SAbR Plus Ipilimumab Plus Nivolumab in Metastatic Melanoma Patients

Inclusion Criteria:

* Histologic diagnosis of metastatic melanoma.
* Any number of prior systemic therapeutic regimens including chemotherapy, pathway inhibitors, biochemotherapy, investigational agents, and immunotherapies other than ipilimumab, nivolumab or other CTLA-4, PD-1 or PD-L1 inhibitors.
* Patients must have measurable disease in at least 2 non-radiated sites as defined by RECIST v1.1. All sites must be evaluated within 4 weeks prior to registration.
* Age ≥ 18 years.
* Eligible for SABR to 1-5 sites of disease (Refer to 3.2.10)
* Performance status ECOG 0-2.
* Adequate organ and marrow function as defined below:

  * leukocytes ≥ 1,000/mcL
  * absolute neutrophil count ≥ 1,000/mcL
  * platelets ≥ 75,000/mcl
  * total bilirubin \< 2.5X institutional upper limit of normal or

    * 3 in subjects with Gilbert's Syndrome
  * AST(SGOT)/ALT(SPGT) ≤ 4 X institutional upper limit of normal
  * creatinine \< 4X institutional upper limit of normal
  * hemoglobin \>7g/dL
* Ability to understand and the willingness to sign a written informed consent.
* Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of protocol treatment. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately. A female of child-bearing potential is any woman (regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria: has not undergone a hysterectomy or bilateral oophorectomy; or has not been naturally postmenopausal for at least 12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive months).

Exclusion Criteria:

* No concomitant therapy with any of the following: IL2, interferon, or other non-study immunotherapy regimens; cytotoxic chemotherapy; immunosuppressive agents; or other investigational therapies; all such therapies must have been discontinued \>4weeks prior to registration.
* No infection with HIV and no known history of hepatitis B or hepatitis C virus indicating acute or chronic infection or active TB.
* Patients are excluded if they have a history of any other malignancy from which the patient has been disease-free for less than 2 years, with the exception of adequately treated (Surgery or radiation) and cured basal or squamous cell skin cancer, superficial bladder cancer, carcinoma in situ of the cervix, or localized adenocarcinoma of the cervix.
* Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
* Patients must not be pregnant or nursing.
* Patients are excluded if they have a history of prior treatment with ipilimumab, CTLA-4 inhibitor or agonist, nivolumab, PD-1 or PD-L1 inhibitor.
* Subjects who have had major surgery within 2 weeks prior to first dose of drug
* Subjects who have had radiation therapy within 2 weeks prior to first dose of drug
* Uncontrolled adrenal insufficiency or active chronic liver disease
* Any history of CNS metastases that is not adequately treated (surgery or radiation ) \>14 days prior to registration.
* Any active known or suspected autoimmune disease. Subjects 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.
* Any condition requiring systemic treatment with either corticosteroids (\> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days prior to the first dose of study drug. Inhaled steroids and adrenal replacement steroid doses up to 10 mg daily prednisone equivalent are permitted (although not encouraged) in the absence of active autoimmune disease.
* Subjects with life expectancy \< 6 months
* Subjects receiving any other investigational or standard antineoplastic agents.