A Randomized Phase 2 Trial of Axitinib and TRC105 Versus Axitinib Alone in Patients With Advanced or Metastatic Renal Cell Carcinoma

Axitinib 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. Axitinib is approved for the treatment of advanced renal cell carcinoma,
following progression on one prior systemic therapy. 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 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. By targeting a non-VEGF pathway that
is upregulated following VEGF inhibition, TRC105 has the potential to complement VEGF
inhibitors and could represent a major advance in cancer therapy. TRC105 potentiates
bevacizumab and VEGFR tyrosine kinases (VEGFR TKI) in preclinical models. In a phase 1b
study, the combination of TRC105 and bevacizumab produced radiographic reductions in tumor
volume in bevacizumab refractory patients. Together, the use of TRC105 with axitinib may
result in more effective angiogenesis inhibition and improved clinical efficacy over that
seen with axitinib alone.

Inclusion Criteria:

1. Histologically confirmed advanced or metastatic renal cell carcinoma with a clear cell
component that has progressed by investigator assessment following treatment with one
and only one multi-targeted tyrosine kinase inhibitor (TKI) other than axitinib that
targets the VEGF receptor (VEGFR) (e.g., sunitinib, pazopanib, sorafenib, tivozanib,
cabozantinib). One prior immunotherapy (interleukin-2 or interferon-alpha or immune
checkpoint inhibitor or tumor vaccine) and one prior mTOR inhibitor treatment are
allowed.

2. No other prior malignancy is allowed except for the following: adequately treated
basal cell or squamous cell skin cancer, adequately treated Stage I or II cancer from
which the patient is currently in complete remission per investigators' clinical
judgment.

3. Measurable disease by RECIST 1.1 criteria

4. Age of 18 years or older

5. ECOG performance status ≤ 1

6. Resolution of all acute adverse events resulting from prior cancer therapies to NCI
CTCAE grade ≤ 1 or baseline (except alopecia)

7. Adequate organ function as defined by the following criteria:

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

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

Exclusion Criteria:

1. Prior treatment with TRC105 or axitinib or any agent targeting the endoglin pathway
(including a fusion protein that binds bone morphogenic protein)

2. Grade 3 or 4 toxicity related to prior VEGFR TKI that did not resolve to grade 1

3. Current treatment on another therapeutic clinical trial

4. Receipt of a small molecule anticancer agent, including an investigational anticancer
small molecule, within 14 days of starting study treatment or receipt of a biologic
anticancer agent (e.g., antibody) within 28 days of starting study treatment.

5. Prior radiation therapy within 28 days of starting the study treatment, except
radiation therapy for bone metastases or radiosurgery is permitted up to 14 days of
starting treatment

6. No major surgical procedure or significant traumatic injury within 6 weeks prior to
study registration, and must have fully recovered from any such procedure; date of
surgery (if applicable). 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, thorascopy, tube thoracostomy, bronchoscopy, endoscopic
ultrasonographic procedures, mediastinoscopy, skin biopsies, incisional biopsies,
imaging-guided biopsy for diagnostic purposes, and routine dental procedures

7. 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)

8. 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.

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 anticoagulated
without the use of warfarin for at least 2 weeks. In this situation, low molecular
weight heparin is preferred.

10. Active bleeding or pathologic condition that carries a high risk of bleeding (e.g.
hereditary hemorrhagic telangiectasia).

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

12. Known active viral or nonviral hepatitis or cirrhosis

13. History of hemorrhage or hemoptysis (> ½ teaspoon bright red blood) within 3 months of
starting study treatment

14. History of peptic ulcer disease within 3 months of treatment, unless treated for the
condition and complete resolution has been documented by esophagogastroduodenoscopy
(EGD) within 28 days of starting study treatment

15. 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)

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

17. Requirement for concomitant medications that strongly induce or inhibit CYP3A4/5

18. 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.

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