Randomized Phase II Study of AB (Nab-Paclitaxel [Abraxane?], Bevacizumab) Versus Ipilimumab for Therapy of Unresectable Stage IV Metastatic Malignant Melanoma

• Histologic or cytologic proof of surgically unresectable stage IV malignant melanoma - including that of uveal and mucosal origin

⁃ Note: biopsy can be of locoregional disease in setting of clinically evident stage IV disease; a biopsy of the primary tumor alone does not fulfill this requirement

• No more than 2 prior courses of systemic therapy for metastatic melanoma

• For patients with metastatic melanoma not of uveal origin, v-raf murine sarcoma viral oncogene homolog B1 (BRAF) V600 mutation determination using a Clinical Laboratory Improvement Amendments (CLIA)-approved testing method on metastatic tumor tissue

⁃ NOTE: patients with metastatic melanoma of uveal origin do not need to have formal BRAF testing due to low probability of a BRAF V600 mutation in their metastatic tumor

• Measurable disease; note: disease that is measurable by physical examination only is not eligible

• Life expectancy of \>= 4 months

• Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1

• Absolute neutrophil count \>=1500/mL (obtained =\< 14 days prior to registration/randomization)

• Platelet count \>= 100,000 x 10\^9/L (obtained =\< 14 days prior to registration/randomization)

• Hemoglobin \>= 9 g/dL (obtained =\< 14 days prior to registration/randomization) (patients may be transfused to meet this requirement)

• Creatinine =\< 1.5 x upper limit of normal (ULN) (obtained =\< 14 days prior to registration/randomization); institutional norms are acceptable

• Total bilirubin =\< 1.5 mg/dL (obtained =\< 14 days prior to registration/randomization) (exception: patients with documented Gilbert?s syndrome are allowed to participate despite elevated bilirubin)

• Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase \[AST\]) =\< 2.5 x ULN and serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase \[ALT\]) =\< 2.5 x ULN (obtained =\< 14 days prior to registration/randomization)

• Alkaline phosphatase =\< 2.5 x ULN (obtained =\< 14 days prior to registration/randomization); if bone metastasis is present in the absence of liver metastasis then =\< 5 x ULN

• Urine dipstick for proteinuria \< 2+ (obtained =\< 14 days prior to registration/randomization) (patients discovered to have \>= 2+ proteinuria on dipstick urinalysis at baseline should undergo a 24 hour urine collection and must demonstrate =\< 1 g of protein in 24 hours to be eligible)

• Negative serum pregnancy test done =\< 7 days prior to registration/randomization, for women of childbearing potential only

⁃ Note:

∙ Females: adequate contraception must be used by both patient and partner while receiving study drug and for 12 weeks after the last dose of study drug

‣ Males: adequate contraception must be used by both patient and partner while receiving study drug; men who have a partner of childbearing age should also avoid fathering a child for 6 months after the last dose of study drug

• Ability to understand and the willingness to sign a written informed consent document

• Mayo Rochester patients only: willingness to provide mandatory blood samples for research purposes