38], prostate cancer [39, 40], colorectal cancer [41, 42], gastric 
cancer [43], endometrial cancer [44], astrocytic brain tumors [45], hepatocellular carcinoma [46], 
ovarian cancer [47, 48], esophageal adenocarcinoma [49], and head and neck cancer [50, 51].   


5.3.5.2 Clinical Protocol 
 
105GTN201 Amendment #3 
EudraCT 2015-005475-25 
 
20SEP2016 
Page 23 of 102 
 
Plasma CD105 levels measured by sandwich ELISA 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 
[41].   In the study, a positive correlation was observed between CD105 concentration and stage 
of disease.  For example, patients with advanced cancer had higher plasma CD105 levels than 
those with early-stage disease (r=0.20, p=0.0470).  In another study, the mean soluble CD105 
(sCD105) concentration in 59 patients with advanced metastatic solid cancer was 63.8 ng/mL 
versus 41.0 ng/mL in cancer patients without metastases, and 28.3 ng/mL in patients without a 
cancer diagnosis [52].  In a study of breast cancer patients receiving hormonal therapy, the upper 
limit of normal for sCD105 was determined to be 8.70 ng/mL, and patients with elevated 
sCD105 had shorter overall survival than those who did not [37].  These sCD105 concentrations 
are relatively low compared to TRC105 concentrations > 100,000 ng/mL that were safely 
achieved in cancer patients treated with TRC105 monotherapy on Study 105ST101. 
CD105 is expressed directly on certain cancers in addition to its expression on the tumor vessels. 
Choriocarcinoma is a vascular cancer that arises form trophoblast tissue that densely expresses 
CD105 [56].  CD105 has been shown to induce trophoblastic outgrowth and migration.  Hence, 
patients with choriocarcinoma are viewed as excellent candidates for treatment with 
angiogenesis inhibitors, especially a therapy that directly targets CD105 expressed on 
choriocarcinoma. 
2.2. 
TRC105 Background 
 
TRC105 is a genetically engineered human/murine chimeric monoclonal antibody directed 
against human CD105 [53], a growth proliferation receptor found on the surface of normal and 
proliferating endothelial cells.   
The antibody is an IgG1 kappa immunoglobulin containing murine variable region sequences 
and human constant region sequences [53].  TRC105 has an approximate molecular weight of 
148 kDa. TRC105 has a binding avidity for human CD105 of approximately 5 pM.   
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 [21].  Reactivity with tumor tissues is restricted to the 
tumor endothelium, as CD105 is not generally expressed on epithelial tumor cells [21].  TRC105 
induces ADCC on proliferating HUVECs and cancer cells at low conentrations and induces 
apoptosis and growth inhibition at higher concentrations. In a trophoblastic cell line, TRC105 
was shown to directly inhibit  growth in a dose dependent and methotrexate independent manner.  
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.  Studies of 
TRC105 in prostate, bladder, liver and ovarian cancer, a phase 1b study of TRC105 in 
combination with capecitabine in breast 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/2 study of TRC105 in 
combination with axitinib in renal cell carcinoma, a phase 1b/2 study of TRC105 in combination 


5.3.5.2 Clinical Protocol 
 
105GTN201 Amendment #3 
EudraCT 2015-005475-25 
 
20SEP2016 
Page 24 of 102 
 
with pazopanib in sarcoma and phase 2 studies of TRC105 in combination with bevacizumab in 
glioblastoma multiforme and renal cell carcinoma.   
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 5). 
Figure 5: 
Single-Dose and Multiple-Dose Pharmacokinetic Data from Study 105ST101 
 
 


5.3.5.2 Clinical Protocol 
 
105GTN201 Amendment #3 
EudraCT 2015-005475-25 
 
20SEP2016 
Page 25 of 102 
 
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. 
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 or 15 mg/kg every 2 weeks.  Three of 4 patients at 15 mg/kg 
weekly developed grade 3 hypoproductive 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 
[55].  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 


5.3.5.2 Clinical Protocol 
 
105GTN201 Amendment #3 
EudraCT 2015-005475-25 
 
20SEP2016 
Page 26 of 102 
 
infusion reactions were not observed in patients dosed at 10 or 15 mg/kg who maintained 
TRC105 serum levels known to saturate CD105 binding sites for the full dosing interval.  At 
dose levels where continuous TRC105 serum levels were achieved, glucocorticoids were safely 
discontinued and the infusion duration reduced to 1 hour. 
Three patients developed grade 1 cutaneous telangiectasia on the trunk early in the course of 
therapy, all at dose levels of 10 or 15 mg/kg weekly that resulted in continuous serum levels of 
TRC105 known to saturate CD105 sites on human endothelium.  Grade 1 or 2 hemorrhage was 
reported, including intermittent postcoital vaginal bleeding (that also occurred prior to TRC105 
treatment), epistaxis, and superficial gingival bleeding.    
Grade 1 or 2 headaches were observed, mainly in patients treated at doses of TRC105 above 3 
mg/kg.  Headaches began the day following infusion and were generally manageable with 
acetaminophen.  However, grade 2 headache in one patient at 15 mg/kg weekly prompted 
discontinuation prior to completion of the dose-limiting toxicity evaluation period.  Fatigue was 
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.   


5.3.5.2 Clinical Protocol 
 
105GTN201 Amendment #3 
EudraCT 2015-005475-25 
 
20SEP2016 
Page 27 of 102 
 
2.2.1.2. 
Phase 1b 105ST102 Study with Bevacizumab 
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 
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.  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 Osler-Weber-Rendu 
syndrome, that is caused by endoglin haploinsufficiency), and were also observed routinely 


5.3.5.2 Clinical Protocol 
 
105GTN201 Amendment #3 
EudraCT 2015-005475-25 
 
20SEP2016 
Page 28 of 102 
 
within the first month of dosing of 10 mg/kg weekly in the single agent TRC105 dose escalation 
study.   
Infusion reactions were, as expected, more notable at lower doses, and were rare at the MTD of 
TRC105 of 10 mg/kg, when TRC105 serum concentrations were maintained continuously.  Two 
of nineteen patients (10%) dosed with 10 mg/kg of TRC105 each experienced a single infusion 
reaction of grade 2 severity, both with the initial dose of TRC105, that required a brief 
interruption of the infusion prior to completion of the scheduled dose. 
Clinically significant anemia was not reported in patients dosed with 3 mg/kg or 6 mg/kg of 
TRC105, was reported in three of seven patients (43%; all grade 3) dosed with 8 mg/kg of 
TRC105, and was observed in nine of 19 (47%; three of grade 2 and six of grade 3 severity) of 
patients dosed with 10 mg/kg of TRC105.  Anemia prompted transfusion of packed red blood 
cells in 10 patients and growth factors were used in five patients. 
Other, less frequent, suspected adverse reactions included hypothyroidism, periorbital edema 
(which was generally noted prior to splitting the initial dose of TRC105), gingival pain, nausea, 
oral pain, vomiting, edema, decreased appetite, dyspnea, nasal congestion, rash and flushing. 
Other adverse events characteristic of each individual drug were not increased in frequency or 
severity when the two drugs were administered together.  Of note, the concurrent administration 
of bevacizumab and TRC105 did not potentiate the known toxicities of bevacizumab of 
hypertension, hemorrhage (including tumor-associated hemorrhage, and pulmonary hemorrhage 
or hemoptysis), or proteinuria.  Reversible posterior leukoencephalopathy syndrome (RPLS), 
congestive heart failure, fistulae, gastrointestinal perforation, impaired wound healing, and 
arterial thromboembolic events, were not observed. 
Notably, hypertension and 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 that remained on treatment for more than 28 months.  A total of 14 
patients (45%) had decreases in overall tumor burden, of whom 10 received prior VEGF 
inhibitor treatment (usually bevacizumab with chemotherapy).  Notably, the duration of 
treatment with TRC105 and bevacizumab of six patients (20% of those with 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.  


5.3.5.2 Clinical Protocol 
 
105GTN201 Amendment #3 
EudraCT 2015-005475-25 
 
20SEP2016 
Page 29 of 102 
 
Time to progression ranged from 0 to 861 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.   
2.2.2. 
Gestational Trophoblastic Neoplasia 
Gestational trophoblastic disease (GTD) is the term used to describe a group of rare diseases that 
originate in the placenta and have the potential to locally invade the uterus and metastasize. The 
pathogenesis of GTD is unique because the maternal tumor arises from gestational rather than 
maternal tissue.  The major histologic entities for this disease include complete molar pregnancy, 
partial molar pregnancy, invasive mole, and choriocarcinoma.  Molar pregnancies although 
benign are considered to be premalignant because they have the capability of developing into a 
malignancy. The term gestational trophoblastic neoplasia (GTN) is used when molar and non-
molar pregnancies become malignant, and comprise the morphologic entities of invasive mole, 
choriocarcinoma, placental site trophoblastic tumor (PSTT), and epithelioid trophoblastic tumor 
(ETT).  Choriocarcinoma, the most common type of GTN, consists of invasive, highly vascular 
and anaplastic trophoblastic tissue made up of cytotrophoblasts and syncytiotrophoblasts without 
villi. Choriocarcinoma metastasizes hematogenously and can follow any type of pregnancy, but 
most commonly develops after complete hydatidiform mole.  The most common metastatic site 
is the lungs, which are involved in over 80 percent of patients with metastases.  Staging for GTN 
is based on a number of unique criteria that differs from the usual staging procedures and 
prognosis is dependent upon factors that are not reflected in the anatomic extent of disease such 
as age, type of antecedent pregnancy, interval between the antecedent pregnancy and the 
persistent disease and serum hCG level.  These risk factors are used to establish a WHO Risk 
score [56]. 
Almost all trophoblastic malignancies develop from the cyto-and syncytial cells of the villous 
trophoblast and produce abundant amounts of hCG, the measurement of which serves as a 
reliable tumor marker for diagnosis, monitoring treatment response and follow-up to detect 
recurrence.  Currently, with sensitive quantitative assays for hCG and highly effective 
chemotherapy, most women with GTN can be cured and their reproductive function preserved 
providing they are managed according to well-established guidelines.   
GTN is uniquely sensitive to chemotherapy, which is the major treatment modality. Selection of 
an appropriate regimen should take into account the FIGO Stage and WHO Prognostic Score as 
defined below.  Despite the success of chemotherapy, other modalities such as surgery and 
radiation therapy should also be utilized where indicated, particularly in the patients with high-
risk scores.  Most patients with low risk disease are cured with single agent chemotherapy with 
the most active agents being methotrexate and actinomycin D.  For those that present with high 
risk disease or have relapse/resistance to monotherapy, multiagent chemotherapy regimens are 
used.  These regimens include EMA-CO, EMA-EP, TE-TP and are often able to produce cure for 
these women.  Rarely, if standard chemotherapy options have been ineffective there are reports 
of salvage with use of 5-FU or stem cell transplant.   


5.3.5.2 Clinical Protocol 
 
105GTN201 Amendment #3 
EudraCT 2015-005475-25 
 
20SEP2016 
Page 30 of 102 
 
Table 3: 
FIGO 2000 Scoring System for GTN [59] 
Prognostic factor 
Score 
0 
1 
2 
4 
Age (years) 
<40 
≥40 
– 
– 
Antecedent 
pregnancy (AP) 
Mole 
Abortion 
Term 
– 
Interval (end of 
AP to 
chemotherapy in 
months) 
<4 
4 – 6  
7 – 12  
>12 
hCG (IU/L) 
<103 
103 – 104  
104 – 105 
>105 
Number of 
metastases 
0 
1 – 4  
5 – 8  
>8 
Site of metastases 
Lung 
Spleen and kidney 
GI tract 
Brain and liver 
Largest tumor 
mass 
– 
3 – 5 cm 
>5 cm 
– 
Prior 
chemotherapy 
– 
– 
Single drug 
≥2 drugs 
   The total score for a patient is obtained by adding the individual scores for each prognostic factor.  Low risk, 0 – 6; 
high risk, ≥7.  PSTT should not be scored and instead requires staging.  Stage I, disease confined to the uterus; 
stage II, disease extending into the pelvis; stage III, disease spread to lungs and/or vagina; stage IV, all other 
metastatic sites including liver, kidney, spleen, and brain. 
2.2.3. 
Rationale for Sequential Single Agent Treatment and Combination Treatment 
with TRC105 and Bevacizumab 
TRC105 is a monoclonal antibody that binds to endoglin, an angiogenic target highly expressed 
on the tumor vessels and tumor cells in GTN. Bevacizumab is an approved monoclonal antibody 
to vascular endothelial growth factor (VEGF) that inhibits angiogenesis and extends survival in 
patients with a wide variety of solid tumor types.  TRC105 has been well tolerated as a single 
agent and when dosed with bevacizumab.  In a trophoblastic cell line, TRC105 was shown to 
directly inhibit  growth in a dose dependent and methotrexate independent manner.  Furthermore, 
bevacizumab complements TRC105 in preclinical models. 
A single patient study of TRC105 and bevacizumab demonstrated significant activity, including 
a complete response to treatment as evidenced by normalization of hCG, a reliable marker highly 
correlated with disease burden, in a heavily treated and chemotherapy refractory patient with 
metastatic choriocarcinoma, an aggressive form of GTN.  Given the limited experience treating 
patients with TRC105 and bevacizumab, this trial will limit toxicity and maximize the 
opportunity of each individual patient to respond to treatment with either TRC105 or 
bevacizumab, and if necessary, both agents, by employing a sequential treatment design 
(Figure 1 - Figure 4). 
The patients enrolled in this trial will initially be treated with TRC105 as a single agent.  In the 
case of progression on TRC105 (without a response to single agent TRC105), the patient will be 


5.3.5.2 Clinical Protocol 
 
105GTN201 Amendment #3 
EudraCT 2015-005475-25 
 
20SEP2016 
Page 31 of 102 
 
treated with bevacizumab alone to assess the activity of single agent bevacizumab.  In the 
absence of response to bevacizumab dosed as a single agent, the patient will receive TRC105 in 
combination with bevacizumab.  In the case that the patient has an objective, but incomplete, 
response to initial treatment with TRC105 as a single agent, bevacizumab will be added to 
TRC105 therapy (i.e., the patient will not be treated with bevacizumab alone).      
2.2.4. 
Complete Response in a Single Patient Study of TRC105 and Bevacizumab in 
Metastatic and Refractory Choriocarcinoma 
TRC105 is currently being studied in combination with bevacizumab in a 38 year old woman 
with metastatic choriocarcinoma who received 6 previous lines of therapy.  She responded well 
to treatment, with normalization of serum hCG occurring after 4 months of treatment, with 
TRC105 in combination with bevacizumab; the complete response by hCG is ongoing as of 
April 2016 after more than 6 months off treatment.  She also has an ongoing partial response by 
RECIST 1.1.  Of note, hCG did not normalize following each of the six treatments prior to 
TRC105 and bevacizumab therapy, with the exception of stem cell transplant.  After stem cell 
transplant, her hCG normalized for two weeks but had risen again when checked for 
confirmation. 
2.3. 
Potential Risks and Benefits to Human Patients 
2.3.1. 
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, growth factors, 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 the Osler-Weber-Rendu syndrome, a disease of CD105 haplotype insufficiency.  
Patients with Osler-Weber-Rendu 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, 


5.3.5.2 Clinical Protocol 
 
105GTN201 Amendment #3 
EudraCT 2015-005475-25 
 
20SEP2016 
Page 32 of 102 
 
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.  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 
combination with sorafenib.  Grade 3 pancreatitis was also observed in this study.  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. A third patient with glioblastoma with a history of 
recurrent meningitis developed recurrent grade 3 bacterial meningitis while treated with 
bevacizumab and TRC105. 
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.   
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 


5.3.5.2 Clinical Protocol 
 
105GTN201 Amendment #3 
EudraCT 2015-005475-25 
 
20SEP2016 
Page 33 of 102 
 
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.   
Reversible grade 3 colitis was reported in a patient treated with TRC105 and pazopanib. 
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.   
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. As the long term 
effects of bevacizumab treatment are unknown, patients should be advised to consider 
preservation of oocytes or ovarian tissue prior to study enrollment. 
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.   
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 


5.3.5.2 Clinical Protocol 
 
105GTN201 Amendment #3 
EudraCT 2015-005475-25 
 
20SEP2016 
Page 34 of 102 
 
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-induced nephrogenic systemic 
fibrosis in patients with poor renal function. 
Magnetic Resonance Imaging (MRI) 
MRI is a noninvasive imaging test used to diagnose and evaluate medical conditions.  MRI does 
not use radiation and there are no known harmful side-effects.  However, MRI may cause 
anxiety for people due to the loud banging made by the machine and the confined space of the 
testing area.  People with pacemakers, aneurysm clips, artificial heart valves, ear implants, or 
metal implants or foreign objects in their body are not permitted to have an MRI. 
Bone Scans 
A bone scan is a test that can find cancer that has spread to the bones.  A bone scan can often 
find a problem days to months earlier than a regular X-ray test.  During a bone scan, a 
radioactive substance called a tracer is injected into a vein in your arm.  The tracer travels 
through your bloodstream and into your bones.  Then a special camera takes pictures of the 
tracer in your bones.  A bone scan poses no greater risk than do conventional X-ray procedures.  
The tracers used in a bone scan produce very little radiation exposure – less than half that of a 
CT scan. 
Pelvic Ultrasound 
A pelvic ultrasound is a diagnostic exam that uses sound waves to produce images that are used 
to assess organs and structures within the female pelvis. The ultrasound is safe, noninvasive and 
does not use ionizing radiation.  
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 unbor children therefore patients should not become 
pregnant while participating in this study.  Patients should not nurse while on this study.  Women 
must be of non-child bearing potential due to surgical sterilization (at least 6 weeks following 
surgical bilateral oophorectomy with or without hysterectomy or tubal ligation) confirmed by 
medical history or menopause; or must agree to use two acceptable methods of birth control, one 
of which must be highly effective (see below), at the same time during study treatment 
(including during temporary breaks from treatment), and for at least 180 days after stopping 
TRC105 or bevacizumab. Women that enter the study with a hCG > 100 IU/L and had maintained 
that level continuously after exclusion of pregnancy by a previous pelvic ultrasound are excluded 
from the birth control requirement unless their hCG decreases to ≤ 100 IU/L.  The long term risk 
of infertility is unknown.  Ovarian failure has been observed with other antiangiogenic agents.  
 
Acceptable birth control methods considered highly effective: 


5.3.5.2 Clinical Protocol 
 
105GTN201 Amendment #3 
EudraCT 2015-005475-25 
 
20SEP2016 
Page 35 of 102 
 
 Combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation 
 oral 
 intravaginal 
 transdermal 
 Progestogen-only hormonal contraception associated with inhibition of ovulation 
 oral 
 injectable 
 implantable 
 Bilateral tubal ligation 
 Intrauterine device (IUD) 
 Vasectomy of partner that has received medical assessment of surgical success 
 Sexual abstinence* 
* In the context of this protocol, sexual abstinence is considered a highly effective method of 
birth control only if refraining from heterosexual intercourse during the entire period of risk 
(i.e., during study treatment, including temporary breaks from treatment, and for at least 180 
days after stopping TRC105 or bevacizumab).  If sexual abstinence is the highly effective 
method of birth control used, a second acceptable method is not required. 
 
Acceptable birth control methods not considered highly effective: 
 Male or female condom with spermicide* 
 Cap, diaphragm, or sponge with spermicide 
* A female condom and a male condom should not be used together as friction between the 
two can result in either product failing. 
2.3.2. 
Potential Benefits 
TRC105 is an investigational product, and its efficacy has not been established.  Bevacizumab is 
an approved anticancer agent that has not been approved in gestational trophoblastic disease.  It 
is possible that the administration of TRC105 as a single agent, bevacizumab as a single agent, or 
the combination of TRC105 and bevacizumab may result in clinical benefit (i.e., tumor response 
or prolonged stable disease). 
2.4. 
Conduct 
This clinical trial will be conducted in compliance with the protocol, GCP, and the applicable 
regulatory requirements. 


5.3.5.2 Clinical Protocol 
 
105GTN201 Amendment #3 
EudraCT 2015-005475-25 
 
20SEP2016 
Page 36 of 102 
 
3. 
TRIAL OBJECTIVES  
3.1. 
Primary: 
 To determine objective response rate (ORR) of single agent TRC105 and of the 
combination of TRC105 and bevacizumab (in bevacizumab refractory patients) in 
patients with refractory GTN (including choriocarcinoma, placental site trophoblastic 
tumor [PSTT], and epithelioid trophoblastic tumor [ETT]) 
3.2. 
Secondary: 
 To determine PFS 
 To determine ORR of single agent bevacizumab in patients with refractory GTN 
(including choriocarcinoma, PSTT, and ETT) 
 To evaluate the formation of TRC105 anti-product antibodies 
 To evaluate PK of TRC105 and bevacizumab 
 To determine the frequency and severity of adverse events as assessed by NCI 
CTCAE (Version 4.03) 
3.3. 
Exploratory: 
 To correlate efficacy endpoints with endoglin expression on tumor samples 
 To explore the effects of TRC105 and bevacizumab on circulating angiogenic protein 
biomarkers 
 To explore the effects of CD16 genotype on response to TRC105 therapy 


5.3.5.2 Clinical Protocol 
 
105GTN201 Amendment #3 
EudraCT 2015-005475-25 
 
20SEP2016 
Page 37 of 102 
 
4. 
INVESTIGATIONAL PLAN 
4.1. 
Overall Study Design and Plan: Description 
4.1.1. 
Trial Overview 
This is a study of sequential treatment with single agent TRC105, with the option of treatment 
with single agent bevacizumab, and the combination of both TRC105 and bevacizumab in 
patients with GTN that has progressed following treatment with at least one chemotherapy 
regimen that included two or more agents (see Figures 1-4). TRC105 will be initially 
administered weekly at a dose of 10 mg/kg on days 1, 8, 15, and 22 of each 28-day cycle. The 
first weekly dose of TRC105 will be split with 3 mg/kg administered on cycle 1 day 1 and 7 
mg/kg administered on cycle 1 day 4, and then the full dose of 10 mg/kg given on cycle 1 day 8 
and weekly thereafter. Patients who achieve CR on single-agent TRC105 and have received at 
least 2 cycles of weekly TRC105 may transition to TRC105 15 mg/kg administered every two 
weeks. 
All patients will initially receive TRC105 as a single agent for two 28-day cycles at which time 
formal measurement for response will be made.  The following scenarios are possible: 
1. Single agent TRC105 
a. Complete response after 2 cycles:  The patient will receive at least 3 cycles of 
consolidation therapy with single agent TRC105. 
b. Partial response after 2 cycles:  The patient will continue single agent TRC105 for an 
additional 2 cycles and re-evaluate the response, unless the patient has clear 
progression any time after completing 2 cycles of treatment then add bevacizumab.  If 
there is continued improvement in response after 4 cycles of treatment, continue 
single agent TRC105. If there is no improvement in response, add bevacizumab for 
combination therapy.  If there is a complete response any time after completing 2 
cycles of treatment, the patient will receive at least 3 cycles of consolidation therapy. 
c. Progression after 2 cycles or clear progression before 2 cycles:  Transition to single 
agent bevacizumab after a 2 week washout period.  Patients who have documented 
disease progression on a prior bevacizumab containing regimen will transition 
directly to TRC105 plus bevacizumab combination therapy. 
2. Single agent bevacizumab 
a. Complete response after 2 cycles:  The patient will receive at least 3 cycles of 
consolidation therapy with single agent bevacizumab. 
b. Partial response after 2 cycles:  The patient will continue single agent bevacizumab 
for an additional 2 cycles are re-evaluate the response unless the patient has clear 
progression any time after completing 2 cycles of treatment then add TRC105.  If 
there is continued improvement in response after 4 cycles of treatment, continue 
single agent bevacizumab. If there is no improvement in response, add TRC105 for 
combination therapy.  If there is a complete response any time after completing 2 
cycles of treatment, the patient will receive at least 3 cycles of consolidation therapy. 
c. Progression after 2 cycles or clear progression before 2 cycles:  Add TRC105 and 
treat with combination therapy. 
3. Combination therapy with TRC105 + bevacizumab 


5.3.5.2 Clinical Protocol 
 
105GTN201 Amendment #3 
EudraCT 2015-005475-25 
 
20SEP2016 
Page 38 of 102 
 
a. Complete response after 2 cycles:  The patient will receive at least 3 cycles of 
consolidation therapy with the combination. 
b. Partial response after 2 cycles:  The patient will continue combination therapy for 
another 2 cycles to confirm partial response.  Combination therapy will be continued 
until remission or progression. 
c. Progression after 2 cycles or clear progression before 2 cycles:  The patient will come 
off study. 
Bevacizumab will be dosed at 5 mg/kg every 2 weeks as a single agent or in combination with 
TRC105. Patients who achieve a complete response on single agent TRC105 or single agent 
bevacizumab and subsequently progress while receiving the single agent will receive TRC105 in 
combination with bevacizumab (e.g., patients who initially achieve a CR while on single agent 
TRC105 but subsequently progress during treatment will transition directly to the TRC105 + 
bevacizumab therapy regimen and will NOT dose with bevacizumab alone).  
Improvement in response is defined as a continued decline in hCG and/or a continued decrease 
in tumor volume by RECIST 1.1 for patients with measurable disease. For patients with 
choriocarcinoma, disease progression, response and stable disease will be assessed using hCG 
central lab results, starting two weeks after initiation of treatment:   
 Disease progression is defined as >20% increase (the absolute increase must be ≥10 
IU/L) above the nadir on consecutive measurements separated by at least two weeks;   
 Partial response is defined as a hCG decrease of 50% or more from starting value on 
consecutive measurements;   
 Complete response will be defined as normalization of hCG on consecutive 
measurements separated by at least two weeks;   
 Stable disease will be defined as the absence of response or progression on 3 
consecutive measurements separated by at least two weeks.   
Assessment of patients with PSTT and ETT will use radiographic criteria integrated with weekly 
hCG assessment (refer to Section 7.3.2).    
If a patient achieves complete response they will be treated with at least 3 consolidation cycles of 
therapy that produced the response (single agent TRC105, single agent bevacizumab, or 
combination of TRC105 + bevacizumab). Patients who achieve a CR following at least 3 cycles 
of consolidation therapy can remain off study treatment for ≤ 6 months and subsequently re-
initiate the treatment (whereby they achieved the CR) should they start to relapse (i.e. hCG 
increase on consecutive measurements separated by at least two weeks or increase in overall 
tumor burden) during the 6 months.   
4.1.2. 
Trial Procedures 
All on-study procedures are permitted within the time window indicated in the Schedule of 
Assessments (Table 4, Table 5 and Table 6).  
4.1.2.1. 
Screening 
The following screening procedures must be performed within 30 days prior to the first day of 
study therapy.  Hematology, serum chemistry, coagulation, and urinalysis collected within 7 days 


5.3.5.2 Clinical Protocol 
 
105GTN201 Amendment #3 
EudraCT 2015-005475-25 
 
20SEP2016 
Page 39 of 102 
 
of cycle 1 day 1 do not need to be repeated. The following will be performed according to the 
Schedule of Assessments (Table 4, Table 5 and Table 6).  
 Patient signature on current approved informed consent form. Prior to undergoing any 
study-specific procedure, each patient must read and sign the current approved 
informed consent form.  Patients may sign consent prior to the 30 day screening 
period. 
 Medical history, prior cancer therapy, prior cancer surgery, prior radiation therapy, 
drug allergies, disease present at screening, primary diagnosis and demographics. 
 Physical examination including examination of all major body systems, ECOG 
performance status, and vital signs. 
 Hematology (including serum iron, ferritin, and total iron binding capacity), 
coagulation (PT or INR) and serum chemistry (including thyroid stimulating hormone 
(TSH)) to be performed locally. 
 Urinalysis to be performed locally.  Microscopic analysis and/or urine protein-
creatinine ratio (UPCR) should be performed as clinically indicated. 
 Blood sampling for hCG (and other tumor markers if indicated), to be analyzed at a 
central lab. 
 Urine sampling for hCG (per PI discretion only to rule out suspected false positives 
from blood hCG test), to be analyzed by local lab. 
 CT or MRI scans of chest, abdomen and pelvis in addition to any other applicable 
sites of disease. Bone scans to be performed if metastasis is suspected prior to starting 
the study. 
 CT or MRI of the brain with contrast 
 Single tracing 12-Lead ECG (QT, PR and QRS intervals and heart rate will be 
captured).  
 Assessment of baseline emergent Adverse Events (serious and nonserious) from the 
date of informed consent. 
 Assessment of concomitant medications from 30 days prior to the start of study 
treatment.  
 Archival Tumor Tissue Specimens:  Archival specimens (formalin-fixed, paraffin-
embedded) of the primary cancer specimen and/or metastatic cancer specimen for 
each study participant, if they are available.  It is preferable that the entire paraffin 
block be submitted, but if this is not feasible, then at least 10 unstained slides are 
requested for immunohistochemical analysis (sections of ~5 microns are preferred).  
Patients without available archival tumor tissue specimens are still eligible to 
participate in the study.  See separate laboratory guide for further collection and 
shipment information. 
 Pelvic ultrasound for patients of child bearing potential, except women that enter the 
study with serum hCG > 100 IU/L and had maintained that level continuously after 
exclusion of pregnancy by a previous pelvic ultrasound.  


5.3.5.2 Clinical Protocol 
 
105GTN201 Amendment #3 
EudraCT 2015-005475-25 
 
20SEP2016 
Page 40 of 102 
 
4.1.2.2. 
Trial Period 
Hematology, blood chemistry, urinalysis, and physical examination 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 
unless otherwise indicated in the Schedule of Assessments. Each cycle is 4 weeks in duration. 
The following will be performed according to the Schedule of Assessments (Table 4, Table 5 and 
Table 6). 
 Physical examination including examination of all major body systems, ECOG 
performance status, and vital signs.  
 Assessment of vital signs during infusion of TRC105 and/or bevacizumab: Vital 
signs are to be assessed pre-infusion (within 30 minutes of starting TRC105 or 
bevacizumab infusions) and every 30 minutes during the infusion.  Vital signs 
should be monitored more frequently and/or beyond the completion of the 
infusion if medically indicated (e.g. if a patient experiences an infusion reaction 
that has not yet resolved). 
 Hematology (including serum iron, ferritin, and total iron binding capacity), 
coagulation (PT or INR) and serum chemistry to be performed locally. 
 Urinalysis to be performed locally. Microscopic analysis and/or urine protein-
creatinine ratio (UPCR) should be performed as clinically indicated. 
 Blood sampling for TRC105 and bevacizumab pharmacokinetics will include trough 
and peak sample collections (see laboratory manual for specific instructions regarding 
collection times, procedures, processing, storage and shipment). 
 Blood sampling for immunogenicity (APA concentrations) (see laboratory manual for 
specific instructions regarding collection, processing, storage and shipment). 
 Blood sampling for hCG tumor markers, to be analyzed at a central lab. 
 Urine sampling for hCG (per PI discretion), to be analyzed by local lab. 
 Blood sampling for angiogenic protein biomarkers (see laboratory manual for specific 
instructions regarding collection, processing, storage and shipment). 
 Blood sampling for CD16 genotype (see laboratory manual for specific instructions 
regarding collection, processing, storage and shipment).  Patients who decline to provide 
a CD16 sample are still eligible to participate in the study. 
 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. 
Scans will be performed every 56 days from cycle 1 day 1. Brain and bone scans are 
to be performed if metastasis is suspected.  
 Administration of TRC105. TRC105 diluted in normal saline will be administered 
according to the schedule of assessments as a 1 to 4 hour infusion (+/- 15 minutes) 


5.3.5.2 Clinical Protocol 
 
105GTN201 Amendment #3 
EudraCT 2015-005475-25 
 
20SEP2016 
Page 41 of 102 
 
following premedication (see Section 6.7, Table 4 and Table 6). TRC105 will be 
administered intravenously utilizing an infusion pump.  TRC105 must be 
administered using a low protein binding, non-DEHP infusion set with a 0.2 micron 
downstream filter.  Duration of infusion administration may be increased as medically 
necessary. The allowable dosing window is +/- 2 days.  TRC105 will be given 30 
minutes following completion of bevacizumab when both agents are given on the 
same day. 
 Administration of bevacizumab at 5 mg/kg every 2 weeks as described in the 
bevacizumab package insert.  
 Assessment of TRC105 and bevacizumab drug accountability. 
 Assessment of adverse events. 
 Assessment of concomitant medications and concomitant treatments. 
 Pelvic ultrasound every 8 weeks for patients of child bearing potential, except women 
not pregnant by pelvic ultrasound at study entry who enter the study with serum hCG 
> 100 IU/L and continuously maintain serum hCG > 100 IU/L  
4.1.3. 
Complete Response Discontinuation of Therapy Visit and/or Change in Therapy 
Visit  
Assessments need to be completed if they were not completed during the previous 2 weeks on a 
given therapy (1) prior to transitioning to another study therapy (e.g. transition from single agent 
TRC105 to single bevacizumab, etc.) or (2) if the patient discontinues study therapy due to CR 
following at least 3 cycles of consolidation therapy. The following will be performed according 
to the Schedule of Assessments (Table 4, Table 5 and Table 6). 
 Physical examination including examination of all major body systems, ECOG 
performance status, and vital signs. 
 Hematology (including serum iron, ferritin, and total iron binding capacity), 
coagulation (PT or INR) and serum chemistry to be performed locally. 
 Urinalysis to be performed locally. Microscopic analysis should be performed as 
clinically indicated. 
 Blood sampling for TRC105 and bevacizumab pharmacokinetics will include trough 
sample collections (see laboratory manual for specific instructions regarding 
collection times, procedures, processing, storage and shipment). 
 Blood sampling for immunogenicity (APA concentrations) (see laboratory manual for 
specific instructions regarding collection, processing, storage and shipment). 
 Blood sampling for hCG tumor markers, to be analyzed at a central lab.  Blood 
sampling for hCG should be repeated at this visit if not completed during the previous 
7 days on a given therapy. 
 Urine sampling for hCG (per PI discretion), to be analyzed by local lab. 
 Blood sampling for angiogenic protein biomarkers (see laboratory manual for specific 
instructions regarding collection, processing, storage and shipment). 


5.3.5.2 Clinical Protocol 
 
105GTN201 Amendment #3 
EudraCT 2015-005475-25 
 
20SEP2016 
Page 42 of 102 
 
 CT or MRI scans of chest, abdomen and pelvis in addition to any other applicable 
sites of disease.  Scans should be repeated at this visit if not completed during the 
previous 7 days on a given therapy. 
 Assessment of adverse events. 
 Assessment of concomitant medications and concomitant treatments. 
4.1.4. 
End of Study Visit Assessments  
Assessments need to be completed if they were not completed during the previous 2 weeks on a 
given therapy if the patient permanently discontinues all study therapy due to AE, patient 
decision etc.  If the patient completed a “CR Discontinuation of Therapy Visit” and subsequently 
permanently discontinues the trial due to (1) continued CR, the “End of Study Visit” does not 
need to be completed and the “CR Discontinuation of Therapy Visit” will count as the end of 
study visit or (2) progression, adverse event or any other reason except continued CR the “End of 
Study” visit should be completed.   The following will be performed according to the Schedule 
of Assessments (Table 4, Table 5 and Table 6). 
 Physical examination including examination of all major body systems, ECOG 
performance status, and vital signs. 
 Hematology (including serum iron, ferritin, and total iron binding capacity), 
coagulation (PT or INR) and serum chemistry to be performed locally. 
 Urinalysis to be performed locally. Microscopic analysis should be performed as 
clinically indicated. 
 Blood sampling for TRC105 and bevacizumab pharmacokinetics will include trough 
sample collections (see laboratory manual for specific instructions regarding 
collection times, procedures, processing, storage and shipment). 
 Blood sampling for immunogenicity (APA concentrations) (see laboratory manual for 
specific instructions regarding collection, processing, storage and shipment). 
 Blood sampling for hCG tumor markers, to be analyzed at a central lab.  Blood 
sampling for hCG should be repeated at this visit if not completed during the previous 
7 days on a given therapy. 
 Urine sampling for hCG (per PI discretion only to rule out suspected false positives 
from blood hCG test), to be analyzed by local lab. 
 Blood sampling for angiogenic protein biomarkers (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.  Scans should be repeated at this visit if not completed during the 
previous 7 days on a given therapy. 
 Assessment of adverse events. 
 Assessment of concomitant medications and concomitant treatments. 


5.3.5.2 Clinical Protocol 
 
105GTN201 Amendment #3 
EudraCT 2015-005475-25 
 
20SEP2016 
Page 43 of 102 
 
4.1.5. 
Post Treatment Follow-up 
The total post treatment follow-up period is up to 2 years.  The following will be performed 
according to the Schedule of Assessments (Table 4, Table 5 and Table 6).  
 Assessment of adverse events. The Investigator should continue to report any related 
or possibly related adverse events that occur beyond adverse event reporting period if 
applicable (i.e. beyond the 28-day post treatment follow-up visit). 
 Assessment of concomitant medications and concomitant treatments. 
 Patients with a CR who come off study treatment following consolidation therapy 
will have hCG levels measured every 2 weeks for 6 months or until resumption of 
study therapy; after 6 months, patients are no longer eligible for study therapy and 
will have hCG levels measured every month until disease progression, start of new 
therapy, or for a maximum of 2 years total follow-up.  Patients with measurable hCG 
who come off study therapy for reasons other than CR should have hCG levels 
measured at least every 2 weeks from last measurement until start of new therapy.  
The allowable time window for hCG sample collection is +/- 2 days. 
 Long term survival telephone call every month following discontinuation of treatment 
for two years  


5.3.5.2 Clinical Protocol 
 
105GTN201 Protocol Amendment #3 
EudraCT 2015-005475-25 
 
20SEP2016 
Page 44 of 102 
Table 4: 
Single Agent TRC105 Schedule of Assessments   
 


5.3.5.2 Clinical Protocol 
 
105GTN201 Protocol Amendment #3 
EudraCT 2015-005475-25 
 
20SEP2016 
Page 45 of 102 
Single Agent TRC105 Dosing Schedule of Assessments Footnotes: 
1. Days of Treatment with TRC105: All assessments should be performed prior to dosing with TRC105 unless otherwise indicated.  Each 
cycle is 28 days in duration.  
2. Cycle 1 day 1: Hematology, blood chemistry, urinalysis, coagulation, and physical examination are not required if acceptable screening 
assessment is performed within 7 days prior to the start of treatment on cycle 1 day 1.  
3. CR TRC105 Single Agent Therapy Discontinuation or Change in Study Therapy Visit: Assessments need to be completed if they 
were not completed during the previous 2 weeks on single agent TRC105 (previous 7 days for radiologic tumor assessments) (1) prior to 
transitioning from single agent TRC105 to single agent bevacizumab and/or (2) if the patient discontinues therapy due to CR following at 
least 3 cycles of consolidation therapy. Note: patients are eligible for treatment on this trial until they progress on the combination portion 
of the study (i.e., treatment with TRC105 combined with bevacizumab). 
4. End of Study Visit:  Assessments need to be completed if they were not completed during the previous 2 weeks on a given study therapy 
(previous 7 days for radiologic tumor assessments) if the patient permanently discontinues all study therapy due to AE, patient decision, 
investigator decision or any other reason.  If the patient completed a “CR Discontinuation of Therapy Visit” and subsequently permanently 
discontinues the trial due to (1) continued CR, the “End of Study Visit” does not need to be completed and the “CR Discontinuation of 
Therapy Visit” will be the end of study visit or (2) progression, adverse event or any other reason except continued CR the “End of Study” 
visit should be completed. 
5. Informed Consent: Must be obtained prior to undergoing any study specific procedure and may occur prior to the 30-day screening 
period. 
6. Medical/Oncologic History and Demographics: 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.  
7. Physical Examination: Examination of major body systems and ECOG performance status.  
8. Vital Signs: Heart rate, temperature, blood pressure, respiratory rate, weight. Assessment of Vital Signs during TRC105 Infusions: Vital 
signs (except weight) are to be assessed pre-infusion (within 30 min of starting TRC105 infusions), every 30 minutes during the infusion 
(+/- 15 minutes), and at the end of infusion (within 30 minutes after completing infusion).  Vital signs should be monitored more 
frequently and/or beyond the completion of the infusion if medically indicated (e.g. if a patient experiences an infusion reaction that has 
not yet resolved).  For patients on bevacizumab alone, Vital Signs are only required on days of infusion. 
9. Hematology, Chemistry, Coagulation & TSH:  Testing to be performed locally. Lab assessments may be performed within 3 days prior 
to study drug dosing. In addition to the assessments scheduled for the clinical trial, patients should undergo assessment as appropriate to 
ensure safe treatment. Hematology to include serum ion, ferritin, and total iron binding capacity.  Thyroid stimulating hormone (TSH) is 
to be tested at screening and on study as clinically indicated.  See Section 8.1.1.1  for specific assessments to be performed. 
10. Urinalysis: To be performed locally. Microscopic analysis should be performed as clinically indicated. 


5.3.5.2 Clinical Protocol 
 
105GTN201 Protocol Amendment #3 
EudraCT 2015-005475-25 
 
20SEP2016 
Page 46 of 102 
11. TRC105 Administration: 10 mg/kg IV TRC105 diluted in normal saline will be administered according to Section 6.7. The initial dose 
of TRC105 will be split such that 3 mg/kg is given on cycle 1 day 1 and 7 mg/kg is given on cycle 1 day 4.  In addition, if TRC105 is 
reintroduced while the patient is receiving bevacizumab, the initial dose will be split such that 3 mg/kg is given initially and 7 mg/kg is 
given three days later.  Patients who achieve CR on single-agent TRC105 and have received at least 2 cycles of weekly TRC105 may 
transition to TRC105 15 mg/kg administered every two weeks. 
12. CT or MRI Tumor Imaging: Images of chest, abdomen, and pelvis to be performed at screening and on-study as outlined in the 
assessment table. In addition, a brain MRI or CT with contrast to be performed at screening to ensure absence of CNS metastases and on 
study as needed if metastases are suspected. Known areas of disease should be consistently followed throughout the study with the same 
modality used at screening.  Assessments should also be performed whenever disease progression is suspected. Allowable window for 
tumor imaging studies is +/- 7 days. Scans will be performed every 56 days from cycle 1 day 1.  Brain scans are to be performed prior to 
starting the study and during study conduct if metastasis is suspected. Bone scans: to be performed at screening only if bone metastasis is 
suspected; while on study, if bone metastasis is detected at baseline, then bone scans should be repeated to confirm complete response or 
when progression in bone is suspected but not observed on CT/MRI. If metastasis was not detected at baseline, then bone scans should be 
performed only when progression in bone is suspected but not observed on CT/MRI. 
13. Serum hCG (Other Tumor markers if Indicated): Will be collected and analysed by central lab as indicated in the schedule of events 
and will include other markers in addition to hCG if applicable. See laboratory manual for additional details. 
14. Urine hCG: Will be collected and analysed by local lab per PI discretion to rule out suspected false positive values from the serum hCG 
assessment. 
15. Pelvic Ultrasound: Women of child bearing potential only: ultrasound of pelvis to exclude pregnancy at screening and throughout the 
study, except women that enter the study with serum hCG > 100 IU/L and had maintained that level continuously after exclusion of 
pregnancy by a previous pelvic ultrasound.  Women of childbearing potential must follow birth control guidance while on study therapy 
and for 180 days after discontinuing TRC105 or bevacizumab.  Women of childbearing potential that restart study treatment due to rising 
hCG must have a pelvic ultrasound to exclude pregnancy.  Pregnant patients are excluded from the study. 
16. 12-Lead ECG: Single tracing 12-lead ECG will be performed at screening. If patients develop an arrhythmia, the ECG should be repeated 
on day 1 of each subsequent cycle and as clinically indicated. 
17. Concomitant Medications and Treatments: Concomitant medications and treatments will be recorded from 30 days prior to the start of 
study treatment and up to 28 days following the last dose of study treatment. 
18. Baseline Signs and Symptoms and Adverse Events: Patients must be followed for safety from the day of informed consent until at least 
28 days after the last dose of study treatment, or until all serious or TRC105 related toxicities have resolved or are determined to be 
“chronic” or “stable”, whichever is later.  Adverse events occurring prior to the initiation of the study treatment will be considered 
"Baseline Signs and Symptoms” and will be recorded on “Medical History and Baseline Signs and Symptoms” case report forms. Events 
that occur from the time a patient has taken the first dose of bevacizumab and/or TRC105 study drug through 28 days after the last dose of 


5.3.5.2 Clinical Protocol 
 
105GTN201 Protocol Amendment #3 
EudraCT 2015-005475-25 
 
20SEP2016 
Page 47 of 102 
bevacizumab and/or TRC105 study drug (whichever is later) will be recorded on “Adverse Event” CRFs. Any serious AE that is possibly 
related to TRC105 occurring from the time of first dose or at any point after the reporting period must be promptly reported to TRACON. 
19. TRC105 Pre-Dose PK (Trough): A 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.  See separate laboratory guide for further collection and 
shipment information.  Additional PK samples may also be collected at the time of unexpected clinical events. 
20. TRC105 Post-Dose PK (Peak): A blood sample to be collected at the time-points indicated in the Schedule of Assessments, within 10 
minutes of completion of the TRC105 infusion.  Samples will be stored at approximately -70 °C.  See separate laboratory guide for further 
collection and shipment information.  Additional PK samples may also be collected at the time of unexpected clinical events. 
21. Anti-Product Antibody Testing: A blood sample will be collected to assess APA at the time-points indicated in the Schedule of 
Assessments and stored at approximately -70°C.  See separate laboratory guide for further collection and shipment information.  
Additional APA samples may also be collected at the time of unexpected clinical events. 
22. Protein Biomarkers: A plasma sample (K2EDTA tube) will be collected as indicated in the Schedule of Assessments and stored at 
approximately -70°C. See separate laboratory guide for further collection and shipment information. 
23. CD16 Genotype: A blood sample will be collected on C1D1 to test for the CD16 genotype.  See separate laboratory guide for further 
collection and shipment information.  Patients who decline to provide a CD16 sample are still eligible to participate in the study. 
24. Archival Tumor Tissue: Archival specimens (formalin-fixed, paraffin-embedded) are required of the primary cancer and/or metastatic 
cancer specimen for each study participant, if they are available.  It is preferable that the entire paraffin block be submitted, but if this is 
not feasible, then at least 10 unstained slides are requested for immunohistochemical analysis (sections of 5 microns are preferred).  
Patients without available archival tumor tissue specimens are still eligible to participate in the study. See separate laboratory guide for 
further collection and shipment information. 
25. Follow-up:  The 28 day follow-up visit (occurring 28 days after the CR DC Visit or EOS Visit if applicable) should include Concomitant 
Medications and Adverse Events. Patients with a CR who come off study treatment following consolidation therapy will have hCG levels 
measured every 2 weeks for 6 months or until resumption of study therapy; after 6 months, patients are no longer eligible for study therapy 
and will have hCG levels measured every month until disease progression, start of new therapy, or for a maximum of 2 years. Patients 
with measurable hCG who come off study therapy for reasons other than CR should have hCG levels measured at least every 2 weeks 
from last measurement until start of new therapy.  All patients will also be contacted by phone every month for long term follow-up for 
two years. The allowable visit window is +/- 7 days for follow-up assessments. 
26. Cycle 3+ Responding Patients:  Patients who achieve CR on single-agent TRC105 and have received at least 2 cycles of weekly 
TRC105 may transition to TRC105 15 mg/kg administered every two weeks. 
 


5.3.5.2 Clinical Protocol 
 
105GTN201 Protocol Amendment #3 
EudraCT 2015-005475-25 
 
20SEP2016 
Page 48 of 102 
Table 5: 
Single Agent Bevacizumab Schedule of Assessments 
 


5.3.5.2 Clinical Protocol 
 
105GTN201 Protocol Amendment #3 
EudraCT 2015-005475-25 
 
20SEP2016 
Page 49 of 102 
 Single Agent Bevacizumab Schedule of Assessments Footnotes: 
1. Days of Treatment with Bevacizumab: All assessments should be performed prior to dosing with bevacizumab unless otherwise 
indicated.  Each cycle is 28 days in duration.  
2. CR Bevacizumab Single Agent Therapy Discontinuation or Change in Study Therapy Visit: Assessments need to be completed if 
they were not completed during the previous 2 weeks on single agent bevacizumab (previous 7 days for radiologic tumor assessments) (1) 
prior to transitioning from single agent bevacizumab to combination bevacizumab + TRC105 therapy and/or (2) if the patient discontinues 
bevacizumab therapy due to CR following at least 3 cycles of consolidation therapy. Note: patients are eligible for treatment on this trial 
until they progress on the combination portion of the study (i.e., treatment with TRC105 combined with bevacizumab). 
3. End of Study Visit:  Assessments need to be completed if they were not completed during the previous 2 weeks on a given study therapy 
(previous 7 days for radiologic tumor assessments) if the patient permanently discontinues all study therapy due to AE, patient decision, 
investigator decision or any other reason.  If the patient completed a “CR Discontinuation of Therapy Visit” and subsequently permanently 
discontinues the trial due to (1) continued CR, the “End of Study Visit” does not need to completed and the “CR Discontinuation of 
Therapy Visit” will be the end of study visit or (2) progression, adverse event or any other reason except continued CR the “End of Study” 
visit should be completed. 
4. Physical Examination: Examination of major body systems and ECOG performance status.  
5. Vital Signs: Heart rate, temperature, blood pressure, respiratory rate, weight. Assessment of Vital Signs during TRC105 Infusions: Vital 
signs (except weight) are to be assessed pre-infusion (within 30 min of starting TRC105 infusions), every 30 minutes during the infusion 
(+/- 15 minutes), and at the end of infusion (within 30 minutes after completing infusion).  Vital signs should be monitored more 
frequently and/or beyond the completion of the infusion if medically indicated (e.g. if a patient experiences an infusion reaction that has 
not yet resolved).  For patients on bevacizumab alone, Vital Signs are only required on days of infusion. 
6. Hematology, Chemistry, Coagulation and TSH:  Testing to be performed locally. Lab assessments may be performed within 3 days 
prior to study drug dosing. In addition to the assessments scheduled for the clinical trial, patients should undergo assessment as 
appropriate to ensure safe treatment. Hematology to include serum ion, ferritin, and total iron binding capacity.  Thyroid stimulating 
hormone (TSH) is to be collected as clinically indicated.  See Section 8.1.1.1  for specific assessments to be performed. 
7. Urinalysis: To be performed locally. Microscopic analysis should be performed as clinically indicated. 
8. Bevacizumab Administration: Commercially available bevacizumab will be administered per the package insert in this study according 
to Section 6.10, over at least 30 minutes.  Bevacizumab will be dosed at 5 mg/kg every 2 weeks. 
9. CT or MRI Tumor Imaging: Images of chest, abdomen, and pelvis to be performed as outlined in the assessment table. In addition, a 
brain MRI or CT with contrast and bone scans to be performed on study as needed if metastases are suspected. Known areas of disease 
should be consistently followed throughout the study with the same modality used at screening.  Assessments should also be performed 
whenever disease progression is suspected. Allowable window for tumor imaging studies is +/- 7 days. Scans will be performed every 56 


5.3.5.2 Clinical Protocol 
 
105GTN201 Protocol Amendment #3 
EudraCT 2015-005475-25 
 
20SEP2016 
Page 50 of 102 
days from cycle 1 day 1.  Bone scans: to be performed at screening only if bone metastasis is suspected; while on study, if bone metastasis 
is detected at baseline, then bone scans should be repeated to confirm complete response or when progression in bone is suspected but not 
observed on CT/MRI. If metastasis was not detected at baseline, then bone scans should be performed only when progression in bone is 
suspected but not observed on CT/MRI. 
10. Serum hCG (Other Tumor markers if Indicated): Will be collected and analysed by central lab as indicated in the schedule of events 
and will include other markers in addition to hCG if applicable. See laboratory manual for additional details. 
11. Urine hCG: Will be collected and analysed by local lab per PI discretion. 
12. Pelvic Ultrasound: Women of child bearing potential only: ultrasound of pelvis to exclude pregnancy at screening and throughout the 
study, except women that enter the study with serum hCG > 100 IU/L and had maintained that level continuously after exclusion of 
pregnancy by a previous pelvic ultrasound.  Women of childbearing potential must follow birth control guidance while on study therapy 
and for 180 days after discontinuing TRC105 or bevacizumab.  Women of childbearing potential that restart study treatment due to rising 
hCG must have a pelvic ultrasound to exclude pregnancy.  Pregnant patients are excluded from the study. 
13. Concomitant Medications and Treatments: Concomitant medications and treatments will be recorded from 30 days prior to the start of 
study treatment and up to 28 days following the last dose of study treatment. 
14. Adverse Events (and Baseline Signs and Symptoms): Patients must be followed for safety from the day of informed consent until at 
least 28 days after the last dose of study treatment, or until all serious or TRC105 related toxicities have resolved or are determined to be 
“chronic” or “stable”, whichever is later.  Adverse events occurring prior to the initiation of the study treatment will be considered 
"Baseline-Signs and Symptoms” and will be recorded on “Medical History and Baseline Signs and Symptoms” case report forms. Events 
that occur from the time a patient has taken the first dose of bevacizumab and/or TRC105 study drug through 28 days after the last dose of 
bevacizumab and/or TRC105 study drug (whichever is later) will be recorded on “Adverse Event” CRFs. Any serious AE that is possibly 
related to TRC105 occurring from the time of first dose or at any point after the reporting period must be promptly reported to TRACON. 
15. Bevacizumab Pre-Dose PK (Trough): A blood sample to be collected at the time-points indicated in the Schedule of Assessments, prior 
to starting the bevacizumab infusion.  Samples will be stored at approximately -70°C.  See separate laboratory guide for further collection 
and shipment information.  Additional PK samples may also be collected at the time of unexpected clinical events. 
16. Bevacizumab Post-Dose PK (Peak): A blood sample to be collected at the time-points indicated in the Schedule of Assessments, within 
10 minutes of completion of the bevacizumab infusion.  Samples will be stored at approximately -70°C.  See separate laboratory guide for 
further collection and shipment information.  Additional PK samples may also be collected at the time of unexpected clinical events. 
17. Protein Biomarkers: A plasma sample (K2EDTA tube) will be collected as indicated in the schedule of assessments and stored at 
approximately -70°C. See separate laboratory guide for further collection and shipment information. 
18. Anti-Product Antibody Testing: A blood sample will be collected to assess APA at the time-points indicated in the Schedule of 
Assessments and stored at approximately -70°C.  See separate laboratory guide for further collection and shipment information.  
Additional APA samples may also be collected at the time of unexpected clinical events. 


5.3.5.2 Clinical Protocol 
 
105GTN201 Protocol Amendment #3 
EudraCT 2015-005475-25 
 
20SEP2016 
Page 51 of 102 
19. Long Term Follow-up:  The 28 day follow-up visit (occurring 28 days after the CR DC Visit or EOS Visit if applicable) should include 
Concomitant Medications and Adverse Events. Patients with a CR who come off study treatment following consolidation therapy will 
have hCG levels measured every 2 weeks for 6 months or until resumption of study therapy; after 6 months, patients are no longer eligible 
for study therapy and will have hCG levels measured every month until disease progression, start of new therapy, or for a maximum of 2 
years. Patients with measurable hCG who come off study therapy for reasons other than CR should have hCG levels measured at least 
every 2 weeks from last measurement until start of new therapy.  All patients will also be contacted by phone every month for long term 
follow-up for two years. The allowable visit window is +/- 7 days for follow-up assessments. 


5.3.5.2 Clinical Protocol 
 
105GTN201 Protocol Amendment #3 
EudraCT 2015-005475-25 
 
20SEP2016 
Page 52 of 102 
Table 6: 
Combination Therapy Schedule of Assessments (TRC105 + Bevacizumab) 
 


5.3.5.2 Clinical Protocol 
 
105GTN201 Protocol Amendment #3 
EudraCT 2015-005475-25 
 
20SEP2016 
Page 53 of 102 
Combination Therapy Schedule of Assessments Footnotes: 
1. Days of Treatment with TRC105 and/or Bevacizumab: All assessments should be performed prior to dosing with TRC105 and/or 
bevacizumab unless otherwise indicated.  Each cycle is 28 days in duration.  
2. CR TRC105 + Bevacizumab Therapy Discontinuation Visit: Assessments need to be completed if they were not completed during the 
previous 2 weeks on combination TRC105 + bevacizumab therapy (previous 7 days for radiologic tumor assessments) if the patient 
discontinues TRC105 + bevacizumab therapy due to CR following at least 3 cycles of consolidation therapy. Note: patients are eligible for 
treatment on this trial until they progress on the combination portion of the study (i.e., treatment with TRC105 combined with 
bevacizumab). 
3. End of Study Visit:  Assessments need to be completed if they were not completed during the previous 2 weeks on a given study therapy 
(previous 7 days for radiologic tumor assessments) if the patient permanently discontinues all study therapy due to AE, patient decision, 
investigator decision or any other reason.  If the patient completed a “CR Discontinuation of Therapy Visit” and subsequently permanently 
discontinues the trial due to (1) continued CR then the “End of Study Visit” does not need to be completed and the “CR Discontinuation of 
Therapy Visit” will be the end of study visit or (2) progression, adverse event or any other reason except continued CR the “End of Study” 
visit should be completed.  
4. Physical Examination: Examination of major body systems and ECOG performance status.  
5. Vital Signs: Heart rate, temperature, blood pressure, respiratory rate, weight. Assessment of Vital Signs during TRC105 Infusions: Vital 
signs (except weight) are to be assessed pre-infusion (within 30 min of starting TRC105 infusions), every 30 minutes during the infusion 
(+/- 15 minutes), and at the end of infusion (within 30 minutes after completing infusion).  Vital signs should be monitored more 
frequently and/or beyond the completion of the infusion if medically indicated (e.g. if a patient experiences an infusion reaction that has 
not yet resolved).  For patients on bevacizumab alone, Vital Signs are only required on days of infusion. 
6. Hematology, Chemistry, Coagulation and TSH:  Testing to be performed locally. Lab assessments may be performed within 3 days 
prior to study drug dosing. In addition to the assessments scheduled for the clinical trial, patients should undergo assessment as 
appropriate to ensure safe treatment. Hematology to include serum ion, ferritin, and total iron binding capacity.  Thyroid stimulating 
hormone (TSH) is to be collected as clinically indicated.  See Section 8.1.1.1 for specific assessments to be performed. 
7. Urinalysis: To be performed locally. Microscopic analysis should be performed as clinically indicated. 
8. TRC105 Administration: 10 mg/kg IV TRC105 diluted in normal saline will be administered according to Section 6.7. The initial dose 
of TRC105 for the combination will be split only if there was ≥ 10 days between doses of TRC105: the first dose on resumption of 
TRC105 should be administered over two days as was done for the initial TRC105 dose such that 3 mg/kg is given on day 1 and 7 mg/kg 
is given on day 4. 
9. Bevacizumab Administration: Commercially available bevacizumab will be administered per the package insert in this study according 
to Section 6.10, over at least 30 minutes. 


5.3.5.2 Clinical Protocol 
 
105GTN201 Protocol Amendment #3 
EudraCT 2015-005475-25 
 
20SEP2016 
Page 54 of 102 
10. CT or MRI Tumor Imaging: Images of chest, abdomen, and pelvis to be performed as outlined in the assessment table. In addition, a 
brain MRI or CT with contrast and bone scans to be performed on study as needed if metastases are suspected. Known areas of disease 
should be consistently followed throughout the study with the same modality used at screening.  Assessments should also be performed 
whenever disease progression is suspected. Allowable window for tumor imaging studies is +/- 7 days. Scans will be performed every 56 
days from cycle 1 day 1.  Bone scans: to be performed at screening only if bone metastasis is suspected; while on study, if bone metastasis 
is detected at baseline, then bone scans should be repeated to confirm complete response or when progression in bone is suspected but not 
observed on CT/MRI. If metastasis was not detected at baseline, then bone scans should be performed only when progression in bone is 
suspected but not observed on CT/MRI. 
11. Serum hCG (Other Tumor markers if Indicated): Will be collected and analysed by central lab as indicated in the schedule of events 
and will include other markers in addition to hCG if applicable. See laboratory manual for additional details. 
12. Urine hCG: Will be collected and analysed by local lab per PI discretion to rule out suspected false positive values from the serum hCG 
assessment. 
13. Pelvic Ultrasound: Women of child bearing potential only: ultrasound of pelvis to exclude pregnancy at screening and throughout the 
study, except women that enter the study with serum hCG > 100 IU/L and had maintained that level continuously after exclusion of 
pregnancy by a previous pelvic ultrasound.  Women of childbearing potential must follow birth control guidance while on study therapy 
and for 180 days after discontinuing TRC105 or bevacizumab.  Women of childbearing potential that restart study treatment due to rising 
hCG must have a pelvic ultrasound to exclude pregnancy.  Pregnant patients are excluded from the study. 
14. Concomitant Medications and Treatments: Concomitant medications and treatments will be recorded from 30 days prior to the start of 
study treatment and up to 28 days following the last dose of study treatment. 
15. Adverse Events (and Baseline Signs and Symptoms): Patients must be followed for safety from the day of informed consent until at 
least 28 days after the last dose of study treatment, or until all serious or TRC105 related toxicities have resolved or are determined to be 
“chronic” or “stable”, whichever is later.  Adverse events occurring prior to the initiation of the study treatment will be considered 
"Baseline-Signs and Symptoms” and will be recorded on “Medical History and Baseline Signs and Symptoms” case report forms. Events 
that occur from the time a patient has taken the first dose of bevacizumab and/or TRC105 study drug through 28 days after the last dose of 
bevacizumab and/or TRC105 study drug (whichever is later) will be recorded on “Adverse Event” CRFs. Any serious AE that is possibly 
related to TRC105 occurring from the time of first dose or at any point after the reporting period must be promptly reported to TRACON. 
16. TRC105 Pre-Dose PK (Trough): A 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.  See separate laboratory guide for further collection and 
shipment information.  Additional PK samples may also be collected at the time of unexpected clinical events. 
17. TRC105 Post-Dose PK (Peak): A blood sample to be collected at the time-points indicated in the Schedule of Assessments, within 10 
minutes of completion of the TRC105 infusion.  Samples will be stored at approximately -70°C.  See separate laboratory guide for further 
collection and shipment information.  Additional PK samples may also be collected at the time of unexpected clinical events. 


5.3.5.2 Clinical Protocol 
 
105GTN201 Protocol Amendment #3 
EudraCT 2015-005475-25 
 
20SEP2016 
Page 55 of 102 
18. Bevacizumab Pre-Dose PK (Trough): A blood sample to be collected at the time-points indicated in the Schedule of Assessments, prior 
to starting the bevacizumab infusion.  Samples will be stored at approximately -70°C.  See separate laboratory guide for further collection 
and shipment information.  Additional PK samples may also be collected at the time of unexpected clinical events. 
19. Bevacizumab Post-Dose PK (Peak): A blood sample to be collected at the time-points indicated in the Schedule of Assessments, within 
10 minutes of completion of the bevacizumab infusion.  Samples will be stored at approximately -70°C.  See separate laboratory guide for 
further collection and shipment information.  Additional PK samples may also be collected at the time of unexpected clinical events. 
20. Anti-Product Antibody Testing: A blood sample will be collected to assess APA at the time-points indicated in the Schedule of 
Assessments and stored at approximately -70 °C.  See separate laboratory guide for further collection and shipment information.  
Additional APA samples may also be collected at the time of unexpected clinical events. 
21. Protein Biomarkers: A plasma sample (K2EDTA tube) will be collected as indicated in the schedule of assessments and stored at 
approximately -70°C. See separate laboratory guide for further collection and shipment information. 
22. Long Term Follow-up:  The 28 day follow-up visit (occurring 28 days after the CR DC Visit or EOS Visit if applicable) should include 
Concomitant Medications and Adverse Events. Patients with a CR who come off study treatment following consolidation therapy will 
have hCG levels measured every 2 weeks for 6 months or until resumption of study therapy; after 6 months, patients are no longer eligible 
for study therapy and will have hCG levels measured every month until disease progression, start of new therapy, or for a maximum of 2 
years. Patients with measurable hCG who come off study therapy for reasons other than CR should have hCG levels measured at least 
every 2 weeks from last measurement until start of new therapy.  All patients will also be contacted by phone every month for long term 
follow-up for two years. The allowable visit window is +/- 7 days for follow-up assessments.   
 


5.3.5.2 Clinical Protocol 
 
105GTN201 Protocol Amendment #3 
EudraCT 2015-005475-25 
 
20SEP2016 
Page 56 of 102 
5. 
SELECTION AND WITHDRAWAL OF PATIENTS 
Note: patients must initially qualify for the study according to the following criteria and if study 
therapy is resumed > 56 days after last dose of study drug for patients with a CR who come off 
study treatment following consolidation therapy, the investigator must confirm that the patient 
continues to be eligible to receive study therapy. 
5.1. 
Patient Inclusion Criteria 
1. Willingness and ability to consent for self to participate in study   
2. Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests, 
and other study procedures  
3. Elevated serum hCG (in cases of choriocarcinoma); elevated hCG or measurable disease 
(in cases of PSTT or ETT). 
4. Histologically proven trophoblastic neoplasia, or clinically demonstrated trophoblastic 
neoplasia that has progressed following treatment with at least one chemotherapy 
regimen that included two or more chemotherapy agents. 
5. Female age of 16 years or older 
6. ECOG performance status ≤ 1 
7. Resolution of all acute adverse events resulting from prior cancer therapies to NCI 
CTCAE grade ≤ 1 or baseline (except alopecia or neuropathy) 
8. 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 14 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 
 INR from 0.8 to 1.2 
9. Woman of non-child bearing potential due to surgical sterilization (at least 6 weeks 
following surgical bilateral oophorectomy with or without hysterectomy or tubal ligation) 
confirmed by medical history or menopause (i.e., no menstrual bleeding for more than 12 
months in a woman aged 45 years or more), OR woman of child bearing potential who 
agrees to use at least two acceptable methods of birth control, one of which must be 


5.3.5.2 Clinical Protocol 
 
105GTN201 Protocol Amendment #3 
EudraCT 2015-005475-25 
 
20SEP2016 
Page 57 of 102 
highly effective during the study and for at least 180 days after stopping TRC105 or 
bevacizumab (refer to Section 2.3.1). Women that enter the study with a hCG > 100 IU/L 
and had maintained that level continuously after exclusion of pregnancy by a previous 
pelvic ultrasound are excluded from the birth control requirement unless their hCG 
decreases to ≤ 100 IU/L. 
10. Women of child bearing potential only: ultrasound of pelvis to exclude pregnancy at 
screening except women that enter the study with a hCG > 100 IU/L and had maintained 
that level continuously after exclusion of pregnancy by a previous pelvic ultrasound. 
5.2. 
Patient Exclusion Criteria   
1. Males are excluded from the study 
2. Prior treatment with TRC105 
3. Current treatment on another therapeutic clinical trial 
4. 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 < 150/90 mm 
Hg) 
5. Symptomatic pericardial effusion, pleural effusion, or ascites 
6. Active bleeding or pathologic condition that carries a high risk of bleeding (i.e. hereditary 
hemorrhagic telangiectasia) 
7. Tumors located in the central chest or other location where bleeding is associated with 
high morbidity 
8. Thrombolytic use (except to maintain i.v. catheters) within 10 days prior to first day of 
study therapy 
9. 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 
therapeutically anti-coagulated without the use of warfarin for at least 2 weeks.  In this 
situation, low molecular weight heparin is preferred. 
10. Known active viral or nonviral hepatitis 
11. Pregnant or actively breastfeeding without intention to discontinue prior to initiation of 
study 
12. Open wounds or unhealed fractures within 28 days of starting study treatment 
13. History of peptic ulcer disease or erosive gastritis within the past 6 months, unless treated 
for the condition and complete resolution has been documented by 
esophagogastroduodenoscopy (EGD) within 28 days of starting study treatment 
14. 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) 


5.3.5.2 Clinical Protocol 
 
105GTN201 Protocol Amendment #3 
EudraCT 2015-005475-25 
 
20SEP2016 
Page 58 of 102 
15. Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome 
(AIDS) related illness   
16. Other severe acute or chronic medical (including bone marrow suppressive diseases) or 
psychiatric condition or laboratory abnormality that may increase the risk associated with 
study participation or may interfere with the interpretation of study results and, in the 
judgment of the Investigator, would make the patient inappropriate for this study 
17. 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 brain edema for at least 28 
days. 
18. Receipt of systemic anticancer therapy, or any investigational agents, within 28 days of 
starting study treatment. If anticancer therapy was given within 28 days of starting study 
treatment, patients may be included if 5 times the elimination half-life of the drug has 
passed 
19. 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 cycle 1 day 1 or those patients who have not recovered adequately from side 
effects of such therapy 
20. Major surgical procedure or significant traumatic injury within 6 weeks prior to study 
registration, and or not 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. 
21. Patients with known hypersensitivity to the active substance or any of the excipients, or 
Chinese hamster ovary products or other recombinant human, chimeric, or humanized 
antibodies. 
22. Patients with active infection that requires systemic therapy. 
5.3. 
Patient Withdrawal Criteria 
Patients will 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, Table 5 and Table 6).  Patients will be 
followed for at least 28 days after the last dose of TRC105 or bevacizumab study drug for 
adverse events.  If a 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: 


5.3.5.2 Clinical Protocol 
 
105GTN201 Protocol Amendment #3 
EudraCT 2015-005475-25 
 
20SEP2016 
Page 59 of 102 
1. Disease Progression while receiving TRC105 and bevacizumab as combination therapy.   
2. There is a need for anticancer therapy not specified in the protocol including cancer 
surgery or radiation therapy. 
3. Lost to follow-up or noncompliant. 
4. Arterial thrombosis of any grade (including cerebrovascular ischemia, cardiac 
ischemia/infarction, or peripheral or visceral arterial ischemia) or grade 4 
thromboembolism. For grade 3 venous thromboembolism hold TRC105 and/or 
bevacizumab treatment.  If the planned duration of full dose anticoagulation is < 2 weeks, 
TRC105 and/or bevacizumab should be held until the full dose anticoagulation period is 
over.  If the planned duration of full dose anticoagulation is > 2 weeks, TRC105 and/or 
bevacizumab may be resumed during full dose anticoagulation IF all the following 
criteria are met.  1.  Subject does not have a pathologic condition that carries high risk of 
bleeding (i.e. tumor involving major vessels).  2.  Subject has not had any hemorrhagic 
events > grade 1 on study.  3.  The subject has a stable dose of heparin or a Factor X 
inhibitor or has an in-range INR (usually 2-3) on a stable dose of warfarin prior to 
restarting TRC105 and/or bevacizumab.  4.  If thromboembolism worsens/recurs upon 
resumption of TRC105 and/or bevacizumab, despite anticoagulation, study drugs 
(TRC105 and/or bevacizumab) should be discontinued. 
5. Missed study drug treatment (i.e., single agent TRC105, single agent bevacizumab or 
BOTH TRC105 and bevacizumab if dosing with the combination regimen) for > 8 
consecutive weeks without CR as defined in Section 7 OR discontinuation of study 
therapy (i.e., single agent TRC105, single agent bevacizumab or BOTH TRC105 and 
bevacizumab if dosing with the combination regimen) for > 6 months following CR. 
6. Pregnancy. Pregnant patients should be followed for the duration of the pregnancy and 
the outcome of the pregnancy should be documented. 
7. Discontinuation of bevacizumab treatment for other toxicities is at the discretion of the 
investigator, after considering the individual risk and benefit to the patient of continued 
treatment and per appropriate product labeling. 


5.3.5.2 Clinical Protocol 
 
105GTN201 Protocol Amendment #3 
EudraCT 2015-005475-25 
 
20SEP2016 
Page 60 of 102 
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.   
6.2. 
Composition of TRC105 
TRC105 is an IgG1, kappa immunoglobulin containing murine light- and heavy-chain variable 
region sequences and human constant region sequences.  TRC105 has an approximate molecular 
weight of 148 kDa.  
6.3. 
TRC105 Dose Level 
Patients will receive 10 mg/kg TRC105 weekly as a single-agent, or in combination with 5 
mg/kg bevacizumab every 2 weeks of each 28 day cycle. Patients who respond to TRC105 
monotherapy may receive 15 mg/kg TRC105 every two weeks as a single-agent (see 
Section 6.7.1). 
6.4. 
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 TRC105/4 mL single-use vial 
200 mg TRC105/8 mL single-use vial 
400 mg TRC105/16 mL single-use vial 
6.5. 
TRC105 Storage and Shipping 
TRC105 must be stored upright between 2 °C and 8 °C (36 °F to 46 °F) and protected from light. 
6.6. 
TRC105 Preparation 
TRC105 will be prepared in the pharmacy and diluted into normal saline using appropriate 
aseptic technique.  TRC105 will be administered using an in-line 0.2 micron filter.  No 
incompatibilities between TRC105 and polyvinyl chloride or polyolefin bags have been 
observed.  Multiple vials will be required for a single dose.  The following formulae should be 
used to calculate the volume of TRC105 to be added to normal saline: 
 Patient weight (kg) × dose level (mg/kg) divided by TRC105 concentration (mg/mL) 
= volume of TRC105 (mL) to be administered. 
The volume of TRC105 that is to be administered can be rounded up or down to the nearest 1.0 
mL; in the case of an increment of 0.5 mL the volume should be rounded up.  The maximum 
weight that should be used for dose calculation in this study is 85 kg (note: there is not a 
weight restriction for enrollment purposes).  Patient weight will be assessed at baseline and 


5.3.5.2 Clinical Protocol 
 
105GTN201 Protocol Amendment #3 
EudraCT 2015-005475-25 
 
20SEP2016 
Page 61 of 102 
used for calculation of each TRC105 dose, unless the patient’s weight changes by more than 
10% from baseline, in which case the patient’s weight on the day of treatment will be used for 
calculation of each TRC105 dose. The calculated volume of TRC105 will be diluted with normal 
saline.  Appropriate judgment should be exercised in withdrawing an adequate amount of saline 
necessary to permit injection of the appropriate volume of antibody into a normal saline bag in 
accordance with the dose needed.  The final TRC105 concentration must be between 0.6 mg/mL 
and 10 mg/mL.  The prepared TRC105 must be gently inverted several times in order to ensure a 
homogeneous solution. The diluted infusion solution of TRC105 should be used within 8 hours 
of preparation if stored at room temperature, or within 24 hours of dilution if stored at 2° to 8°C 
(36º to 46ºF). The expiration time should be labeled on the bag.  If the diluted infusion solution 
of TRC105 cannot be infused within 8 hours of preparation (i.e.: the prepared infusion is at room 
temperature for more than 8 hours), a second bag will be prepared that contains the balance of 
the planned dose that was not already delivered. The prepared solution should not be frozen. 
6.7. 
TRC105 Administration 
Patients should be encouraged to drink abundant fluid [e.g. two eight ounce (237 mL) 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 if a patient is thought to be 
volume depleted. 
The following TRC105 premedications should be administered 2 hours to 30 minutes prior to the 
start of each infusion:   
 Acetaminophen at a dose of 500 mg to 1000 mg (e.g., 650 mg) x 1  
 Methylprednisolone 100 mg i.v. (or dexamethasone 20 mg i.v.) will be given prior to 
the Cycle 1 Day 1 and Cycle 1 Day 4 infusions only.  In addition, 
methylprednisolone (or dexamethasone) will be given in the case of a delay of ≥ 
10 days between any two scheduled weekly doses, a delay of ≥ 17 days between 
any two scheduled every other week doses, or if a patient develops an infusion 
reaction > grade 2 during the immediate prior infusion.  
 Famotidine 20 mg i.v. or p.o. (or similar H2 blocker) x 1. Famotidine (or similar H2 
blocker) may be discontinued starting with Cycle 2 in the absence of infusion 
reactions with the prior dose. 
 Cetirizine 10 mg i.v. or p.o. x 1 (or similar oral or intravenous antihistamine). 
Cetirizine (or similar oral or intravenous antihistimine) may be discontinued starting 
with Cycle 2 in the absence of infusion reactions with the prior dose. 
TRC105 premedication, including the methylprednisolone (or dexamethasone) infusion, 
should be administered 2 hours to 30 minutes prior to initiating TRC105 infusions. 
On days of combination dosing with TRC105 and bevacizumab, there will be at least 60 minutes 
between the completion of the bevacizumab infusion and the initiation of the TRC105 infusion. 
TRC105 premedication will be administered after the completion of the bevacizumab infusion 
but at least 30 minutes prior to initiation of the TRC105 infusion.  In addition, 
methylprednisolone or dexamethasone will be administered at least 30 minutes following the 
completion of the bevacizumab infusion. 


5.3.5.2 Clinical Protocol 
 
105GTN201 Protocol Amendment #3 
EudraCT 2015-005475-25 
 
20SEP2016 
Page 62 of 102 
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 a patient will be performed as per standard study site 
procedures.  
Following the appropriate premedication regimen, patients will receive TRC105 on days 1, 4, 8, 
15, and 22 of cycle 1 and on days 1, 8, 15, and 22 of subsequent cycles. The first weekly dose of 
TRC105 will be split with 3 mg/kg administered on cycle 1 day 1 and infused over 4 hours (+/- 
15 minutes) and 7 mg/kg administered on cycle 1 day 4 and infused over 2 hours (+/- 15 
minutes), and then the full dose of 10 mg/kg given on cycle 1 day 8 and weekly thereafter and 
will be administered over 1 hour (+/- 15 minutes).  Patients must complete at least one 4 hour 
infusion (+/- 15 minutes) 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 (+/- 
15 minutes) without the development of any infusion reactions in order to reduce subsequent 
TRC105 infusions to 1 hour (+/- 15 minutes).  If a patient develops infusion reactions of any 
kind they should be managed appropriately (see Section 6.7.3) and the patient is not permitted to 
reduce the duration of the next planned infusion.  
Initially, TRC105 will be administered weekly: 10 mg/kg TRC105 on days 1, 8, 15, and 22 of 
each 28-day cycle, with split dosing on days 1 and 4 of cycle 1.  Patients who achieve CR on 
single-agent TRC105 and have received at least 2 cycles of weekly TRC105 may transition to 
TRC105 15 mg/kg administered every two weeks (see Section 6.7.1).  Note: patients receiving 
TRC105 in combination with bevacizumab will be dosed with TRC105 weekly.  Refer to Section 
4.1.1 for the sequential treatment algorithm and efficacy definitions. 
If a patient misses a TRC105 dose and dosing is resumed ≥ 10 days after the previous infusion, 
the first weekly dose will be split over two days with full premedication, including 
methylprednisolone (or dexamethasone), with 3 mg/kg administered on the first day of dosing 
and 7 mg/kg administered 3 days later, and then the full dose of 10 mg/kg given weekly 
thereafter.  Premedication will also be given if a patient develops an infusion reaction > grade 2 
during the immediate prior infusion. If a patient achieves complete response they will be treated 
with at least 3 consolidation cycles of therapy that produced the response (single agent TRC105, 
single agent bevacizumab, or combination of TRC105 + bevacizumab). 
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 at least 20 mL of 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. 
 
 


5.3.5.2 Clinical Protocol 
 
105GTN201 Protocol Amendment #3 
EudraCT 2015-005475-25 
 
20SEP2016 
Page 63 of 102 
Table 7: 
Ideal Cycle 1 TRC105 Dosing Schema 
C1D1 
C1D4 
C1D8 
C1D15 
C1D22 
C2D1+ 
TRC105 Dose: 
     10 mg/kg weeklya 
3 mg/kg 
7 mg/kg 
10 mg/kg 
10 mg/kg 
 
 
10 mg/kg 
 
 
10 mg/kg 
Infusion Duration 
4 hrs 
2 hrs 
1 hr 
1 hr 
 
1 hr 
 
1 hr 
Premedicationb 
 
Methylprednisoloned 
100 mg i.v. 
100 mg i.v. 
Nonec 
None 
None 
 
None 
Famotidine (or similar 
H2 blocker) 
20 mg 
i.v. or p.o. 
20 mg 
i.v. or p.o. 
20 mg 
i.v. or p.o. 
20 mg 
i.v. or p.o. 
20 mg 
i.v. or p.o. 
 
Nonec 
Cetirizine (or similar 
antihistamine) 
10 mg 
i.v. or p.o. 
10 mg 
i.v. or p.o. 
10 mg 
i.v. or p.o. 
10 mg 
i.v. or p.o. 
10 mg 
i.v. or p.o. 
 
Nonec 
Acetaminophen 
500 - 1000 
mg 
500 - 1000 
mg 
500 - 1000 
mg 
500 - 1000 
mg 
500 - 1000 
mg 
500 - 1000 
mg 
aIf a patient misses a TRC105 dose and dosing is resumed ≥ 10 days after the last infusion, the first weekly TRC105 
dose should be administered over two days as was done for the initial dose. 
bPremedication will be given in the case of a delay of  ≥ 10 days between any two doses or if a patient develops an 
infusion reaction > grade 2 during the immediate prior infusion.  
cMay be discontinued in the absence of infusion reaction with the prior dose (starting with Cycle 2 for famotidine 
and cetirizine). 
dDexamethasone (20 mg i.v.) may be substituted for methylprednisolone. 
6.7.1. 
TRC105 15 mg/kg Every 2 Week Dosing 
Patients who achieve CR on single-agent TRC105 and have received at least 2 cycles of weekly 
TRC105 may transition to TRC105 15 mg/kg administered every two weeks. The first 
administration of TRC105 at 15 mg/kg does not need to be split over two days unless there has 
been delay of ≥ 10 days since the last weekly infusion. In this case, TRC105 will be 
administered over two days with 3 mg/kg administered on day 1 and 12 mg/kg on day 4 and 
premedication will be given as outlined for C1D1 and C1D4 in the Ideal Cycle 1 TRC105 
Dosing Schema table above. 
The first non-split dose of TRC105 at 15 mg/kg will be infused over 90 minutes (+/- 15 minutes) 
and the second non-split dose will be infused over 60 minutes (+/- 15 minutes) with full 
premedication, including methylprednisolone (or dexamethasone), given 2 hours to 30 minutes 
prior to the start of infusion as described above. Premedication (except acetaminophen) may be 
discontinued in the absence of infusion reaction for subsequent doses of TRC105 at 15 mg/kg 
and infused over 60 minutes (+/- 15 minutes). If the administration of the first non-split dose of 
TRC105 at 15 mg/kg is after a split dose of TRC105 15 mg/kg was given, the infusion time can 
be decreased to 60 minutes (+/- 15 minutes) for this first dose as long as there was no infusion 
reaction with the prior dose.  
If a patient misses a TRC105 dose and dosing is resumed ≥ 17 days after the last every two week 
infusion, the first TRC105 dose should be administered over two days with full premedication, 
including methylprednisolone (or dexamethasone). Premedication will also be given if a patient 
develops an infusion reaction > grade 2 during the immediate prior infusion. 


5.3.5.2 Clinical Protocol 
 
105GTN201 Protocol Amendment #3 
EudraCT 2015-005475-25 
 
20SEP2016 
Page 64 of 102 
Table 8: 
Ideal Monotherapy TRC105 15 mg/kg Dosing Schema 
C3D1 
C3D15 
C4D1 
C4D15 
C5D1+ 
TRC105 Dose: 
     15 mg/kg every 2 weeksa 
15 mg/kg 
15 mg/kg 
15 mg/kg 
15 mg/kg 
 
15 mg/kg 
Infusion Duration 
1.5 hrs 
1 hr 
1 hr 
1 hr 
 
1 hr 
Premedicationb 
 
Methylprednisoloned 
100 mg i.v. 
100 mg i.v. 
Nonec 
None 
None 
Famotidine 
(or similar H2 blocker) 
20 mg 
i.v. or p.o. 
20 mg 
i.v. or p.o. 
Nonec 
None 
None 
Cetirizine 
(or similar antihistamine) 
10 mg 
i.v. or p.o. 
10 mg 
i.v. or p.o. 
Nonec 
None 
None 
Acetaminophen 
500 mg - 
1000 mg 
500 mg - 
1000 mg 
500 mg - 
1000 mg 
500 mg - 
1000 mg 
500 mg - 
1000 mg 
aIf a patient misses an every 2 week TRC105 dose and dosing is resumed ≥ 17 days after the last infusion, the dose 
should be administered over two days (3 mg/kg on the first day and the balance three days later). 
bPremedication will be given in the case of a delay of  ≥ 17 days between any two doses or if a patient develops an 
infusion reaction > grade 2 during the immediate prior infusion.  
cMay be discontinued in the absence of infusion reaction with the prior dose (starting with Cycle 4 for famotidine 
and cetirizine). 
dDexamethasone (20 mg i.v.) may be substituted for methylprednisolone. 
6.7.2. 
TRC105 Dose Modification/Dose Interruptions 
TRC105 dose reductions are allowed for grade 3 or 4 related adverse events that resolve to grade 
1 or baseline (including anemia).  Treatment dose delays cannot exceed 8 consecutive weeks 
(i.e., either TRC105 or bevacizumab as single agents or in combination). However, patients with 
a complete response may remain off therapy for a maximum of 6 months following consolidation 
therapy.  Following treatment on the combination portion of the study, if a patient cannot tolerate 
bevacizumab or TRC105 therapy and demonstrates a response of complete response (CR), 
partial response (PR) or stable disease (SD) with the combination, and is thought to benefit from 
continued single agent therapy, the patient may continue on study on TRC105 or bevacizumab 
alone.   
TRC105 should be held for two weeks prior to and for two weeks following surgical procedures.  
However, resumption of study treatment can be shorter (but no less than 7 days) or longer than 
two weeks based on clinical judgement of adequate wound healing and recovery from the 
procedure.   
 


5.3.5.2 Clinical Protocol 
 
105GTN201 Protocol Amendment #3 
EudraCT 2015-005475-25 
 
20SEP2016 
Page 65 of 102 
Table 9: Allowable TRC105 Dose Modifications 
Toxicity Attributed to 
TRC105 
Dose Adjustment for Next Dose of TRC105 
Dose Schedule 
10 mg/kg weekly 
15 mg/kg every 2 weeks 
Grade 1 or 2 
Maintain Dose Level 
Maintain Dose Level 
Grade 3 or 4 
 
 
1st appearance 
8 mg/kg weekly 
12 mg/kg every 2 weeksa 
 
2nd appearance 
6 mg/kg weekly 
10 mg/kg every 2 weeksa 
 
3rd appearance 
4 mg/kg weekly 
8 mg/kg every 2 weeksa 
 
4th appearance 
Discontinue treatment permanently 
Discontinue treatment permanentlya 
aAfter discussion with and agreement of the Sponsor, patients receiving TRC105 every two weeks have the option 
to return to weekly dosing if dosing every 2 weeks is not tolerable (i.e., 4th appearance of a Grade 3 or 4 toxicity 
attributable to TRC105 occurs) and the investigator believes that the patient is receiving benefit from the 
treatment.  
Note: if a patient is dose reduced and subsequently misses a dose, the first dose of TRC105 following the break 
needs to be split into two doses, 3 mg/kg should be given on the first day and the remainder of the dose (i.e., 5 
mg/kg in the case of a dose reduction to 8 mg/kg) will be given 3 days later. 
TRC105 (and bevacizumab) will be discontinued for arterial thrombosis of any grade (including 
cerebrovascular ischemia, cardiac ischemia/infarction, or peripheral or visceral arterial ischemia) 
or grade 4 thromboembolism. For grade 3 venous thromboembolism hold TRC105 and 
bevacizumab treatment.  If the planned duration of full dose anticoagulation is < 2 weeks, 
TRC105 and/or bevacizumab should be held until the full dose anticoagulation period is over.  If 
the planned duration of full dose anticoagulation is > 2 weeks, TRC105 and/or bevacizumab may 
be resumed during full dose anticoagulation IF all the following criteria are met:  1.  Subject does 
not have a pathologic condition that carries high risk of bleeding (i.e. tumor involving major 
vessels);  2.  Subject has not had any hemorrhagic events > grade 1 on study; 3.  The subject has 
a stable dose of heparin or a Factor X inhibitor or has an in-range INR (usually 2-3) on a stable 
dose of warfarin prior to restarting TRC105 and/or bevacizumab.  If thromboembolism 
worsens/recurs upon resumption of TRC105 and/or bevacizumab, despite anticoagulation, study 
drugs (TRC105 and/or bevacizumab) should be discontinued. 
6.7.3. 
Management of TRC105 Infusion Reactions 
If patients experience grade 2 or higher adverse reaction during infusion, the infusion should be 
interrupted and 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 patients 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.   


5.3.5.2 Clinical Protocol 
 
105GTN201 Protocol Amendment #3 
EudraCT 2015-005475-25 
 
20SEP2016 
Page 66 of 102 
Table 10: 
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). 
6.7.4. 
TRC105 Study Drug Accountability 
The Investigator must maintain an accurate accounting of TRC105 supplied by TRACON.  
During the study, the following information must be recorded: 
 Date of receipt, quantity and lot number of the TRC105 study drug received from 
TRACON 
 ID number of the patient to whom the product is dispensed 
 The date(s) and quantity of the product dispensed 
 Dates and quantity of product returned, lost or accidentally or deliberately destroyed 
Investigational Drug Accountability Logs should be maintained by the site and must be readily 
available for inspection. 
6.7.5. 
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 


5.3.5.2 Clinical Protocol 
 
105GTN201 Protocol Amendment #3 
EudraCT 2015-005475-25 
 
20SEP2016 
Page 67 of 102 
TRACON.  Disposal of TRC105 should occur in accordance with institutional policy. The Site 
Pharmacist will be responsible for documenting the destruction (according to country-
specific/institutional requirements) of used or expired vials. 
6.8. 
Bevacizumab Packaging 
Bevacizumab is available as 100 mg pack containing one 4 mL single-dose vial and 400 mg pack 
containing one 16 mL single-dose vial.  
6.9. 
Bevacizumab Preparation 
Patients will receive 5 mg/kg every 2 weeks for each 28-day cycle.  Bevacizumab should be 
prepared according to the appropriate product labeling and institutional policy and using aseptic 
technique.  Withdraw the necessary amount of bevacizumab and dilute to the required 
administration volume with 0.9% sodium chloride solution.  The concentration of the final 
bevacizumab solution should be kept within the range of 1.4-16.5 mg/mL as described in the 
Avastin product labeling (Section 20).  
6.10. 
Bevacizumab Administration 
In the case of a sustained partial response (see Section 7) without continued improvement 
following treatment with single-agent TRC105, the patient will receive bevacizumab in addition 
to TRC105. In the absence of a partial or complete response to single agent TRC105, the patient 
will be receive single agent bevacizumab.  Single agent bevacizumab should be initiated 2 weeks 
following discontinuation of single agent TRC105 (i.e., patients should wash out for 2 weeks 
prior to starting bevacizumab therapy). No washout is required for initiation of combination 
therapy. Bevacizumab will be administered at 5 mg/kg every 2 weeks for each 28-day cycle in 
all cases. Bevacizumab will be administered according to the appropriate product labeling 
and on days of combination dosing, there will be at least 60 minutes between the 
completion of the bevacizumab infusion and the initiation of the TRC105 infusion. 
6.10.1. 
Bevacizumab Dose Modification 
Dose reduction of bevacizumab for adverse reactions is not recommended.  If indicated, 
bevacizumab should either be discontinued or temporarily suspended, see the current applicable 
product labeling for bevacizumab for specific information related to different adverse events. 
However, following treatment on the combination portion of the study, if a patient cannot 
tolerate bevacizumab or TRC105 therapy, demonstrates a response of complete response (CR), 
partial response (PR) or stable disease (SD) with the combination and is thought to benefit from 
continued single agent therapy, patients may continue on study on TRC105 or bevacizumab 
alone.   
Bevacizumab and TRC105 will be discontinued for arterial thrombosis of any grade (including 
cerebrovascular ischemia, cardiac ischemia/infarction, or peripheral or visceral arterial ischemia) 
or grade 4 thromboembolism. For grade 3 venous thromboembolism hold TRC105 and 
bevacizumab treatment.  If the planned duration of full dose anticoagulation is < 2 weeks, 
TRC105 and/or bevacizumab should be held until the full dose anticoagulation period is over.  If 
the planned duration of full dose anticoagulation is > 2 weeks, TRC105 and/or bevacizumab may 
be resumed during full dose anticoagulation IF all the following criteria are met:   


5.3.5.2 Clinical Protocol 
 
105GTN201 Protocol Amendment #3 
EudraCT 2015-005475-25 
 
20SEP2016 
Page 68 of 102 
1. Subject does not have a pathologic condition that carries high risk of bleeding (i.e. tumor 
involving major vessels);   
2. Subject has not had any hemorrhagic events > grade 1 on study;  
3. The subject has a stable dose of heparin or a Factor X inhibitor or has an in-range INR 
(usually 2-3) on a stable dose of warfarin prior to restarting TRC105 and/or bevacizumab.  
If thromboembolism worsens/recurs upon resumption of TRC105 and/or bevacizumab, 
despite anticoagulation, study drugs (TRC105 and/or bevacizumab) should be 
discontinued.  
6.11. 
Bevacizumab Drug Accountability 
The Investigator must maintain an accurate accounting of bevacizumab.  During the study, the 
following information must be recorded: 
 ID number of the patient to whom the product is dispensed 
 The date(s), quantity, and lot number(s) 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. 
6.12. 
Bevacizumab Handling and Disposal 
Bevacizumab vials [100 mg (NDC 50242-060-01) and 400 mg (NDC 50242-061-01)] are stable 
at 2−8°C (36−46°F). Bevacizumab vials should be protected from light. Do not freeze or shake. 
Diluted bevacizumab solutions may be stored at 2−8°C (36−46°F) for up to 8 hours. 
Bevacizumab vials should be stored in their original carton until time of use. No 
incompatibilities between bevacizumab and polyvinylchloride or polyolefin bags have been 
observed. Partially used vials should be properly destroyed according to institution guidelines.  
6.13. 
Concomitant Medications 
No other approved or investigational anticancer treatment will be permitted during the study 
period, including chemotherapy, biological response modifiers, immunotherapy, or radiotherapy.   
Low dose aspirin may be used if medically indicated. Patients who receive NSAIDs on study 
should also receive peptic ulcer disease (PUD) prophylaxis with an H2 or proton pump inhibitor. 
Narcotic analgesics, nonsteroidals, anti-inflammatory drugs, and triptans (e.g. sumatriptan) may 
be offered as needed for relief of pain or headaches.  Triptans are recommended for patients who 
experience a migraine headache following dosing, and may be taken prior to the occurrence of 
headache, as a prophylactic medication.  Antihistamines and decongestants may be offered for 
the treatment of sinus congestion. 
Packed red blood cell, colony stimulating factors, and platelet transfusions should be 
administered as clinically indicated.   


5.3.5.2 Clinical Protocol 
 
105GTN201 Protocol Amendment #3 
EudraCT 2015-005475-25 
 
20SEP2016 
Page 69 of 102 
6.14. 
Treatment Compliance 
6.14.1. 
TRC105 
All TRC105 infusions will occur at the trial site under the direct supervision of the treating 
physician or his or her designee.  
6.14.2. 
Bevacizumab 
All bevacizumab infusions will occur at the trial site under the direct supervision of the treating 
physician or his or her designee. 
6.15. 
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 site binder will be provided and will include detailed instructions for 
the manual enrollment process.  


5.3.5.2 Clinical Protocol 
 
105GTN201 Protocol Amendment #3 
EudraCT 2015-005475-25 
 
20SEP2016 
Page 70 of 102 
7. 
ASSESSMENT OF EFFICACY  
7.1. 
Assessment of Efficacy by Serum hCG 
Treatment decisions will be made based on central lab serum hCG results.  Tumor Response by 
serum hCG measurement results will be defined as follows: 
 Complete response (CR) is defined as normalization of serum hCG on two 
consecutive measurements separated by at least two weeks 
 Partial response (PR) is defined as > 50% decrease of serum hCG from starting 
value on consecutive measurements separated by at least two weeks. (A change in 
study treatment should be made for a sustained partial response without evidence of 
continued disease improvement over 4 consecutive weekly hCG measurements after 
partial response is confirmed for patients on single agent TRC105 or single agent 
bevacizumab.) 
 Progressive disease (PD) is defined as a rise in hCG of >20% (the absolute increase 
must be ≥10 IU/L) above nadir on consecutive measurements separated by at least 
two weeks 
 Stable disease (SD) is defined as absence of response or progression on three 
consecutive hCG measurements separated by at least two weeks 
7.2. 
Radiologic Tumor Assessment  
Radiologic assessment of Target and Non-target lesions will be done by RECIST version 1.1, 
based on objective tumor assessments made by the Investigator.  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, Table 5 and Table 6), and whenever disease progression is suspected in 
patients with measurable disease.  Another tumor assessment will be performed at the End of 
Study Visit if an assessment has not been performed within the prior 7 days.   
Measurability of Tumor Lesions 
At Screening, individual tumor lesions will be categorized by the Investigator as either target or 
non-target according to the RECIST 1.1 criteria described below. 


5.3.5.2 Clinical Protocol 
 
105GTN201 Protocol Amendment #3 
EudraCT 2015-005475-25 
 
20SEP2016 
Page 71 of 102 
 Measurable:  Lesions that can be accurately measured in at least one dimension 
(longest diameter to be recorded) as ≥ 10 mm with spiral CT scan.  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, 
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, and disease documented by indirect 
evidence only (e.g. by laboratory tests such as alkaline phosphatase).  
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.   
7.2.1. 
Definitions of Tumor Response by RECIST 1.1 
7.2.1.1  
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. (A change in 
study treatment should be made for a sustained partial response without evidence of 
continued disease improvement at the subsequent imaging evaluation after partial 
response is confirmed for patients on single agent TRC105 or single agent 
bevacizumab.) 
 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 radiographic 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. 


5.3.5.2 Clinical Protocol 
 
105GTN201 Protocol Amendment #3 
EudraCT 2015-005475-25 
 
20SEP2016 
Page 72 of 102 
7.2.1.2  
Non-Target Lesions 
 Complete response (CR) is defined as the disappearance of all non-target lesions and 
normalization of tumor marker levels to ≤ ULN. 
 Non-CR/non-PD is defined as a persistence of ≥ 1 non-target lesions and/or 
maintenance of tumor marker levels > ULN. 
 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. 
7.2.2. 
Determination of Overall Response by RECIST 1.1 
Assessment of efficacy by RECIST 1.1 is an exploratory endpoint in patients with 
choriocarcinoma and measurable disease.  When both target and non-target lesions are present, 
individual assessments will be recorded separately.  The overall assessment of response will 
involve all parameters as depicted in Table 11 below. 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 11: 
Response Evaluation Criteria in Solid Tumors 
Target Lesionsa 
Non-target Lesionsb 
New Lesionsc 
Overall Response 
CR 
CR 
No 
CR 
CR 
non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all 
evaluated 
No 
PR 
SD 
Non-PD or not all 
evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
Not Evaluable 
PD 
Any Response 
Yes or No 
PD 
Any Response 
PD 
Yes or No 
PD 
Any Response 
Any Response 
Yes 
PD 
aMeasurable lesions only. 
bMay include measurable lesions not followed as target lesions or non-measurable lesions. 
cMeasurable or nonmeasurable lesions.  


5.3.5.2 Clinical Protocol 
 
105GTN201 Protocol Amendment #3 
EudraCT 2015-005475-25 
 
20SEP2016 
Page 73 of 102 
7.3. 
Determination of Best Overall Response by Histology 
7.3.1. 
Determination of Best Overall Response in Patients with Choriocarcinoma 
In patients with choriocarcinoma, determination of antitumor efficacy will be based solely on 
serum hCG measurement (per Section 7.1) and investigators will make treatment decisions based 
on this assessment. Patients with choriocarcinoma and measurable disease will also undergo 
radiologic assessment by RECIST 1.1 as an exploratory endpoint (per Section 7.2). 
7.3.2. 
Determination of Best Overall Response in Patients with PSTT and ETT 
Best Overall Response in Patients with PSTT and ETT will be determined per Table 12 using 
radiologic assessments and hCG. In cases where hCG is within the normal range at baseline, 
efficacy will be determined using RECIST (Table 11). In cases where hCG is elevated and no 
lesion can be measured, patients will be assessed without employing target lesion criteria (i.e., 
radiographic lesions will be considered exclusively as non-target lesions). 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 12 below. As is the case 
in RECIST 1.1 guidelines, a modest increase in the size of one or more non-target lesions is 
usually not sufficient to qualify for unequivocal progression status. 
Table 12: 
Best overall response in PSTT and ETT patients with measurable disease 
and who are also evaluable by hCG 
Target 
Lesiona 
Nontargetb 
New Lesion 
hCG 
Overall Best 
Response 
 
 
Best RECIST 
1.1 response 
for CR and PR 
also requires it 
to be 
confirmed and 
maintained for 
at least 28 
days 
CR 
CR 
No 
Normal 
CR 
CR 
Non-CR Non-
PD 
No 
Not PD 
PR 
CR 
CR 
No  
PR but not 
normal 
PR 
CR 
NE 
No 
PR 
PR 
PR 
Non-PD or 
NAE 
No  
Not PD 
PR 
NAE 
Non-PD 
No 
PR 
PR 
PD or New >28 days from hCG PRc 
PR 
PR 
SDd 
Non-PD 
No  
PR 
PR 
SDd 
Non-PD or 
NAE 
No 
Not PR and 
not PD 
SD 
PD or New ≤28 days from hCG PRc 
PR 
PD 
PD 
Any 
Yes or No 
Any 
PD 
Any 
PD 
Yes or No 
Any 
PD 
Any 
Any 
Yes 
Any 
PD 
Any 
Any 
Yes or No 
PD 
PD 
aTarget lesions include up to 5 measurable lesions (2 per organ) as defined by RECIST 1.1. 
bNontarget lesions include ascites and peritoneal thickening which are not measurable according to RECIST 1.1. 
cPatients who have a hCG response that occurs more than 28 days from PD according to RECIST 1.1 are considered 
a PR, according to best response, but PD if the RECIST 1.1 PD is within 28 days of hCG response. 
dThe protocol should specify the minimum time interval between 2 measurements for classification as stable disease. 
NE, Not evaluated; NAE, not all evaluated. 


5.3.5.2 Clinical Protocol 
 
105GTN201 Protocol Amendment #3 
EudraCT 2015-005475-25 
 
20SEP2016 
Page 74 of 102 
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).  Each patient’s radiographic 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 
“symptomatic deterioration.”  Every effort should be made to document the objective 
progression even after discontinuation of treatment.     


5.3.5.2 Clinical Protocol 
 
105GTN201 Protocol Amendment #3 
EudraCT 2015-005475-25 
 
20SEP2016 
Page 75 of 102 
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, and coagulation 
profile.  In addition, an ECG will be recorded at baseline and as clinically indicated throughout 
the study.   
8.1.1. 
Laboratory Safety Assessments 
Abnormal and clinically significant laboratory tests should be recorded as adverse events.  
8.1.1.1. 
Hematology, Serum Chemistry, Coagulation  
Assessments will be performed at the time points indicated in the Schedule of Assessments 
(Table 4, Table 5 and Table 6) 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: Prothrombin Time (PT) or Internalized Normalized Ration (INR) will 
be assessed 
 Serum Chemistry: Total bilirubin, alanine transaminase (ALT), aspartate 
transaminase (AST), alkaline phosphatase, lipase, amylase, total protein, albumin, 
sodium, potassium, bicarbonate, chloride, calcium, phosphorus, blood urea nitrogen, 
creatinine, thyroid stimulating hormone (TSH), and glucose 
8.1.1.2. 
Urinalysis  
Urine analysis will be performed at time points indicated in the Schedule of Assessments 
(Table 4, Table 5 and Table 6) and analyzed by local laboratories. Microscopic analysis and/or 
urine protein-creatinine ratio (UPCR) should be performed as clinically indicated. 
8.1.2. 
Other Safety Assessments 
8.1.2.1. 
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, Table 5 and Table 6).  The 
physical examination will include examination of known and suspected sites of disease.   


5.3.5.2 Clinical Protocol 
 
105GTN201 Protocol Amendment #3 
EudraCT 2015-005475-25 
 
20SEP2016 
Page 76 of 102 
8.1.2.2. 
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, Table 5 and Table 6). Assessment 
of vital signs during TRC105 infusion: Vital signs are to be assessed pre-infusion and every 30 
minutes during 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).  
8.1.2.3. 
Performance Status  
The ECOG scale will be used to assess performance status at Screening.  
8.1.2.4. 
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 according to the Schedule of Assessments (Table 4, Table 5 and Table 6) 
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 and/or bevacizumab 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:  
 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). 
 Signs and symptoms resulting from drug overdose, abuse, misuse, withdrawal, 
sensitivity, dependency, interaction or toxicity.   
 All possibly related and unrelated illnesses, including the worsening of a 
preexisting illness.  
 Injury or accidents.  Note that if a medical condition is known to have caused the 
injury or accident (hip fracture from a fall secondary to dizziness), the medical 
condition (dizziness) and the outcome of the accident (hip fracture from a fall) 
should be reported as 2 separate adverse events.   
 Symptoms or signs resulting from exposure in utero. 


5.3.5.2 Clinical Protocol 
 
105GTN201 Protocol Amendment #3 
EudraCT 2015-005475-25 
 
20SEP2016 
Page 77 of 102 
 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.): 
 Test result that is associated with accompanying symptoms 
 Test result that requires additional diagnostic testing or medical/surgical 
intervention 
 Test result that leads to a change in TRC105 study drug dosing not stipulated in 
the protocol, or discontinuation from the trial, significant additional concomitant 
drug treatment, or other therapy 
 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 (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 serious adverse events unless the outcome is fatal during the trial or 
within the safety reporting period. Hospitalizations due to signs and symptoms of disease 
progression should not be reported as serious adverse events.  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 a serious adverse event with CTC grade 5.  


5.3.5.2 Clinical Protocol 
 
105GTN201 Protocol Amendment #3 
EudraCT 2015-005475-25 
 
20SEP2016 
Page 78 of 102 
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 
 Same day surgery 
 Hospitalization or prolongation of hospitalization in the absence of precipitating 
clinical adverse events as follows: 
 Admission for treatment of preexisting condition not associated  with the 
development of a new adverse event or with a worsening of the preexisting 
condition  
 Social admission 
 Administrative admission (e.g. for yearly physical exam) 
 Protocol-specified admission during a clinical trial 
 Optional admission not associated with a precipitating clinical adverse event (e.g. 
for elective cosmetic surgery) 
 Preplanned treatments or surgical procedures 
 Admission exclusively for the administration of blood products 
 Diagnostic and therapeutic noninvasive and invasive procedures, such as surgery, 
should not be reported as adverse events.  The medical condition for which the 
procedure was performed should be reported if it meets the definition of an adverse 
event (e.g. acute appendicitis that begins during the adverse event reporting period 
should be reported as an adverse event and the appendectomy should be recorded as a 
concomitant treatment). 


5.3.5.2 Clinical Protocol 
 
105GTN201 Protocol Amendment #3 
EudraCT 2015-005475-25 
 
20SEP2016 
Page 79 of 102 
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 will be considered "baseline-signs 
and symptoms” and will be recorded on “Medical History and Baseline Signs and Symptoms” 
case report forms. The adverse event reporting period for this trial begins when the patient has 
taken the first dose of bevacizumab and/or TRC105 study drug and ends 28 days after the last 
dose of bevacizumab and/or TRC105 study drug is administered, whichever is later. 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 a 
serious adverse event 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, and under no circumstances should this exceed 24 hours 
following knowledge of an SAE or of a change in an event that renders it reportable.  This 
notification should be made to: 
Primary Medical Monitor 
Richard Yocum, MD 
TRACON Pharmaceuticals, Inc. 
8910 University Center Lane, Suite 700 
San Diego, California 92122 
Office Phone:  1.858.550.0780 x230 
Cell Phone:  1.858.229.8585 
Email: ryocum@traconpharma.com  
 
Secondary Medical Monitor 
Charles Theuer, MD, PhD 
TRACON Pharmaceuticals, Inc. 
8910 University Center Lane, Suite 700 


5.3.5.2 Clinical Protocol 
 
105GTN201 Protocol Amendment #3 
EudraCT 2015-005475-25 
 
20SEP2016 
Page 80 of 102 
San Diego, California 92122 
Office Phone:  1.858.550.0780 x233 
Cell Phone:  1.858.344.9400 
Email: ctheuer@traconpharma.com  
 
Following this notification, the Investigator will report the SAE via the AE CRF via the data 
management system.  The initial AE CRF is to be updated with followed more detailed adverse 
event information within 5 calendar days of the event. 
In the rare event that the Investigator does not become aware of the occurrence of a serious 
adverse event immediately (for example, if a patient initially seeks treatment elsewhere), the 
Investigator is to report the event immediately upon learning of it (within 24 hours) and 
document his/her first awareness of the serious adverse event. 
TRACON Pharmaceuticals Inc. may also be contacted via telephone 24 hours a day at +1 (858) 
229-8585. 
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 TRC105 will be reported 
to the US Food and Drug Administration (FDA), Competent Authorities and Ethics Committees 
in other countries taking part in the study, as well as all participating clinical sites in all 
countries.  Investigators should report to their local IEC/IRB as dictated by their board’s policies 
and procedures.  For events which are fatal or life-threatening, unexpected, and associated with 
use of the investigational product, a 7-day Alert Report will be submitted to the regulatory 
authorities within 7 calendar days of receipt of the SAE information.  For all other events that are 
serious, unexpected, and associated with use of TRC105, 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. 
Investigative sites are responsible for bevacizumab safety reporting to the manufacturer.   
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.  
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.   


5.3.5.2 Clinical Protocol 
 
105GTN201 Protocol Amendment #3 
EudraCT 2015-005475-25 
 
20SEP2016 
Page 81 of 102 
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 
CTCAE 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 13: 
Adverse Event Grading 
Grade 
Non-CTCAE Severity 
Definition 
1 
Mild  
Does not interfere with patient’s usual function 
2 
Moderate 
Interferes to some extent with patient’s usual function 
3 
Severe 
Interferes significantly with patient’s usual function 
4 
Life-Threatening 
Results in immediate risk of patient’s death 
5 
Fatal 
Results in patient’s death 
Note the distinction between the severity and the seriousness of an 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 
In this study, TRC105 study drug is given in combination with bevacizumab.  The relationship of 
an adverse event to TRC105 study drug and bevacizumab should be classified by the Investigator 
using the following guidelines: 
 Suspected Adverse Reaction to TRC105: There is a reasonable possibility that 
TRC105 caused the adverse event (i.e.: there is evidence to suggest a causal 
relationship between TRC105 and the adverse event). 
 Suspected Adverse Reaction to bevacizumab: There is a reasonable possibility that 
bevacizumab caused the adverse event (i.e., there is evidence to suggest a causal 
relationship between bevacizumab and the adverse event). 
 Not related: there is no reasonable possibility that the adverse event is associated with 
TRC105 study drug or bevacizumab.  
AEs may be related to both drugs.  AEs related to TRC105 study drug or bevacizumab are 
considered Adverse Drug Reactions (ADR). 
8.3.7. 
Expectedness  
All adverse events and adverse drug reactions are reaction considered “unexpected” if it 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 


5.3.5.2 Clinical Protocol 
 
105GTN201 Protocol Amendment #3 
EudraCT 2015-005475-25 
 
20SEP2016 
Page 82 of 102 
reactions that are mentioned in the investigator brochure as occurring with a class of drugs or as 
anticipated from the pharmacological properties of the drug, but are not specifically mentioned 
as occurring with the particular drug under investigation. 
8.3.8. 
Exposure in Utero 
If patients are status post a hysterectomy then no exposure in utero is possible.  If patients still 
have a uterus in situ then appropriate contraceptive measures will be undertaken to prevent both 
exposure in utero but also prevent pregnancy which would result in a rising serum hCG which 
could be confused for progression of disease.  Appropriate contraception should be continued 
during follow up and for 180 days after the last dose of TRC105 or bevacizumab to prevent 
pregnancies which could be confused with recurrence or progression. 
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; every effort should be made to make this determination by the 28 day follow-
up visit.  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”; every effort should be made to make this 
determination by the 28 day follow-up visit.  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 
 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.  


5.3.5.2 Clinical Protocol 
 
105GTN201 Protocol Amendment #3 
EudraCT 2015-005475-25 
 
20SEP2016 
Page 83 of 102 
9. 
OTHER ASSESSMENTS 
9.1. 
Other Laboratory Assessments  
9.1.1. 
TRC105 Trough Concentration 
A blood sample will be collected immediately prior to dosing with TRC105 on the days 
indicated within the Schedule of Assessments (Table 4 and Table 6).  Samples will be stored at 
approximately -70 °C.  See separate laboratory guide for further collection and shipment 
information.  
9.1.2. 
TRC105 Peak Concentration 
A blood sample will be collected within 10 minutes after completion of the TRC105 infusion on 
the days indicated within the Schedule of Assessments (Table 4 and Table 6).  Samples will be 
stored at approximately -70 °C.  See separate laboratory guide for further collection and 
shipment information. 
9.1.3. 
Bevacizumab Trough Concentration 
A blood sample will be collected immediately prior to dosing with bevacizumab on the days 
indicated within the Schedule of Assessments (Table 5 and Table 6).  Samples will be stored at 
approximately -70 °C.  See separate laboratory guide for further collection and shipment 
information.   
9.1.4. 
Bevacizumab Peak Concentration 
A blood sample will be collected within 10 minutes after completion of the bevacizumab 
infusion on the days indicated within the Schedule of Assessments (Table 4 and Table 6).  
Samples will be stored at approximately -70 °C.  See separate laboratory guide for further 
collection and shipment information. 
9.1.5. 
TRC105 Immunogenicity 
Anti-Product Antibody (APA) concentrations will be measured using validated ELISA methods 
at the time points specified within the Schedule of Assessments (Table 4, Table 5 and Table 6).  
APA concentrations will be evaluated in the context of pharmacokinetic profiles and AE profiles. 
Samples will be separated and stored at approximately -70 °C.  See separate laboratory guide for 
further collection and shipment information.   
9.1.6. 
Protein Biomarker 
A K2EDTA plasma blood sample will be collected on the days indicated within the Schedule of 
Assessments (Table 4, Table 5 and Table 6). Samples will be stored at approximately -70 °C. 
Duke University Medical Center will analyze plasma for several biomarkers including but not 
limited to VEGF, PDGF, and TGFβ. Please see the separate laboratory guide for further 
collection and shipment information. 


5.3.5.2 Clinical Protocol 
 
105GTN201 Protocol Amendment #3 
EudraCT 2015-005475-25 
 
20SEP2016 
Page 84 of 102 
9.1.7. 
CD16 Genotype 
A blood sample will be collected on Cycle 1 Day 1 according to the Schedule of Assessments 
(Table 4, Table 5 and Table 6). Samples will be stored at approximately -70 °C.  See separate 
laboratory guide for further collection and shipment information. 
9.1.8. 
Archival Tumor Specimens 
Archival specimens (formalin-fixed, paraffin-embedded) of the primary cancer and/or metastatic 
cancer specimen for each study participant will be obtained, if they are available.  It is preferable 
that the entire paraffin block be submitted, but if this is not feasible, then at least 10 unstained 
slides are requested for immunohistochemical analysis (sections of ~5 microns are preferred).  
Samples will be stored at room temperature and shipped to a third party laboratory for storage 
until the time of analysis.  See separate laboratory guide for further collection and shipment 
information. 


5.3.5.2 Clinical Protocol 
 
105GTN201 Protocol Amendment #3 
EudraCT 2015-005475-25 
 
20SEP2016 
Page 85 of 102 
10. 
STATISTICS 
10.1. 
Data Analysis 
10.1.1. 
Analysis of Co-Primary Objectives 
ORR by hCG in cases of choriocarcinoma or by integrated radiologic and hCG assessments in 
cases of PSTT or ETT, will be calculated form the time of cycle 1 day 1 until the time of 
progression, and will include separate assessments while on TRC105, bevacizumab and while 
receiving both agents. hCG for purposes of calculating ORR (and overall treatment decisions) 
will be measured by the central laboratory.  ORR to single agent TRC105 will include PR or CR.  
ORR to the combination of TRC105 and bevacizumab will include PR or CR.  ORR for purposes 
of determining the co-primary endpoints will include the ORR to TRC105 given as a single 
agent and when combined with bevacizumab (in bevacizumab refractory patients) in each 
patient.  
The point estimates and two-sided exact binomial 95% confidence intervals will be provided for 
ORR for each of the two co-primary populations. 
10.1.2. 
Analysis of Secondary Objectives 
Secondary endpoints include progression-free survival (PFS) and duration of response (DR).  
PFS is defined as the time from initial dosing until time of progression or death, with progression 
documented either hCG in cases of choriocarcinoma or by integrated radiologic and hCG 
assessments in cases of PSTT or ETT.  DR is defined as the time from initial documentation of 
response until time of progression or death, whichever occurs first.  PFS and DR will include 
separate assessments while on TRC105, bevacizumab and while receiving both agents. 
The distribution of PFS will be analyzed using the Kaplan-Meier method.  Secondary endpoints 
defined as proportions will be summarized using point estimates and two-sided exact binomial 
95% confidence intervals. 
The secondary objectives including the assessments of frequency and severity of toxicities, 
efficacy, pharmacokinetics, and angiogenic protein biomarkers will be evaluated as described 
below. 
10.1.2.1. Analysis for Pharmacokinetics 
Serum TRC105 and bevacizumab concentrations will be measured using validated methods and 
assessed for potential correlations with response, PFS, survival, adverse events, baseline 
characteristics and immunogenicity using descriptive statistics and models as appropriate. 
10.1.2.2. Analysis of Protein Biomarkers 
Angiogenic protein biomarker data for each patient who received at least one dose of study drug 
will be compared based on treatment with TRC105, bevacizumab and while receiving both 
agents. 


5.3.5.2 Clinical Protocol 
 
105GTN201 Protocol Amendment #3 
EudraCT 2015-005475-25 
 
20SEP2016 
Page 86 of 102 
10.1.2.3. Analysis of CD16 Genotype 
CD16 genotype will be quantified for each patient who received at least one dose of study drug 
and will be listed by cohort. 
10.1.2.4. Analysis of Archival Tumor Tissue 
CD105 expression within the tumor vasculature will be quantified for each patient who received 
at least one dose of study drug and will be listed by cohort.  Expression will be determined by 
IHC and/or by PCR.  Other markers that may relate to efficacy or toxicity of TRC105 will also 
be explored. 
10.2. 
Sample Size Justification 
The sample size of 30 patients is not based on statistical considerations.  If five or more 
responses to TRC105 given as a single agent or when combined with bevacizumab (in a 
bevacizumab refractory patient) are detected among 30 patients, then the lower limit of the two-
sided exact binomial 95% confidence interval will be greater than 5%.  For example, with five 
responses, the 95% confidence interval would be (5.64%, 34.72%). 
 


5.3.5.2 Clinical Protocol 
 
105GTN201 Protocol Amendment #3 
EudraCT 2015-005475-25 
 
20SEP2016 
Page 87 of 102 
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.   


5.3.5.2 Clinical Protocol 
 
105GTN201 Protocol Amendment #3 
EudraCT 2015-005475-25 
 
20SEP2016 
Page 88 of 102 
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 (QA) audits performed by TRACON or its representatives. 
It is important that the Investigator(s) and their relevant personnel are available during the 
monitoring visits, audits, and inspections and that sufficient attention, time, and support is 
devoted to the process.  
TRACON and its representatives will be governed by applicable regulations, good clinical 
practice standards, and internal SOPs for the conduct of monitoring visits and QA audits.    
Protocol deviations will be captured in TRACON’s electronic data capture system. 


5.3.5.2 Clinical Protocol 
 
105GTN201 Protocol Amendment #3 
EudraCT 2015-005475-25 
 
20SEP2016 
Page 89 of 102 
13. 
ETHICS 
13.1. 
Health Authorities and Independent Ethics Committees/Institutional 
Review Boards  
Before this study starts, the trial protocol, protocol amendments, informed consent forms, and 
any other information for patients will be submitted to the FDA, EMA, or other national health 
authority and to eat IEC/IRB for review, as applicable. As required, the study will not start at a 
given investigational center before the IEC/IRB and health authority (where applicable) for the 
center gives written approval or a favorable opinion. 
All correspondence and other evidence of appropriate and timely communications with the 
IRB/IEC should be retained in the Investigator/site files. Copies of all IRB/IEC approvals should 
also be forwarded to TRACON. 
The only circumstance in which an amendment may be initiated prior to relevant 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/health authorities 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 each patient prior to undertaking any trial-related 
procedure.  Each patient must be informed about her right to withdraw from the trial at any time.  
Furthermore, it is the responsibility of the Investigator to ensure each patient is appropriately 
informed before obtaining signed and dated consent. Signatures from the investigator conducting 
the informed consent discussion should also be obtained prior to undertaking any trial-related 
procedure. Consent by a legally authorized representative is not permitted. Should an impartial 
witness be needed, ICHE6 requirements for impartial witnesses will apply.  
The Investigator will retain each patient’s original signed consent form in the Investigator/site 
files. 


5.3.5.2 Clinical Protocol 
 
105GTN201 Protocol Amendment #3 
EudraCT 2015-005475-25 
 
20SEP2016 
Page 90 of 102 
13.4. 
Patient Compensation 
Patients will not be compensated for participation in this trial; this will be outlined in the 
informed consent form. 


5.3.5.2 Clinical Protocol 
 
105GTN201 Protocol Amendment #3 
EudraCT 2015-005475-25 
 
20SEP2016 
Page 91 of 102 
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 
TRC105.  Screen failure CRF’s will not be collected.  Nevertheless, records of potential patients 
identified and screened shall be retained on site screening logs. The completed original CRFs are 
the sole property of TRACON and should not be made available in any form to third parties 
without written permission from TRACON (except for authorized representatives of the HRA 
and in accordance with HIPAA regulations). 
It is the Investigator’s responsibility to ensure completion and to review and approve all CRF 
data. The investigator will sign off on his/her data per patient.  These signatures serve to attest 
that the investigator has reviewed and approved the information contained on the case report 
forms and that the information is complete, accurate, and true.   At all times, the Investigator has 
final personal responsibility for the accuracy and authenticity of all clinical and laboratory data 
entered on the CRFs.   
The use of electronic CRFs (eCRFs) to capture study data using automated computerized data 
capture systems does not change the principles and requirements for collecting study data.  The 
investigator still retains final personal responsibility for eCRF data and any associated data 
pertaining to it (e.g. metadata including any record of change to the originally recorded data).  
The investigator’s signed approval of the eCRF data serves to attest that the electronic data and 
all of its associated metadata (including changes) has been reviewed and accepted as complete, 
accurate, and true for each patient in the study. 
All CRF/eCRF data must be verifiable in the patient’s source records by TRACON or its 
designee.  TRACON will review CRF data as compared to source records in an attempt to 
identify missing and spurious data and notify the investigator of findings so that proper 
corrections can be made.  TRACON representatives (monitors and auditors), and regulatory 
inspectors shall have direct access to the original source records in its original recorded format: 
electronic or hardcopy.   
TRACON (or its designee) will perform all data management functions associated with the 
study.  Data will be captured electronically.  Automated data verification (“edit checks”) will be 
used to ensure that the data are logical and consistent. Any inconsistencies will be queried for 
clarification or correction as appropriate by the clinical site.   
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.   
Essential documents will be retained until at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or at least 2 years have elapsed since the formal discontinuation of 
clinical development of the investigational product.  These documents should be retained for a 


5.3.5.2 Clinical Protocol 
 
105GTN201 Protocol Amendment #3 
EudraCT 2015-005475-25 
 
20SEP2016 
Page 92 of 102 
longer period, however, if required by the applicable regulatory requirements or by an agreement 
with the sponsor.   
If the Investigator relocates, retires, or for any reason withdraws from the study, then TRACON 
should be prospectively notified.  The study records must be transferred to an acceptable 
designee, such as another Investigator, another institution, or to TRACON.  The Investigator 
must inform TRACON of any such transfer of responsibilities and properly identify the person or 
institution assuming the responsibility.  The responsible investigator/institution must obtain 
TRACON’s written permission before disposing of any records.  


5.3.5.2 Clinical Protocol 
 
105GTN201 Protocol Amendment #3 
EudraCT 2015-005475-25 
 
20SEP2016 
Page 93 of 102 
15. 
DEFINITION OF END TRIAL 
15.1. 
End of Trial in all Participating Countries 
End of trial in all participating countries is defined as the time at which the patient enrolled in the 
study has completed treatment on study.  
For clinical investigational centers located in the EU, a declaration of the end of the clinical 
study will be made according to the procedures outlined in Directive 2001/20/ED, Article 10(c); 
for other countries, local regulations will be followed. 
15.2. 
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 the participating patient 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.  


5.3.5.2 Clinical Protocol 
 
105GTN201 Protocol Amendment #3 
EudraCT 2015-005475-25 
 
20SEP2016 
Page 94 of 102 
16. 
PUBLICATION OF TRIAL RESULTS 
Publication of trial results is discussed in the Clinical Trial Agreement.  
The sponsor is responsible for ensuring that the public has access to the appropriate information 
about the study by conforming to local and regional requirements for registration and posting of 
results. 
The study will be listed in public databases on clinical studies www.clinicaltrials.gov and the 
European clinical trials database (EudraCT).  The summary of the study results will also be 
available on www.clinicaltrials.gov and www.clinicaltrialsregister.eu websites. 


5.3.5.2 Clinical Protocol 
 
105GTN201 Protocol Amendment #3 
EudraCT 2015-005475-25 
 
20SEP2016 
Page 95 of 102 
17. 
FINANCING AND INSURANCE 
Financing and Insurance are discussed in detail in the Clinical Trial Agreement.  


5.3.5.2 Clinical Protocol 
 
105GTN201 Protocol Amendment #3 
EudraCT 2015-005475-25 
 
20SEP2016 
Page 96 of 102 
18. 
INVESTIGATOR PROTOCOL AGREEMENT: 105GTN201 
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 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. 
 


5.3.5.2 Clinical Protocol 
 
105GTN201 Protocol Amendment #3 
EudraCT 2015-005475-25 
 
20SEP2016 
Page 97 of 102 
19. 
REFERENCES 
1. 
Carmeliet, P., Angiogenesis in health and disease. Nat Med, 2003. 9(6): p. 653-60. 
2. 
Folkman, J. and Y. Shing, Angiogenesis. J Biol Chem, 1992. 267(16): p. 10931-4. 
3. 
Hurwitz, H., et al., Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic 
colorectal cancer. N Engl J Med, 2004. 350(23): p. 2335-42. 
4. 
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. 
5. 
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. 
6. 
Friedman, H.S., et al., Bevacizumab alone and in combination with irinotecan in recurrent 
glioblastoma. J Clin Oncol, 2009. 27(28): p. 4733-40. 
7. 
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. 
8. 
Escudier, B., et al., Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med, 2007. 
356(2): p. 125-34. 
9. 
Llovet, J.M., et al., Sorafenib in advanced hepatocellular carcinoma. N Engl J Med, 2008. 
359(4): p. 378-90. 
10. 
Motzer, R.J., et al., Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J 
Med, 2007. 356(2): p. 115-24. 
11. 
Rini, B.I., Vascular endothelial growth factor-targeted therapy in metastatic renal cell 
carcinoma. Cancer, 2009. 115(10 Suppl): p. 2306-12. 
12. 
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. 
13. 
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. 
14. 
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. 
15. 
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. 
16. 
Li, D.Y., et al., Defective angiogenesis in mice lacking endoglin. Science, 1999. 284(5419): p. 
1534-7. 
17. 
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. 
18. 
Seon, B.K., Expression of endoglin (CD105) in tumor blood vessels. Int J Cancer, 2002. 99(2): p. 
310-1; author reply 312. 
19. 
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. 
20. 
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. 
21. 
Takahashi, N., et al., Antiangiogenic therapy of established tumors in human skin/severe 
combined immunodeficiency mouse chimeras by anti-endoglin (CD105) monoclonal antibodies, 
and synergy between anti-endoglin antibody and cyclophosphamide. Cancer Res, 2001. 61(21): p. 
7846-54. 


5.3.5.2 Clinical Protocol 
 
105GTN201 Protocol Amendment #3 
EudraCT 2015-005475-25 
 
20SEP2016 
Page 98 of 102 
22. 
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. 
23. 
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. 
24. 
Guo, B., et al., CD105 inhibits transforming growth factor-beta-Smad3 signalling. Anticancer 
Res, 2004. 24(3a): p. 1337-45. 
25. 
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. 
26. 
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. 
27. 
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. 
28. 
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. 
29. 
van Laake, L.W., et al., Endoglin has a crucial role in blood cell-mediated vascular repair. 
Circulation, 2006. 114(21): p. 2288-97. 
30. 
Lenato, G.M. and G. Guanti, Hereditary Haemorrhagic Telangiectasia (HHT): genetic and 
molecular aspects. Curr Pharm Des, 2006. 12(10): p. 1173-93. 
31. 
Sabba, C., et al., Life expectancy in patients with hereditary haemorrhagic telangiectasia. Qjm, 
2006. 99(5): p. 327-34. 
32. 
Lastres, P., et al., Regulated expression on human macrophages of endoglin, an Arg-Gly-Asp-
containing surface antigen. Eur J Immunol, 1992. 22(2): p. 393-7. 
33. 
Pece, N., et al., Mutant endoglin in hereditary hemorrhagic telangiectasia type 1 is transiently 
expressed intracellularly and is not a dominant negative. J Clin Invest, 1997. 100(10): p. 2568-
79. 
34. 
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. 
35. 
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. 
36. 
Kumar, S., et al., Breast carcinoma: vascular density determined using CD105 antibody 
correlates with tumor prognosis. Cancer Res, 1999. 59(4): p. 856-61. 
37. 
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. 
38. 
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. 
39. 
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. 
40. 
Svatek, R.S., et al., Preoperative plasma endoglin levels predict biochemical progression after 
radical prostatectomy. Clin Cancer Res, 2008. 14(11): p. 3362-6. 
41. 
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. 
42. 
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. 
43. 
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. 


5.3.5.2 Clinical Protocol 
 
105GTN201 Protocol Amendment #3 
EudraCT 2015-005475-25 
 
20SEP2016 
Page 99 of 102 
44. 
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. 
45. 
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. 
46. 
Yang, L.Y., et al., Correlation between CD105 expression and postoperative recurrence and 
metastasis of hepatocellular carcinoma. BMC Cancer, 2006. 6: p. 110. 
47. 
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. 
48. 
Taskiran, C., et al., The prognostic value of endoglin (CD105) expression in ovarian carcinoma. 
Int J Gynecol Cancer, 2006. 16(5): p. 1789-93. 
49. 
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. 
50. 
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. 
51. 
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. 
52. 
Takahashi, N., et al., Association of serum endoglin with metastasis in patients with colorectal, 
breast, and other solid tumors, and suppressive effect of chemotherapy on the serum endoglin. 
Clin Cancer Res, 2001. 7(3): p. 524-32. 
53. 
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. 
54. 
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. 
55. 
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. 
56. 
Horowitz, N.S., et al., Management of gestational trophoblastic neoplasia. Semin Oncol, 2009 
Apr. 36(2): p. 181-89.  
57. 
Burger, R.A., et al., Incorporation of bevacizumab in the primary treatment of ovarian cancer.  N 
Engl J Med, 2011 Dec 29. 365(26): p. 2473-83. 
58. 
Tewari, K.S., et al., Bevacizumab for advanced cervical cancer: patient-reported outcomes of a 
randomised, phase 3 trial (NRG Oncology-Gynecologic Oncology Group protocol 240). Lancet 
Oncol, 2015 Mar. 16(3): p. 301-11. 
59. 
Seckl, M.J.., et al., Gestational trophoblastic disease: ESMO Clinical Practice Guidelines for 
diagnosis, treatment and follow-up. Annals of Oncology 00, 1-12, 2013. 
 
 
 
 
 
 


5.3.5.2 Clinical Protocol 
 
105GTN201 Protocol Amendment #3 
EudraCT 2015-005475-25 
 
20SEP2016 
Page 100 of 102 
20. 
APPENDICES 
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://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev4.pdf 
 
 


5.3.5.2 Clinical Protocol 
 
105GTN201 Protocol Amendment #3 
EudraCT 2015-005475-25 
 
20SEP2016 
Page 101 of 102 
Appendix 2:  ECOG Performance Status 
 
Grade 
ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction. 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light 
or sedentary nature, 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. 
 
 
 


5.3.5.2 Clinical Protocol 
 
105GTN201 Protocol Amendment #3 
EudraCT 2015-005475-25 
 
20SEP2016 
Page 102 of 102 
Appendix 3:  Avastin Package Insert 
http://www.gene.com/download/pdf/avastin_prescribing.pdf 

SAP_000.pdf: 
CONFIDENTIAL 
 
 
Statistical Analysis Plan 
 
A Phase 2A Study of TRC105 (with Option to add 
Bevacizumab) in Patients with Refractory Gestational 
Trophoblastic Neoplasia (GTN)  
 
Protocol 105GTN201 
 
Version 1.0 
 
Prepared for  
TRACON Pharmaceutical, Inc. 
4510 La Jolla Village Dr., Suite 800 
San Diego, CA 92122 
 
 
 
August 7th, 2018 




Version 1.0 
Statistical Analysis Plan for Protocol 105GTN201 
Page 3 of 13 
 
 
STATISTICAL ANALYSIS PLAN 
 
Table of Contents 
 
Table of Contents........................................................................................................................................................... 3 
1. 
Objectives ............................................................................................................................................................ 4 
1.1. 
Primary Objective ........................................................................................................................................ 4 
1.2. 
Secondary Objective(s) ................................................................................................................................ 4 
1.3. 
Exploratory Objective(s) .............................................................................................................................. 4 
2. 
Study Design ........................................................................................................................................................ 4 
3. 
Sample Size Determination .................................................................................................................................. 6 
4. 
Analysis Population ............................................................................................................................................. 6 
5. 
General Analysis Comments ................................................................................................................................ 6 
6. 
Missing Data ........................................................................................................................................................ 6 
7. 
Patient Accountability and Patient Disposition .................................................................................................... 7 
8. 
Demographics and Baseline Characteristics ........................................................................................................ 7 
9. 
Concomitant Medications and Treatments ........................................................................................................... 7 
10. 
Efficacy Analyses ................................................................................................................................................ 7 
10.1. 
Overall Response Rate (ORR) ..................................................................................................................... 7 
10.2. 
Progression Free Survival (PFS) and Duration of Response (DR) ............................................................... 7 
11. 
Safety Analyses .................................................................................................................................................... 8 
11.1. 
Extent of Exposure ....................................................................................................................................... 8 
11.2. 
Adverse Events ............................................................................................................................................ 8 
11.3. 
Laboratory Evaluations ................................................................................................................................ 8 
11.4. 
Physical Examination ................................................................................................................................... 9 
11.5. 
Vital Signs .................................................................................................................................................... 9 
11.6. 
Electrocardiogram ........................................................................................................................................ 9 
11.7. 
ECOG Performance Scale ............................................................................................................................ 9 
12. 
Pharmacokinetic Analysis ............................................................................................................................ 9 
13. 
Additional Analysis .................................................................................................................................... 10 
14.1 
Analysis of Protein Biomarkers ................................................................................................................. 10 
14.2 
Analysis of Immunogenicity ...................................................................................................................... 10 
14.3 
Analysis of Serum and Urine Tumor Biomarkers ...................................................................................... 10 
14.4 
Analysis of CD16 Genotype ...................................................................................................................... 10 
14. 
Changes from the Protocol-Specified Analysis .................................................................................................. 10 
15. 
Programming Considerations ............................................................................................................................. 10 
16. 
Appendices ......................................................................................................................................................... 11 
Appendix 1:  Planned 105GTN201 Tables .............................................................................................................. 11 
Appendix 2:  Planned 105GTN201 Listings ............................................................................................................ 11 
17. 
References .......................................................................................................................................................... 11 
18. 
Appendix 1 Tables ............................................................................................................................................. 12 
1.1. 
Tables in Text: ........................................................................................................................................... 12 
1.2. 
Appended Tables:....................................................................................................................................... 12 
1.3. 
Figures ........................................................................................................ Error! Bookmark not defined. 
2. 
Appendix 2 Listings ........................................................................................................................................... 13 
2.1. 
Appended Listings: .................................................................................................................................... 13 
 
 


Version 1.0 
Statistical Analysis Plan for Protocol 105GTN201 
Page 4 of 13 
 
 
 
1. Objectives 
 
1.1. Primary Objective 
 
To determine the objective response rate (ORR) of single agent TRC105 and of the 
combination of TRC105 and bevacizumab (in bevacizumab refractory patients) in patients 
with refractory GTN (including choriocarcinoma, placental site trophoblastic tumor [PSTT], 
and epithelioid trophoblastic tumor [ETT])   
 
1.2. Secondary Objective(s) 
 
• To determine PFS 
• To determine ORR of single agent bevacizumab in patients with refractory GTN 
(including choriocarcinoma, PSTT, and ETT) 
• To evaluate the formation of TRC105 anti-product antibodies 
• To evaluate PK of TRC105 and bevacizumab 
• To determine the frequency and severity of adverse events as assessed by NCI CTCAE 
(Version 4.03) 
 
1.3. Exploratory Objective(s) 
 
• To correlate efficacy endpoints with endoglin expression on tumor samples 
• To explore the effects of TRC105 and bevacizumab on circulating angiogenic protein 
biomarkers 
• To explore the effects of CD16 genotype on response to TRC105 therapy  
 
 
2. Study Design 
 
This is a multicenter, open-label, nonrandomized, single-arm phase 2 study to assess the 
response rate to treatment with single agent TRC105, single agent bevacizumab, and the 
combination of TRC105 and bevacizumab in patients with GTN that has progressed following 
treatment with at least one chemotherapy regimen that included two or more chemotherapy 
agents.   
All patients will initially receive TRC105 as a single agent.  Patients will receive TRC105 for 
two 28-day cycles at which time formal measurement for response will be made.  The following 
scenarios are possible: 
1. Single agent TRC105 
a. Complete response after 2 cycles:  The patient will receive at least 3 cycles of 
consolidation therapy with single agent TRC105. 
b. Partial response after 2 cycles:  The patient will continue single agent TRC105 for 
an additional 2 cycles and re-evaluate the response, unless the patient has clear 
progression any time after completing 2 cycles of treatment then add 
bevacizumab.  If there is continued improvement in response after 4 cycles of 


Version 1.0 
Statistical Analysis Plan for Protocol 105GTN201 
Page 5 of 13 
 
 
treatment, continue single agent TRC105. If there is no improvement in response, 
add bevacizumab for combination therapy.  If there is a complete response any 
time after completing 2 cycles of treatment, the patient will receive at least 3 
cycles of consolidation therapy. 
c. Progression after 2 cycles or clear progression before 2 cycles:  Transition to 
single agent bevacizumab after a 2 week washout period.  Patients who have 
documented disease progression on a prior bevacizumab containing regimen will 
transition directly to TRC105 plus bevacizumab combination therapy. 
2. Single agent bevacizumab 
a. Complete response after 2 cycles:  The patient will receive at least 3 cycles of 
consolidation therapy with single agent bevacizumab. 
b. Partial response after 2 cycles:  The patient will continue single agent 
bevacizumab for an additional 2 cycles are re-evaluate the response unless the 
patient has clear progression any time after completing 2 cycles of treatment then 
add TRC105.  If there is continued improvement in response after 4 cycles of 
treatment, continue single agent bevacizumab. If there is no improvement in 
response, add TRC105 for combination therapy.  If there is a complete response 
any time after completing 2 cycles of treatment, the patient will receive at least 3 
cycles of consolidation therapy. 
c. Progression after 2 cycles or clear progression before 2 cycles:  Add TRC105 and 
treat with combination therapy. 
3. Combination therapy with TRC105 + bevacizumab 
a. Complete response after 2 cycles:  The patient will receive at least 3 cycles of 
consolidation therapy with the combination. 
b. Partial response after 2 cycles:  The patient will continue combination therapy for 
another 2 cycles to confirm partial response.  Combination therapy will be 
continued until remission or progression. 
c. Progression after 2 cycles or clear progression before 2 cycles:  The patient will 
come off study. 
Improvement in response is defined as a continued decline in hCG and/or a continued decrease 
in tumor volume by RECIST 1.1 for patients with measurable disease. For patients with 
choriocarcinoma, efficacy will be assessed using weekly hCG central lab results, starting two 
weeks after initiation of treatment:   
• Disease progression is defined as >20% increase (the absolute increase must be ≥10 
IU/L) above nadir on consecutive measurements separated by at least two weeks;  
• Partial response is defined as a hCG decrease of 50% or more from starting value on 
consecutive measurements separated by at least two weeks;  
• Complete response is defined as normalization of hCG on consecutive measurements 
separated by at least two weeks;  
• Stable disease is defined as the absence of response or progression on 3 consecutive 
measurements separated by at least two weeks.  
Efficacy assessment of patients with PSTT and ETT will use standard RECIST 1.1 radiographic 
criteria integrated with weekly hCG assessment.    


Version 1.0 
Statistical Analysis Plan for Protocol 105GTN201 
Page 6 of 13 
 
 
 
Regular safety and toxicity assessments are performed. Toxicities will be graded according to the 
NCI Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0.  
 
3. Sample Size Determination 
 
The sample size of 30 patients is not based on statistical considerations.  If five or more 
responses to TRC105 given as a single agent or when combined with bevacizumab (in a 
bevacizumab refractory patient) are detected among 30 patients, then the lower limit of the two-
sided exact binomial 95% confidence interval will be greater than 5%.  For example, with five 
responses, the 95% confidence interval would be (5.64%, 34.72%).  
 
4. Analysis Population 
 
The safety and efficacy populations include all patients who receive at least a portion of one dose 
of the study drug, TRC105.  
 
5. General Analysis Comments 
 
Summary statistics will consist of frequencies and percents of responses in each category for 
discrete measures; and of means, medians, standard deviations, minimum and maximum values 
for continuous measures. By-patient listings of data represented on the Case Report Form (CRF) 
will be provided.  
 
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. 
 
SAS®, Version 9.0 or higher, or R v 3.23 or higher, or Python v 2.0 or higher or PostgreSQL v 
9.2.14 or higher will be used to perform all statistical analyses. 
 
 
6. Missing Data 
 
All data collected, including unscheduled visits, will be presented in the data listings.  Summary 
tables will generally be limited to planned visits.  
 
In all analyses (except where partial dates are allowed), it is expected that only observed values 
will be presented; no imputation of missing data will be conducted.  Where partial dates are 
allowed (i.e., medical history, adverse events, prior systemic therapy, prior radiation therapy, 
prior surgery, concomitant medications and concomitant treatments) the largest possible window 
for the event/item will be reported.  
 
 


Version 1.0 
Statistical Analysis Plan for Protocol 105GTN201 
Page 7 of 13 
 
 
7. Patient Accountability and Patient Disposition 
 
The number of patients enrolled and number of cycles completed will be presented. A summary 
of reasons for discontinuation will be provided. The number of patients in the safety population 
and the number of patients excluded from the safety population will also be presented. Study 
completion status, including reasons for discontinuation will be listed. 
 
8. Demographics and Baseline Characteristics 
 
Demographics and baseline characteristics will be summarized. Demographic variables, 
including age, gender, race, and ethnicity will be summarized in a tabular form. 
 
Primary diagnosis (histological classification), prior cancer surgery, prior radiotherapy, prior 
cancer therapy, and medical history will be listed and will also be summarized.  
 
9. Concomitant Medications and Treatments 
 
A listing of all concomitant medications and treatment will be provided by patient ID number, 
drug name, dosage, frequency of use, start and stop dates, whether the medication or treatment 
was ongoing. Concomitant medications will be coded by using WHO Drug Dictionary version 
September 2012. 
 
10. Efficacy Analyses 
 
10.1. 
Overall Response Rate (ORR) 
 
ORR by hCG in cases of choriocarcinoma or by integrated radiologic and hCG assessments 
in cases of PSTT or ETT, will be calculated form the time of cycle 1 day 1 until the time of 
progression, and will include separate assessments while on TRC105, bevacizumab and 
while receiving both agents. hCG for purposes of calculating ORR (and overall treatment 
decisions) will be measured by the central laboratory.  ORR to single agent TRC105 will 
include PR or CR.  ORR to the combination of TRC105 and bevacizumab will include PR or 
CR.  ORR for purposes of determining the co-primary endpoints will include the ORR to 
TRC105 given as a single agent and when combined with bevacizumab (in bevacizumab 
refractory patients) in each patient.  
The point estimates and two-sided exact binomial 95% confidence intervals will be provided 
for ORR for each of the two co-primary populations. 
 
 
10.2. 
Progression Free Survival (PFS) and Duration of Response (DR) 
 
 
 


Version 1.0 
Statistical Analysis Plan for Protocol 105GTN201 
Page 8 of 13 
 
 
PFS is defined as the time from initial dosing until time of progression or death, with 
progression documented either hCG in cases of choriocarcinoma or by integrated radiologic 
and hCG assessments in cases of PSTT or ETT.   
DR is defined as the time from initial documentation of response until time of progression or 
death, whichever occurs first.  PFS and DR will include separate assessments while on 
TRC105, bevacizumab and while receiving both agents. 
The distribution of PFS will be analyzed using the Kaplan-Meier method.  Secondary 
endpoints defined as proportions will be summarized using point estimates and two-sided 
exact binomial 95% confidence intervals. 
 
11. Safety Analyses 
 
Safety will be assessed by examining vital signs, physical exams, clinical laboratory tests, and 
adverse events (AEs). These analyses will be conducted on the safety population. Baseline will 
be defined as the last available measurement prior to the first TRC105 dose. Where this 
definition does not apply, the definition for that analysis will be specified. 
 
 
11.1. 
Extent of Exposure 
 
The extent of exposure to TRC105 study drug and bevacizumab will be summarized by the 
number of doses completed, and the number of cycles completed and dose received in 
milligrams. A cycle is considered completed if the patient received all treatment infusions 
required during a given cycle. Actual extent of exposure versus expected extent of exposure 
will be provided for both TRC105 and bevacizumab.  
 
11.2. 
Adverse Events 
 
Adverse Events (AEs) and Serious Adverse Events (SAEs) will be coded by using the 
Medical Dictionary for Regulatory Activities (MedDRA Version 14.1) system organ class 
(SOC) and preferred term (PT). AEs and SAEs will be graded according to the CTCAE 
Version 4.0, where available.  
 
All AEs and SAEs will be listed by patient ID number. TRC105 treatment-emergent AEs 
will be summarized. Treatment-emergent is defined as all events starting during or after the 
first dose of TRC105 study drug. The number and percentage of patients with AEs will be 
displayed by SOC and PT according to the worst severity experienced. Summaries will be 
provided of AEs by grade and of AEs by relationship to study medication. Serious AEs, AEs 
leading to study discontinuation, AEs resulting in dose delay, and AEs with an outcome of 
death will be summarized and listed.  
 
 
11.3. 
Laboratory Evaluations 
 


Version 1.0 
Statistical Analysis Plan for Protocol 105GTN201 
Page 9 of 13 
 
 
Quantitative laboratory test results will be summarized at each visit for hematology, 
coagulation, serum chemistry panel, and urinalysis.  
 
The Investigator will determine whether abnormal lab values are clinically significant.  Such 
results are to be reported as adverse events and CTCAE grading will be assigned (except for 
urinalysis) where applicable. 
 
Laboratory results that are abnormal and clinically significant will be flagged. Abnormal and 
clinically significant results will be presented in listings with Investigator comments. 
 
The number and percentage of patients who exhibit clinically significant abnormal laboratory 
results will be produced at each visit. 
 
11.4. 
Physical Examination 
 
The physical examination results will be displayed at each cycle. Listing of results of 
examinations will be provided by anatomical sites, assessment dates, and description of 
physical abnormalities.  
 
11.5. 
Vital Signs 
 
Vital signs will be summarized at each visit for systolic blood pressure, diastolic blood 
pressure, pulse, respiratory rate, temperature, and weight. Listing of vital signs will be 
provided. 
 
11.6. 
Electrocardiogram 
 
ECG results including ECG time, heart rate (bpm), PR interval (ms), QRS interval (ms), and 
QT interval (ms) (normal; abnormal, not clinically significant; abnormal, clinically 
significant), QTc, and comments for clinically significant abnormalities will be reported for 
each patient using Bazett’s Formula as follows: 
QTB = 
 
 
11.7. 
ECOG Performance Scale 
 
The Eastern Cooperative Oncology Group (ECOG) performance grade scale will be used to 
measure patient ECOG performance status. Individual patient data at screening will be 
tabulated and individual patient data throughout the study will be displayed in a listing. 
 
12. Pharmacokinetic Analysis 
 
Serum samples will be assayed to measure the concentration of TRC105 and bevacizumab. Only 
concentrations greater than or equal to the limit of qualification (LOQ) from the assay will be 
used.  The following parameters will be determined: 


Version 1.0 
Statistical Analysis Plan for Protocol 105GTN201 
Page 10 of 13 
 
 
• 
Cmax (ng/mL) [Maximal TRC105 or bevacizumab concentration] 
• 
Cmin (ng/mL) [Minimal TRC105 or bevacizumab concentration] 
 
Descriptive statistics of Cmax and Cmin, following drug administrations will be calculated by time 
of treatment (baseline versus treatment completion Summary PK analyses will include all 
patients and also include only patients who develop positive APA titers. 
 
Listings of individual patient serum concentrations, actual blood sampling times, and 
pharmacokinetic parameters will be provided.  
 
13. Additional Analysis 
 
14.1 
Analysis of Protein Biomarkers 
 
Angiogenic protein biomarker data for each patient who received at least one dose of 
TRC105 study drug will be listed. 
 
14.2 
Analysis of Immunogenicity 
 
TRC105 anti-product antibody concentrations will be measured using validated ELISA 
methods at the timepoints specified in the Schedule of Assessments. 
 
TRC105 anti-product antibody concentrations will be evaluated in the context of 
pharmacokinetic parameters and AE profiles. 
 
14.3 
Analysis of Serum and Urine Tumor Biomarkers 
 
Urine and Serum hCG tumor marker data for each patient who received at least one dose of 
TRC105 study drug will be listed. 
 
14.4 
Analysis of CD16 Genotype 
 
CD16 genotype for each patient who received at least one dose of TRC105 study drug will be 
listed. 
 
14. Changes from the Protocol-Specified Analysis 
 
The details of analysis as indicated in this plan are based on the specifications of the study 
protocol as amended on September 20th, 2016. Any later changes to the protocol may require 
consequential revision of this plan. 
 
15. Programming Considerations 
 
The format of listing and table shells should be followed as closely as possible during SAS or R 
programming, however, changes in format may be made due to space considerations and 


Version 1.0 
Statistical Analysis Plan for Protocol 105GTN201 
Page 11 of 13 
 
 
abbreviation of labels etc. The number of decimal places for presentation of the data should be 
based on the actual data, not the format presented in the shells (i.e., xx.xx is only a place holder). 
 
 
16. Appendices 
 
Appendix 1:  Planned 105GTN201 Tables 
Appendix 2:  Planned 105GTN201 Listings 
 
17. References 
 
1. Therasse P, Arbuck SG, Eisenhauer EA, et al.  New guidelines to evaluate the response to 
treatment in solid tumors.  European Organization for Research and Treatment of Cancer, 
National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl 
Cancer Inst 2000; 92:205-16. 
2. NCI Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0. 
http://www.acrin.org/Portals/0/Administration/Regulatory/CTCAE_4.02_2009-09-
15_QuickReference_5x7.pdf 
3. MedDRA: Medical Dictionary for Regulatory Activities terminology. Version 14.1. 
Reston, VA: Northrop Grumman, MedDRA MSSO.  
 


Version 1.0 
Statistical Analysis Plan for Protocol 105GTN201 
Page 12 of 13 
 
 
18. Appendix 1 Tables 
 
1.1. Tables in Text: 
• Protocol Versions under which Each Patient was Enrolled  
• Individual Response Data 
• Summary of Serum TRC105 Pharmacokinetic Parameters Following Multiple 
Intravenous Infusions of TRC105 
• Treatment-Emergent Adverse Events by Maximum CTCAE Grade  
• Treatment-Emergent TRC105 Drug-Related Adverse Events by Maximum CTCAE 
Grade  
• TRC105 APA Results 
 
1.2. Appended Tables: 
• Serious Treatment-Emergent Adverse Events 
• Adverse Events Leading to Discontinuation 
 
 


Version 1.0 
Statistical Analysis Plan for Protocol 105GTN201 
Page 13 of 13 
 
 
2. Appendix 2 Listings 
 
2.1. Appended Listings: 
Listing 16.1.1 Listing of Informed Consent and Reconsent 
Listing 16.2.1 Patient Disposition 
Listing 16.2.2 Protocol Deviation 
Listing 16.2.2.1 Inclusion and Exclusion Criteria 
Listing 16.2.3 Patients Excluded from Efficacy Analysis 
Listing 16.2.4.1 Demographics and Baseline Characteristics 
Listing 16.2.4.3 Primary Diagnosis 
Listing 16.2.4.4 Prior Cancer Therapy (Including Hormonal Therapy) 
Listing 16.2.4.5 Prior Cancer Surgery 
Listing 16.2.4.6 Prior Cancer Radiation Therapy 
Listing 16.2.4.7 Medical History and Baseline Emergent Adverse Events 
Listing 16.2.4.8 Concomitant Medications 
Listing 16.2.4.9 Concomitant Treatments 
Listing 16.2.4.10 TRC105 Pre-Medications 
Listing 16.2.4.11 Drug Allergies 
Listing 16.2.5.1 TRC105 Dosing Record 
Listing 16.2.5.2 Bevacizumab Dosing Record  
Listing 16.2.6.1 Investigator Response Assessment 
Listing 16.2.6.3 Tumor Assessment - Target Lesions 
Listing 16.2.6.4 Tumor Assessment - Non-Target Lesions 
Listing 16.2.6.5 Scans 
Listing 16.2.6.6 APA 
Listing 16.2.6.7 Archival Tumor Specimens 
Listing 16.2.6.9 Protein Biomarker Samples 
Listing 16.2.6.10 Serum Tumor Markers 
Listing 16.2.6.11 Urine Tumor Markers 
Listing 16.2.7.1 All Adverse Events 
Listing 16.2.7.3 Serious Adverse Events 
Listing 16.2.7.4 Adverse Events Leading to Discontinuation 
Listing 16.2.7.5 Adverse Events Leading to Death 
Listing 16.2.8.1 Abnormal Laboratory Results – Hematology 
Listing 16.2.8.2 Abnormal Laboratory Results – Coagulation 
Listing 16.2.8.3 Abnormal Laboratory Results – Chemistry 
Listing 16.2.8.4 Abnormal Laboratory Results – Urinalysis 
Listing 16.2.9.1 Vital Signs 
Listing 16.2.9.2 Abnormal Physical Exam Results 
Listing 16.2.9.3 ECG Results 
Listing 16.2.9.4 ECOG Performance Status 
Listing 16.2.9.5 Pregnancy at Screening 
Listing 16.2.9.6 24 Hr-Urine Collection 
Listing 16.2.9.7 Microscopic Urinalysis 
Listing 16.2.9.8 Urine Protein to Creatinine Ratio 
Listing 16.2.9.9 Pre-Dose PK (TRC105 and bevacizumab)