This study to evaluate treatment in patients with metastatic renal cell carcinoma (RCC) which has progressed through 2 to 3 prior lines of therapy, with the investigational drug CRLX101 in combination with bevacizumab compared to treatment with a standard of care therapy. The study will compare which treatment resulted in longer time before progression of the RCC. Patients will be treated and followed for progression of their disease on average for up to 6 months.

Inclusion Criteria:

• Must have histologically confirmed renal cell carcinoma of any pathologic subtype.
• Must have unresectable metastatic disease, and have tumor(s) present that is (are) evaluable by the RECIST, v1.1; may have spinal-associated metastases but must have concluded dexamethasone therapy and be evaluated by the Investigator to have stable CNS disease.
• Must have received 2 or 3 prior lines of conventional molecularly targeted therapy
• Must have full recovery from any toxicities from prior therapy CTCAE Grade 1 or less with the exception of Grade 2 alopecia) prior to randomization.
• ECOG performance status 0 or 1.
• Age 18 years and older.
• Life expectancy of at least 3 months.
• Must have normal organ and marrow function reported within 14 days prior to randomization
• Ability to understand and willingness to sign a written informed consent document.
• Able to comply with study visit schedule and assessments.

Exclusion Criteria:

• Any conventional molecularly targeted therapy within 2 weeks or, chemotherapy or radiotherapy within 2 weeks (local) or 4 weeks (systemic) prior to entering the study.
• Failure to recover to grade 1 or less all prior adverse events.
• Any major surgery within 4 weeks of study randomization.
• Any prior treatment with topoisomerase I therapy.
• Prior treatment with any drugs or therapies that will be administered during the course of this trial including CRLX101, any topoisomerase 1 inhibitor, bevacizumab or the conventional molecularly targeted agent intended for use as standard of care treatment.
• Patients receiving any other current investigational therapeutic agent.
• Other active malignancies
• Patients with brain metastasis treated or untreated, or other CNS disease
• Any clinically significant cardiac disease defined as NYHA class III or IV.
• Uncontrolled hypertension
• Uncontrolled concurrent illness
• History of non-healing wounds or ulcers.
• Pregnancy, or inadequate contraception for men or women of childbearing age, or lactating / breast-feeding
• Patients with known HIV or with solid organ transplant