Ipilimumab and Nivolumab before Surgery for the Treatment of Recurrent, High Risk, Resectable Stage IIIB-IV Metastatic Melanoma (NeoRelapse)

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 while receiving or within 3 months of completion of adjuvant anti-PD1 therapy
• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1
• Absolute neutrophil count (ANC) ≥ 1500/mm^3
• Platelet count ≥ 100,000/mm^3
• Hemoglobin ≥ 10 g/dL
• Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN)
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) ≤ 3 x institutional ULN * Subjects with liver metastases will be allowed to enroll with AST and ALT levels ≤ 5 x ULN
• 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
• Subject has adequate archival tissue or agrees to undergo a fresh tissue biopsy if sufficient archival tissue is unavailable
• Recovery to baseline or ≤ grade 1 Common Terminology Criteria for Adverse Events (CTCAE) version (v)5 from toxicities related to any prior treatments, unless adverse events (AEs) 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

• 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 ** Corrected QT (QTc) prolongation defined as a Fredericia's Correction Formula (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 tuberculosis [TB] testing in line with local practice), hepatitis B (positive hepatitis B virus [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 (hepatitis C virus [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 (National Cancer Institute [NCI] CTCAE v5.0 grade ≥ 3)
• Subjects taking prohibited medications. 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