The goal of this clinical trial is to study the impact of Neoadjuvant ipilimumab and nivolumab for melanoma patients that had recurrence during or after adjuvant anti-PD-1 therapy.

Participants will receive 2 cycles of treatment prior to their standard of care surgery. After surgery participants will receive standard of care adjuvant therapy and be followed for response.

Inclusion Criteria:

• Subjects aged ≥ 18 years.

• Histologically confirmed Stage IIIB-D or Stage IV recurrent metastatic melanoma that is resectable or borderline resectable as determined by a Surgical Oncologist.

• Recurrent disease at eligibility must have been confirmed with biopsy after receiving prior anti-PD1 based systemic therapy (either adjuvant, neoadjuvant, or definitive therapy).

• ECOG Performance Status ≤ 1.

• Adequate organ function as defined as:

  • Hematologic:

    • Absolute neutrophil count (ANC) ≥ 1500/mm3
    • Platelet count ≥ 100,000/mm3
    • Hemoglobin ≥ 10 g/dL

  • Hepatic:

    • Total Bilirubin ≤ 1.5x institutional upper limit of normal (ULN)

    • AST(SGOT)/ALT(SGPT) ≤ 3 × institutional ULN

      • Subjects with liver metastases will be allowed to enroll with AST and ALT levels ≤ 5 x ULN.

  • Renal:

    • Estimated creatinine clearance ≥ 50 mL/min by Cockcroft-Gault formula:

• For subjects of childbearing potential: Negative pregnancy test or evidence of post-menopausal status or evidence of permanent surgical sterilization. The post-menopausal status will be defined as having been amenorrheic for 12 months without an alternative medical cause. The following age-specific requirements apply:

  • Subjects < 50 years of age:

    • Amenorrheic for ≥ 12 months following cessation of exogenous hormonal treatments; and
    • Luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution

  • Subjects ≥ 50 years of age:

    • Amenorrheic for ≥ 12 months following cessation of all exogenous hormonal treatments; or
    • Had radiation-induced menopause with last menses >1 year ago; or
    • Had chemotherapy-induced menopause with last menses >1 year ago

• Subjects of childbearing potential and subjects with a sexual partner of childbearing potential must agree to use a highly effective method of contraception.

• Recovery to baseline or ≤ Grade 1 CTCAE v5 from toxicities related to any prior treatments, unless AE(s) are clinically nonsignificant and/or stable on supportive therapy per the treating investigator.

• Able to provide informed consent and willing to sign an approved consent form that conforms to federal and institutional guidelines.

Exclusion Criteria:

• Prior exposure to anti-CTLA4 therapy.

• Receiving other investigational agents currently or within 28 days of study treatment.

• Prior systemic anti-cancer therapy ≤ 14 days or within five half-lives prior to starting study treatment, whichever is shorter.

• Prior radiotherapy 45 days prior to the first dose of study treatment.

• Major surgery 4 weeks prior to starting study drug or who have not fully recovered from major surgery.

• Active infection requiring the use of systemic antibiotics.

• Systemic steroid therapy greater than physiologic equivalent (10mg prednisone/day) or any other form of systemic immunosuppressive therapy within 7 days prior to registration.

• Active secondary malignancy, unless the malignancy is not expected to interfere with the evaluation of safety

• Known brain metastases or cranial epidural disease.

• Current evidence of uncontrolled, significant intercurrent illness including, but not limited to, the following conditions:

  • Cardiovascular disorders:

    • Congestive heart failure New York Heart Association Class III or IV, unstable angina pectoris, serious cardiac arrhythmias.
    • Stroke (including transient ischemic attack [TIA]), myocardial infarction (MI), or other ischemic events, or thromboembolic event (eg, deep venous thrombosis, pulmonary embolism) within 3 months before the first dose.
    • QTc prolongation defined as a QTcF > 500 ms.
    • Known congenital long QT.
    • Left ventricular ejection fraction < 55%.
    • Uncontrolled hypertension defined as ≥ 140/90 as assessed from the mean of three consecutive blood pressure measurements taken over 10 minutes.

  • Any other condition that would, in the Investigator's judgment, contraindicate the subject's participation in the clinical study due to safety concerns or compliance with clinical study procedures (e.g., infection/inflammation, intestinal obstruction, unable to swallow medication, [subjects may not receive the drug through a feeding tube], social/psychological issues, etc.)

• HIV infection with a detectable viral load within 6 months of the anticipated start of treatment.

  --Note: Subjects on effective antiretroviral therapy with an undetectable viral load within 6 months of the anticipated start of treatment are eligible for this trial.

• Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination, radiographic findings, and TB testing in line with local practice), hepatitis B (positive HBV surface antigen (HBsAg) result), or hepatitis C.

  --Note: Subjects with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Subjects positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA.

• Medical, psychiatric, cognitive, or other conditions that may compromise the subject's ability to understand the subject information, give informed consent, comply with the study protocol or complete the study.

• Known prior severe hypersensitivity to investigational product (IP) or any component in its formulations (NCI CTCAE v5.0 Grade ≥ 3).

• Subjects taking prohibited medications as described in Section 6.7.2. A washout period of prohibited medications for a period of at least five half-lives or as clinically indicated should occur before the start of treatment.