Randomized Phase 2 Trial of Axitinib and TRC105 Versus Axitinib Alone in Patients Renal Cell Carcinoma

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