Neoadjuvant Ipilimumab/Nivolumab for Patients With Recurrent, High Risk, Resectable Melanoma

Inclusion Criteria:

• Subjects aged ≥ 18 years.

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

• Recurrent disease at eligibility must have been confirmed with biopsy whilereceiving or within 3 months of completion of adjuvant anti-PD1 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 livermetastases 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 ofpost-menopausal status or evidence of permanent surgical sterilization. Thepost-menopausal status will be defined as having been amenorrheic for 12 monthswithout an alternative medical cause. The following age-specific requirements apply:

• Subjects < 50 years of age:

• Amenorrheic for ≥ 12 months following cessation of exogenous hormonaltreatments; and

• Luteinizing hormone and follicle-stimulating hormone levels in thepost-menopausal range for the institution

• Subjects ≥ 50 years of age:

• Amenorrheic for ≥ 12 months following cessation of all exogenous hormonaltreatments; 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 ofchildbearing potential must agree to use a highly effective method of contraceptionas described in Section 5.3.1.

• Subject has adequate archival tissue or agrees to undergo a fresh tissue biopsy ifsufficient archival tissue is unavailable.

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

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

Exclusion Criteria:

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

• Prior systemic anti-cancer therapy ≤ 14 days or within five half-lives prior tostarting 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 recoveredfrom 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 toregistration.

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

• Known brain metastases or cranial epidural disease.

• Current evidence of uncontrolled, significant intercurrent illness including, butnot limited to, the following conditions:

--Cardiovascular disorders:

• Congestive heart failure New York Heart Association Class III or IV, unstableangina 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 ofthree consecutive blood pressure measurements taken over 10 minutes.

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

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

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

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

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

• Medical, psychiatric, cognitive, or other conditions that may compromise thesubject'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 componentin its formulations (NCI CTCAE v5.0 Grade ≥ 3).

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