A Study of AGS-16C3F vs. Axitinib in Metastatic Renal Cell Carcinoma

Inclusion Criteria: * Histologically confirmed diagnosis of RCC * Non-clear subjects must be ENPP3 positive, defined as IHC H-score ≥15 * Has evidence of progression on or after the last regimen received: * Clear cell subject: must have received at least 2 prior systemic regimens, one of which is an anti-VEGF agent. * Non-clear cell subject: must have received at least one prior anti-VEGF regimen * Has measurable disease according to Response Criteria for Solid Tumors (RECIST v.1.1) * Has Eastern Cooperative Group (ECOG) performance status of 0 or 1 * Has archive tumor tissue from primary tumor or metastatic site (excluding bone), for which the source and availability have been confirmed. * If no archive tissue is available, the subject may elect to have a biopsy performed to obtain tissue. * Has adequate organ function including: * Hematopoietic function as follows: 1. Absolute neutrophil count (ANC) ≥ 1.5 x 10 9/L 2. Platelet count ≥ 100 x 10 9/L 3. Hemoglobin ≥ 9 g/dL (transfusions are allowed) * Renal Function as follows: 1\. Creatinine ≤ 1.5 x upper limit of normal (ULN), or calculated glomerular filtration rate (GFR) \> 40 mL/min (Cockcroft-Gault) if creatinine \> 1.5x ULN * Hepatic function, as follows: 1. Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) ≤ 2.5 x ULN or ≤ 5x ULN if known liver metastases 2. Total bilirubin ≤ 1.5 x ULN * Prothrombin time (PT) and activated partial thromboplastin time (aPTT) levels ≤1.5 x ULN. If institution does not report PT value, the international normalization ratio (INR) must be ≤ ULN. * If subject is receiving Coumadin (warfarin), a stable international normalization ratio (INR) of 2-3 is required. * No clinical symptoms of hypothyroidism * Urine Protein to Creatinine Ratio (uPCR) \< 2.0 * If uPCR ≥ 2.0 then a 24-hour urine collection can be performed to qualify. If this is performed to qualify, the protein result must be \< 2 g per 24 hours. * Female subject must either: * Be of non-childbearing potential: 1. post-menopausal (defined as at least 1 year without any menses) prior to Screening, or 2. documented surgically sterile * Or, if of childbearing potential, 1. Agree not to try to become pregnant during the study and for 6 months after the final study drug administration 2. And have a negative serum pregnancy test ≤ 10 days of cycle 1, day 1 (C1D1) * And, if heterosexually active, agree to consistently use 2 forms of highly effective birth control\* (at least one of which must be a barrier method) starting at Screening and throughout the study period and for 6 months after the final study drug administration. * Female subject must agree not to breastfeed starting at Screening and throughout the study period, and for 6 months after the final study drug administration. * Female subject must not donate ova starting at Screening and throughout the study period, and for 6 months after the final study drug administration. * Male subject and their female spouse/partners who are of childbearing potential must be using highly effective contraception\* consisting of 2 forms of birth control (at least one of which must be a barrier method) starting at Screening and continue throughout the study period, and for 6 months after the final study drug administration * Male subject must not donate sperm starting at Screening and throughout the study period and, for 6 months after the final study drug administration Note: \*Highly effective forms of birth control include: * Consistent and correct usage of established oral contraception. * Established intrauterine device (IUD) or intrauterine system (IUS). * Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository Exclusion Criteria: * Has previously been treated with axitinib, AGS-16C3F, or AGS-16M8F * Has untreated brain metastasis. In the case of a solitary brain metastasis which has been resected, there must be evidence of a disease-free interval of at least 3 months post-surgery. For brain metastases treated with whole brain or stereotactic radiation therapy, brain imaging must be stable \> 3 months. All subjects previously treated for brain metastases must be stable off corticosteroid therapy for at least 28 days prior to C1D1. * Has uncontrolled hypertension defined as blood pressure \> 150/90 on medication(s) by 2 blood pressure readings taken at least 1 hour apart. * Has gastrointestinal abnormalities including: * inability to take oral medication; * requirement for intravenous alimentation; * prior surgical procedures affecting absorption including total gastric resection; * active gastrointestinal bleeding, unrelated to cancer, as evidenced by hematemesis, hematochezia or melena in the past 3 months without evidence of resolution documented by endoscopy or colonoscopy; * malabsorption syndromes such as celiac disease, cystic fibrosis, inflammatory bowel disease, systemic sclerosis, and carcinoid syndrome * Has ocular conditions such as: * Active infection or corneal ulcer * Monocularity * Visual acuity of 20/70 or worse in both eyes * History of corneal transplantation * Contact lens dependent (if using contact lens, must be able to switch to glasses during the entire study duration) * Uncontrolled glaucoma (topical medications allowed) * Uncontrolled or active ocular problems (e.g., retinopathy, macular edema, active uveitis, wet macular degeneration) requiring surgery, laser treatment, or intravitreal injections * Papilledema or other active optic nerve disorder * Has used any investigational drug (including marketed drugs not approved for this indication) ≤ 14 days of C1D1. No time limit applies to the use of marketed drugs approved for this indication provided that the subject has progressed on the treatment and all toxicities attributable to the drug have resolved, returned to baseline or stabilized. * Has known sensitivity to any of the ingredients of: * investigational product AGS-16C3F and/or, * Inlyta® (axitinib) and/or, * 1% prednisolone acetate ophthalmic suspension and any other corticosteroids. * Is currently using (i.e., within 14-days prior to first dose) drugs that are known strong CYP3A4/5 inhibitors / inducers. * Thromboembolic event (e.g., deep vein thrombosis \[DVT\] and pulmonary embolism \[PE\]) ≤ 4 weeks of C1D1. * Subjects who had a thromboembolic event ≤ 4 weeks of C1D1 must be receiving adequate anticoagulation treatment for at least 2 weeks before C1D1 and must continue as clinically indicated post first dose * Has history bleeding disorders (e.g., pulmonary hemorrhage, significant hemoptysis, menometrorrhagia not responding to hormonal treatment) ≤ 2 months before C1D1 * Has active angina or Class III or IV Congestive Heart Failure (New York Heart Association CHF Functional Classification System) or clinically significant cardiac disease within 6 months of randomization, including myocardial infarction, unstable angina, Grade 2 or greater peripheral vascular disease, congestive heart failure, or arrhythmias not controlled by medication. * Had major surgery ≤ 4 weeks of C1D1 * Is pregnant (confirmed by positive serum pregnancy test) or lactating * Has active infection requiring treatment with systemic (intravenous or oral) anti-infectives (antibiotic, antifungal, or antiviral agent) ≤ 10 days of C1D1 * Is unwilling or unable to comply with study requirements * Has any medical or psychiatric disorder that compromises the ability of the subject to give written informed consent, and/or comply with the study procedures.