A RANDOMIZED PHASE 3 TRIAL OF TRC105 AND PAZOPANIB VERSUS PAZOPANIB ALONE IN PATIENTS WITH ADVANCED ANGIOSARCOMA

TRC105 (carotuximab) is a monoclonal antibody to endoglin (CD105), an essential angiogenic
target highly expressed on tumor vessels that is distinct from VEGFR. Endoglin is also
expressed directly on tumor cells in angiosarcoma and is upregulated following VEGF
inhibition. TRC105 inhibits angiogenesis, tumor growth and metastases in preclinical models
and complements the activity of bevacizumab and multi-kinase inhibitors that target the
VEGFR.

Pazopanib is an oral inhibitor of multiple receptor tyrosine kinases, including vascular
endothelial growth factor receptor (VEGFR)-1, VEGFR-2, and VEGFR-3 at therapeutic plasma
concentrations. These receptors are implicated in pathologic angiogenesis, tumor growth, and
cancer progression.

By targeting a non-VEGF pathway that is upregulated following VEGF inhibition, TRC105 has the
potential to complement VEGFR tyrosine kinase inhibitors (TKIs) and could represent a major
advance in the treatment of angiosarcoma. Together, the use of TRC105 with pazopanib may
result in more effective angiogenesis inhibition and improved clinical efficacy over that
seen with pazopanib alone.

Inclusion Criteria:

1. Histologically-confirmed angiosarcoma that is not amenable to curative intent surgery
(e.g., metastatic or bulky disease and disease for which surgical resection would
carry an unacceptable risk to the patient). Pathology report will be reviewed by
sponsor prior to randomization.

2. Documented progression on or following most recent systemic chemotherapy regimen (not
required for chemotherapy-naïve patients), within 4 months prior to screening

3. Measurable disease by RECIST v1.1

4. Age of 18 years or older; in addition, patients age 12 to 17 years may enroll
beginning in Cohort 2 if weight ≥ 40 kg

5. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1

6. Resolution of all acute AEs resulting from prior cancer therapies to National Cancer
Institute Common Terminology Criteria for Adverse Events version 4.03 (NCI CTCAE
v4.03) grade ≤ 1 or to that patient's pre-study baseline (except alopecia or
neuropathy)

7. Adequate organ function

8. Willingness and ability to consent (and assent if under age 18) for self to
participate in study

9. Willingness and ability to comply with scheduled visits, treatment plan, laboratory
tests, and other study procedures

10. Angiosarcoma tumor specimen, if available

11. Men who are sterile (including vasectomy confirmed by post vasectomy semen analysis)
OR agree to use a condom with spermicide (refer to Section 2.6.1.3) and to not donate
sperm during the study and for at least 180 days following last dose of TRC105 or
pazopanib

12. Woman of non-child bearing potential due to surgical sterilization (at least 6 weeks
following surgical bilateral oophorectomy with or without hysterectomy or tubal
ligation) confirmed by medical history or menopause (i.e., no menstrual bleeding for
more than 12 months in a women aged 45 years or more), OR woman of child bearing
potential who test negative for pregnancy at time of enrollment based on serum
pregnancy test and agree to use at least 2 acceptable methods of birth control, one of
which must be highly effective, during the study and for at least 180 days after
stopping TRC105 or pazopanib

Exclusion Criteria:

1. Prior treatment with TRC105

2. Prior treatment with any VEGF inhibitor

3. More than two prior lines (may be combination regimens) of chemotherapy for
angiosarcoma (neoadjuvant/adjuvant treatment does not count as a line of treatment)

4. Current treatment or participation on another therapeutic clinical trial

5. Women who are pregnant or breastfeeding

6. Receipt of systemic anticancer therapy, including investigational agents, within 5
times the agent's elimination half-life of starting study treatment

7. Major surgical procedure or significant traumatic injury within 4 weeks prior to
randomization and must have fully recovered from any such procedure or injury; planned
surgery (if applicable) or the anticipated need for a major surgical procedure within
the next six months. Note: the following are not considered to be major procedures and
are permitted up to 7 days before randomization: Thoracentesis, paracentesis, port
placement, laparoscopy, thoracoscopy, tube thoracostomy, bronchoscopy, endoscopic
ultrasonographic procedures, mediastinoscopy, skin biopsies, and imaging-guided biopsy
for diagnostic purposes

8. Patients who have received wide field radiotherapy ≤ 28 days (defined as > 50% of
volume of pelvic bones or equivalent) or limited field radiation for palliation < 14
days prior to randomization

9. Uncontrolled hypertension defined as systolic > 150 or diastolic > 100 mm Hg on the
average of the 3 most recent BP readings. Anti-hypertensives may be started prior to
randomization.

10. Ascites or pleural effusion requiring intervention or that required intervention or
recurred within three months prior to randomization

11. Pericardial effusion (except trace effusion identified by echocardiogram) within three
months prior to randomization

12. History of brain involvement with cancer, spinal cord compression, or carcinomatous
meningitis, or new evidence of brain or leptomeningeal disease. Patients with radiated
or resected lesions are permitted, provided the lesions are fully treated and
inactive, patients are asymptomatic, and no steroids have been administered for at
least 28 days prior to randomization

13. Angina, myocardial infarction, symptomatic congestive heart failure, cerebrovascular
accident, transient ischemic attack, arterial embolism , pulmonary embolism,
percutaneous transluminal coronary angioplasty (PTCA) or coronary artery bypass graft
(CABG) within 6 months prior to randomization. Deep venous thrombosis within 3 months
prior to randomization unrelated to a central venous catheter, unless the patient is
anti-coagulated without the use of warfarin for at least 2 weeks prior to
randomization. In this situation, low molecular weight heparin is preferred

14. Active bleeding or pathologic condition that carries a high risk of bleeding (e.g.,
hereditary hemorrhagic telangiectasia). Patients with bleeding cutaneous lesions not
actively requiring transfusions are eligible. Patients who have been uneventfully
anti-coagulated with low molecular weight heparin are eligible

15. Hemoptysis (> ½ teaspoon [2.5 mL] of bright red blood) within 6 months prior to
randomization

16. Thrombolytic use (except to maintain i.v. catheters) within 10 days prior to
randomization

17. Known active viral or nonviral hepatitis or cirrhosis

18. Peptic ulcer within the past 3 months prior to randomization, unless treated for the
condition and complete resolution has been documented by esophagogastroduodenoscopy
(EGD)

19. Presence of tumor(s) invading into the heart or great vessels (including carotid
artery) or another location where bleeding is associated with high morbidity including
patients with primary cardiac or great vessel angiosarcoma

20. Gastrointestinal perforation or fistula in the 6 months prior to randomization unless
underlying risk has been resolved (e.g., through surgical resection or repair)

21. Presence of a malabsorption syndrome, gastrointestinal disorder, or gastrointestinal
surgery that could affect the absorption of pazopanib

22. History of prior malignancy except adequately treated basal cell or squamous cell skin
cancer or adequately treated, with curative intent, cancer from which the patient is
currently in complete remission per Investigator's judgment; patients with history of
breast cancer and no evidence of disease on hormonal therapy to prevent recurrence and
patients with prostate cancer on adjuvant hormonal therapy with undetectable PSA are
eligible

23. Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)
related illness

24. Active infection that requires systemic treatment

25. Concurrent use or receipt of a strong CYP3A4 inducer within 12 days prior to
randomization or a strong CYP3A4 inhibitor within 7 days prior to randomization (see
Table 10)

26. History of severe hypersensitivity reaction to any monoclonal antibody

27. Other severe acute or chronic medical (including bone marrow suppressive diseases) or
psychiatric condition or laboratory abnormality that may increase the risk associated
with study participation, impede the ability of the patient to complete all
protocol-specified activities, or may interfere with the interpretation of study
results and, in the judgment of the Investigator, would make the patient inappropriate
for this study