This randomized phase II trial studies how well ziv-aflibercept (VEGF Trap) works in treating patients with kidney cancer that has spread from the primary site to other places in the body (metastatic) or is unable to be removed with surgery (unresectable). Ziv-aflibercept may stop the growth of kidney cancer by blocking blood flow to the tumor.

PRIMARY OBJECTIVE:

I. To determine the effect of two different doses of AVE0005 (vascular endothelial growth factor [VEGF] Trap [ziv-aflibercept]) treatment on the progression-free proportion at 8 weeks in patients with metastatic renal cell carcinoma who had previous treatment with a tyrosine kinase inhibitor (TKI).

SECONDARY OBJECTIVES:

I. To determine the effect of AVE0005 (VEGF Trap) treatment on objective response rate in patients with metastatic renal cell carcinoma who have had previous TKI treatment.

II. To describe progression-free survival among patients who undergo dose escalation following progression on low-dose AVE0005 (VEGF Trap).

III. To evaluate the safety and tolerability of AVE0005 (VEGF Trap) in patients with metastatic renal cell carcinoma who have had previous treatment with a TKI.

OTHER PRE-SPECIFIED OBJECTIVES:

I. To determine the circulating levels of VEGF AVE0005 (VEGF-Trap) complex and correlate it with clinical activity.

II. To evaluate the modulation of specific angiogenesis-related protein expression by AVE0005 (VEGF Trap).

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM A (Higher dose of VEGF Trap): Patients receive a higher dose of ziv-aflibercept intervenously (IV) over 1 hour on day 1.

ARM B (Lower dose of VEGF Trap): Patients receive a lower dose of ziv-aflibercept IV over 1 hour on day 1.

In both arms, courses repeat every 14 days in the absence of disease progression or unacceptable toxicity. Patients receiving treatment on Arm B may crossover and receive treatment on Arm A at the time of disease progression.

After completion of study treatment, patients are followed every 3 months for 2 years and then every 6 months for 1 year.

Inclusion Criteria:

• Histologically confirmed metastatic or unresectable renal cell carcinoma; disease must be conventional clear cell carcinoma or have a component of clear cell carcinoma
• Patient must have measurable lesions according to the Response Evaluation Criteria In Solid Tumors (RECIST); baseline measurements must be performed =< 4 weeks prior to randomization
• Patient must have evidence of progressive disease following treatment with a tyrosine kinase inhibitor (TKI) as assessed by the site investigator on the basis of computed tomography (CT) scans and other appropriate clinical documentation
• Patient must have received at least one prior treatment with a VEGF receptor tyrosine kinase inhibitor for at least 12 weeks; prior treatment with either temsirolimus or everolimus is allowed; prior immunotherapy is limited to cytokine therapy with interleukin 2 and interferon alpha only
• Previous radiotherapy (RT) is permissible provided the measurable disease is outside the RT port; RT must be completed >= 3 weeks prior to randomization
• Eastern Cooperative Oncology Group (ECOG) performance status 0-2
• Patient must have recovered from any toxic effects of prior radiotherapy or surgical procedures within 4 weeks prior to randomization
• Adequate organ function as defined in the protocol
• For women of childbearing potential, a negative serum pregnancy test is required within 1 week prior to randomization
• Women of childbearing potential and sexually active males must agree to use an accepted and effective method of contraception while on this study, and for 6 months after the completion of the study; if a woman becomes pregnant while she is on this study or within 6 months after the last dose of protocol therapy, she must inform her treating physician immediately; if a man impregnates a woman while he is on this study or within 6 months after the last dose of protocol therapy, he must inform his treating physician immediately
• Patients who have had basal cell skin cancer, squamous cell skin cancer, in situ cervical cancer, ductal carcinoma in situ of the breast, or lobular carcinoma in situ of the breast within the past five years are eligible only if treated with curative intent; patients with other malignancies are eligible only if they have been continuously disease-free for > 5 years prior to the time of randomization

Exclusion Criteria:

• True papillary, sarcomatoid features without any clear cell component, chromophobe, oncocytoma, collecting duct tumors and transitional cell carcinoma are not eligible
• Prior immunotherapy other than cytokine therapy with interleukin 2 and interferon alpha
• Prior treatment with bevacizumab
• Prior cellular therapy, vaccine, hormonal or chemotherapy for renal cell carcinoma; prior therapy for other cancers is allowable if therapy ended at least 5 years prior to enrollment
• History of metastatic central nervous system (CNS) disease
• Pregnant or breastfeeding
• Myocardial infarction, severe/unstable angina pectoris, coronary/peripheral artery bypass graft, New York Heart Association (NYHA) class III or IV congestive heart failure, cerebrovascular accident or transient ischemic attack within 24 weeks prior to randomization
• Prior pulmonary embolism, deep vein thrombosis, or other thromboembolic event
• History of uncontrolled or labile hypertension, with or without antihypertensive drug treatment, within 12 weeks prior to drug administration; this is defined as blood pressure > 150/100 mm Hg or systolic blood pressure > 180 mm Hg on at least 2 repeated determinations on separate days
• Active infection, evidence of bleeding or intratumoral bleeding, or underlying bleeding disorder
• History of hypersensitivity to any Trap agents or recombinant proteins
• Human immunodeficiency virus (HIV)-positive patients receiving combination anti-retroviral therapy

Individual participant data may be made available upon request as per the ECOG-ACRIN Data Sharing Policy.