A Phase II Randomized Study of Nivolumab (NSC-748726) with Ipilimumab (NSC-732442) OR Ipilimumab Alone in Advanced Melanoma Patients Refractory to an Anti-PD-1 or Anti-PD-L1 Agent

� Patients must have pathologically confirmed melanoma that is either Stage IV or unresectable Stage III. Patients may have primaries of cutaneous, mucosal or unknown origin. Patients with uveal (ocular) primary are not eligible.
� Patients must have measurable disease per RECIST 1.1 (see Section 10.1).
� Patients with central nervous system (CNS) metastases must have all lesions adequately treated with stereotactic radiation therapy, craniotomy, Gamma Knife� therapy, or whole brain radiotherapy, with no subsequent evidence of CNS progression. Patients must not have required steroids for at least 14 days prior to registration.

PRIOR/CONCURRENT THERAPY CRITERIA
� Patients must have had prior treatment with anti-PD1 or anti-PD-L1 agents and had documented disease progression either while on these agents or after stopping therapy with these agents without intervening therapy. Patients must have discontinued anti-PD-1 or anti-PD-L1 therapy at least 21 days prior to registration.
� Patients must not have: achieved a confirmed partial or complete response to the anti-PD-1 or anti-PD-L1 agents prior to progression; had any systemic therapy, including anti-PD-1 or anti-PD-L1 agents (see Section 5.1c), within 21 days prior to registration; had prior radiation therapy within 14 days prior to registration; had prior treatment with ipilimumab or other CTLA-4 antagonists; had systemic therapy between progression on the anti-PD-1 or anti-PD-L1 agents and registration; NOTE: Systemic therapy (including BRAF-targeting agents) prior to anti-PD-1 or anti-PD-L1 therapy is allowed.
� Patients must not be planning to require any additional form of systemic anti-tumor therapy while on protocol treatment.

CLINICAL/LABORATORY CRITERIA

� Patients must: be greater than or equal to 18 years of age, have Zubrod Performance Status of less than or equal to 2 (see Section 10.4), have complete history and physical examination within 28 days prior to registration, have adequate hematologic function as evidenced by all of the following within 28 days prior to registration: absolute neutrophil count (ANC) greater than or equal to 1,500/mcL; hemoglobin greater than or equal to 8 g/dL; and platelets greater than or equal to 100,000/mcL, have adequate hepatic function as evidenced by all of the following within 28 days prior to registration: total bilirubin less than or equal to 2.5 x Institutional Upper Limit of Normal (IULN) (except patients with Gilbert�s syndrome); and AST and ALT both less than or equal to 5 x IULN, have adequate kidney function as evidenced by serum creatinine less than or equal to 2.0 x IULN within 28 days prior to registration.
� Patients with a known history of HIV must have CD4 count greater than or equal to institutional lower limit of normal within 28 days prior to registration.
� Patients must not have: known active Hepatitis B Virus (HBV) or Hepatitis C Virus (HCV) infection prior to registration, an active infection requiring systemic therapy at time of registration, or organ allografts.
� Patients must not have received systemic treatment with corticosteroids (> 10 mg daily prednisone or equivalent) or other immunosuppressive medications within 14 days prior to registration. Inhaled or topical steroids, and adrenal replacement doses less than or equal to 10 mg daily prednisone or equivalent are permitted in the absence of active autoimmune disease.
� Patients must not have a history of: immune-mediated pneumonitis or colitis that required interruption of therapy or treatment of steroids; congestive heart failure (CHF), cardiomyopathy, myocarditis, myocardial infarction (MI), exposure to cardiotoxic medications, or with a clinical history suggestive of the above must have an EKG and Echocardiogram (ECHO) performed within 42 days prior to registration and as clinically indicated while on treatment.
� Patients with new symptoms of congestive heart failure (CHF), cardiomyopathy, myocarditis, myocardial infarction (MI), or exposure to cardiotoxic medications must have a cardiology consultation, creatinine phosphokinase (CPK), and troponin testing at prestudy and as clinically indicated.
� No other prior malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated Stage 0, I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease free for two years.
� Patients must not be pregnant or nursing due to risk of fetal or nursing infant harm. Females of reproductive potential must have negative serum pregnancy test within 2 days prior to registration and agree to use an effective contraceptive method throughout the study and for 5 months after completion of protocol treatment. Males who are sexually active with women of reproductive potential must have agreed to use birth control throughout the study and for 7 months after completion of protocol treatment.

SPECIMEN SUBMISSION CRITERIA
� Patients must be offered the opportunity to submit archival tissue for translational medicine as described in Section 15.1. Patients must also be willing to undergo biopsies and submit tissue and blood for translational medicine as described in Section 15.1.