Ipilimumab and Nivolumab Followed by Adjuvant Nivolumab in Locally Advanced or Limited Metastatic Melanoma

Inclusion Criteria:

1. Patients must have histologically or cytologically confirmed 8th ed. AJCC Stage IIIB/C/D or Stage IV oligometastatic resectable melanoma. Patients with cutaneous, mucosal, acral, ocular or unknown primary melanomas are eligible for enrollment. Oligometastatic melanoma is defined as three or fewer areas of resectable disease excluding central nervous system and bone involvement. In case of involvement of three areas, one must be superficial (cutaneous-subcutaneous). Resectable tumors are defined as having no significant vascular, neural or bony involvement. A multidisciplinary discussion within surgical oncologists, medical oncologists, and radiologist will assess if disease is resectable.
2. Signed Written Informed Consent.
3. Patients must be willing and able to comply with scheduled visits, treatment schedule, laboratory tests and all protocol procedures.
4. Males and Females, ages ≥18 years of age.
5. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
6. Have measurable disease based on RECIST 1.1.
7. Be willing to provide tissue from a newly obtained core or excisional biopsy of a tumor lesion at baseline and at the time points specified in the Study Procedure Tables.
8. Known BRAF V600 mutation status as determined by local institutional standard. All BRAF statuses (BRAF wild type or BRAF 600 mutation positive) are eligible.
9. Patients who have been previously treated in the adjuvant setting for melanoma will be eligible for treatment after a 28 day washout period.
10. Patients must be medically fit enough to undergo surgery as determined by the treating medical and surgical oncology team.
11. Demonstrate adequate organ function as defined below: Hematologic Absolute neutrophil count (ANC) \>/= 1.5 X 10\^9/L; Hemoglobin \>/= 9.5 g/dL Platelets \>/= 100 X 10\^9/L PT/INR and PTT \</= 1.5 X ULN. Hepatic Total bilirubin \</= 1.5 X ULN (isolated bilirubin \>1.5 X ULN is acceptable if bilirubin is fractionated and direct bilirubin \<35%) AST and ALT Albumin \</= 2.5 X ULN 1 \>/=2.5 g/dL Renal Creatinine OR Calculated creatinine clearance OR 24-hour urine creatinine clearance \</=1.5 X ULN 2 \>/= 50 mL/min \>/= 50 mL/min.
12. Women are eligible to participate if: non-childbearing potential defined as pre-menopausal females with a documented tubal ligation or hysterectomy; or postmenopausal defined as months of spontaneous amenorrhea \[in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) \> 40 MlU/mL and estradiol \< 40 pg/mL (\<140 pmol/L) is confirmatory\]. Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the contraception methods if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of post-menopausal status prior to study enrollment. For most forms of HRT, at least 2-4 weeks will elapse between the cessation of therapy and the blood draw; this interval depends on the type and dosage of HRT.
13. The individual methods of contraception and duration should be determined in consultation with the investigator. Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of investigational product.
14. Women must not be breastfeeding.
15. Men who are sexually active must use any contraceptive method with a failure rate of less than 1% per year. The investigator shall review contraception methods and the time period that contraception must be followed.
16. Women who are not of childbearing potential (i.e., who are postmenopausal or surgically sterile) and azoospermic men do not require contraception

Exclusion Criteria:

1. Currently receiving cancer therapy (chemotherapy, radiation therapy, immunotherapy, or biologic therapy) or investigational anti-cancer drug.
2. Any major surgery within the last 3 weeks.
3. Brain metastases, leptomeningeal disease or bone metastases.
4. Pregnant or lactating female.
5. Unwillingness or inability to follow the procedures required in the protocol.
6. Any serious or uncontrolled medical disorder that, in the opinion of the investigator, may increase the risk associated with study participation or study drug administration, impair the ability of the subject to receive protocol therapy, or interfere with the interpretation of study results.
7. Prior malignancy active within the previous 2 years except for patient's prior diagnosis of melanoma and locally curable cancers that have been apparently cured, such as basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the prostate, cervix, or breast with local control measures (surgery, radiation).
8. Patients with active, known or suspected autoimmune disease. Patients with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll.
9. Patients with a condition requiring systemic treatment with either corticosteroids (\> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement doses \> 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.
10. Prior treatment with an anti-PD-1, anti-PD-L1 or anti-CTLA-4 antibody.
11. Any positive test result for hepatitis B or C virus indicating acute or chronic infection.
12. Known history of testing positive for human immunodeficiency virus or known acquired immunodeficiency syndrome.
13. History of severe hypersensitivity reaction to any monoclonal antibody.
14. Prisoners or patients who are involuntarily incarcerated.
15. Patients who are compulsorily detained for treatment of either a psychiatric or physical (infection disease) illness.