A Phase 1B Dose-escalation and Phase 2a Study of Carotuximab (TRC105) in Combination With Pazopanib in Patients With Advanced Soft Tissue Sarcoma

Pazopanib is an oral inhibitor of multiple receptor tyrosine kinases, including vascular
endothelial growth factor receptor VEGFR-1, VEGFR-2, and VEGFR-3 at therapeutic plasma
concentrations. These receptors are implicated in pathologic angiogenesis, tumor growth, and
cancer progression. Pazopanib is approved for the treatment of advanced soft tissue sarcoma,
following progression on one prior systemic therapy, based on improved progression free
survival. TRC105 is an antibody to CD105, an important angiogenic target on vascular
endothelial cells that is distinct from VEGFR. TRC105 inhibits angiogenesis, tumor growth and
metastases in preclinical models and complements the activity of bevacizumab and multi-kinase
inhibitors that target the VEGFR. In a phase 1 study of advanced solid tumors, TRC105 therapy
caused a global reduction in angiogenic biomarkers and reduced tumor burden at doses that
were well-tolerated. In a phase 1b study, the combination of TRC105 and bevacizumab produced
radiographic reductions in tumor volume in bevacizumab-refractory patients, and was well
tolerated. TRC105 potentiates bevacizumab and VEGFR tyrosine kinases (VEGFR TKI) in
preclinical models. By targeting a non-VEGF pathway that is upregulated following VEGF
inhibition, TRC105 has the potential to complement VEGFR TKIs and could represent a major
advance in cancer therapy. Together, the use of TRC105 with pazopanib may result in more
effective angiogenesis inhibition and improved clinical efficacy over that seen with
pazopanib alone.

Inclusion Criteria:

1. Histologically confirmed unresectable soft tissue sarcoma that has progressed
following treatment with chemotherapy. Prior pazopanib is allowed if the drug was not
discontinued for toxicity ( Phase 1b only)

2. Histologically confirmed metastatic soft tissue sarcoma that has progressed by RECIST
following treatment with anthracycline chemotherapy. Patients may have received up to
four lines of systemic therapy for metastatic disease and no more than two lines of
combination treatment ( Phase 2 only)

3. Histologically confirmed locally advanced (e.g. unresectable) or metastatic
angiosarcoma that has progressed following treatment with prior systemic therapy.
Progression must be documented on or following the most recent systemic therapy. Prior
pazopanib is allowed if the drug was not discontinued for toxicity (Phase 2
angiosarcoma cohorts only)

4. Measurable disease by RECIST

5. Age of 12 years or older (patient must weigh ≥ 40 kg)

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.

9. Willingness and ability to consent for self to participate in study

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

11. Available archival tumor specimen of the soft tissue sarcoma that meets inclusion
criterion #1, #2 or #3

Exclusion Criteria:

1. Prior treatment with TRC105

2. Prior treatment with a VEGFR TKI (including pazopanib) (Phase 2 only)

3. Current treatment on another therapeutic clinical trial

4. Receipt of systemic anticancer therapy, including investigational agents, within 28
days of starting study treatment.

5. No major surgical procedure or significant traumatic injury within 6 weeks prior to
study registration, and must have fully recovered from any such procedure; date of
surgery (if applicable) or the anticipated need for a major surgical procedure within
the next six months.

6. Patients who have received wide field radiotherapy ≤ 28 days 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

7. Uncontrolled chronic hypertension

8. Significant ascites or pericardial or pleural effusion

9. History of brain involvement with cancer, spinal cord compression, or carcinomatous
meningitis, or new evidence of brain or leptomeningeal disease.

10. Angina, MI, symptomatic congestive heart failure, cerebrovascular accident, transient
ischemic attack, arterial embolism, pulmonary embolism, PTCA or CABG within the past 6
months. Deep venous thrombosis within 6 months, unless the patient is anti-coagulated
without the use of warfarin for at least 2 weeks. In this situation, low molecular
weight heparin is preferred.

11. Active bleeding or pathologic condition that carries a high risk of bleeding. Patients
who have been uneventfully anti-coagulated with low molecular weight heparin are
eligible.

12. Thrombolytic use (except to maintain i.v. catheters) within 10 days prior to first day
of study therapy

13. Known active viral or nonviral hepatitis or cirrhosis

14. History of hemorrhage or hemoptysis within 3 months of starting study treatment

15. History of peptic ulcer within the past 3 months of treatment

16. History of gastrointestinal perforation or fistula in the past 6 months, or while
previously on antiangiogenic therapy, unless underlying risk has been resolved

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

18. Receipt of a strong CYP3A4 inducer within 12 days prior to cycle 1 day 1 or a strong
CYP3A4 inhibitor within 7 days prior to cycle 1 day 1.

19. Pregnancy or breastfeeding. Female patients must be surgically sterile (i.e.:
hysterectomy) or be postmenopausal, or must agree to use effective contraception
during the study and for 3 months following last dose of TRC105. All female patients
of reproductive potential must have a negative pregnancy test (serum or urine) within
7 days prior to first dose. Male patients must be surgically sterile or must agree to
use effective contraception during the study and for 3 months following last dose of
TRC105. The definition of effective contraception will be based on the judgment of the
Principal Investigator or a designated associate.

20. Other severe acute or chronic medical or psychiatric condition or laboratory
abnormality that may increase the risk associated with study participation or may
interfere with the interpretation of study results and, in the judgment of the
Investigator, would make the patient inappropriate for this study.