IL2 With Ipilimumab Followed by Nivolumab in Stage 3 or 4 Melanoma Patients

Inclusion Criteria:

• Histologically or cytologically confirmed metastatic melanoma. This includesAmerican Joint Committee on Cancer (AJCC) stage IV or advanced/inoperable stage III.This also includes patients with a history of lower stage melanoma and subsequentrecurrent metastatic disease that is either locally/regionally advanced/inoperabledisease or distant metastases

• Measurable disease, according to RECIST version 1.1

• Must be free of active brain metastasis by contrast-enhanced CT/MRI scans within 4weeks prior to enrollment. If known to have prior brain metastases, these must havebeen adequately managed with standard of care radiation therapy, stereotacticradiosurgery or surgery prior to registration on the study.

• Must have previously received anti-PD1 immunotherapy (nivolumab or pembrolizumab)and later experienced disease progression.

• Must not have received systemic therapy or radiotherapy (including SRS) within thepreceding 3 weeks. Patients must have recovered from adverse events from previoustherapy by the time registration.

• Must be at least 4 weeks from major surgery and have fully recovered from anyeffects of surgery, and must be free of significant detectable infection prior toregistration.

• Patients who have received prior anti-CTLA4 monoclonal antibody therapy (ipilimumabor tremelimumab) are eligible.

• Patients who have previously experienced prior high-grade (grade 3 or 4 by CTCAEcriteria) immune related adverse events with immune checkpoint inhibitors must bediscussed with the study PI and cleared prior to enrollment on this study in orderto ensure patient safety.

• Patients with BRAF V600 mutant melanoma must have previously received BRAF targetedtherapy for metastatic melanoma and later experienced disease progression. Patientswho refuse or decline to receive BRAF targeted therapy or were intolerant of BRAFtargeted therapy are eligible.

• Life expectancy of greater than 3 months in the opinion of the investigator

• Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1

• Must have normal organ and marrow function as specified per protocol.

• Patients on full-dose anticoagulants with Prothrombin Time Test InternationalNormalized Ratio (PT INR) >1.5 are eligible provided that both of the followingcriteria are met: (a) The patient has an in-range INR (usually between 2 and 3) on astable dose of oral anticoagulant or on a stable dose of low molecular weightheparin. (b) The patient has no active bleeding or pathological condition thatcarries a high risk of bleeding (e.g., tumor involving major vessels or knownvarices).

• Pulmonary: Forced Expiratory Volume at 1 second (FEV1) > 2.0 liters or > 75% ofpredicted for height and age. Pulmonary function tests (PFTs) are required forpatients over 50 years old or with significant pulmonary or smoking history

• No evidence of congestive heart failure, symptoms of coronary artery disease,myocardial infarction less than 6 months prior to entry, serious cardiacarrhythmias, or unstable angina.

• Patients who are over 40 years old or have had previous myocardial infarctiongreater than 6 months prior to study entry or have significant cardiac familyhistory (CAD or serious arrhythmias) will be required to have a negative or lowprobability cardiac stress test (for example, thallium stress test, stressmultigated acquisition scan (MUGA), stress echo or exercise stress test) for cardiacischemia within 8 weeks prior to registration.

• No history of cerebrovascular accident or transient ischemic attacks within the past 6 months from registration.

• 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, forthe duration of study participation, and for at least 6 months after completion ofstudy therapy. Should a woman become pregnant or suspect she is pregnant whileparticipating in this study, she should inform her treating physician immediately.

• Women should not be lactating and, if of childbearing age, should have a negativepregnancy test (b-HCG test; serum or urine, minimum sensitivity 25 IU/L orequivalent units of b-HCG) within two weeks of registration in the study.

Exclusion Criteria:

• Patients who have had systemic therapy for melanoma or radiotherapy within 3 weeksprior to registering on the study or those who have not recovered from adverseevents due to agents administered more than 3 weeks earlier. Patients with a historyof endocrinopathies (e.g. hypothyroidism) are eligible if they are stable on hormonereplacement therapy. Patients with a history of adrenal insufficiency are noteligible.

• Patients may not be receiving any other investigational agents.

• Patients with active brain metastasis are excluded

• Patients with clinically significant cardiovascular or cerebrovascular disease

• Uncontrolled intercurrent illness including, but not limited to, ongoing or activeinfection or psychiatric illness/social situations that would limit compliance withstudy requirements.

• Patients who have other current malignancies are not eligible. Patients with othermalignancies are eligible if they have been continuously disease free for > 2 yearsprior to the time of registration. Patients with prior history at any time of any insitu cancer, lobular carcinoma of the breast in situ, cervical cancer in situ,atypical melanocytic hyperplasia or melanoma in situ are eligible. Patients withprior history of basal or squamous skin cancer are eligible. Patients who have hadmultiple primary melanomas are eligible.

• Patients must not have autoimmune disorders or conditions of immunosuppression thatrequire current ongoing treatment with systemic corticosteroids (or other systemicimmunosuppressants), including oral steroids (i.e., prednisone, dexamethasone) orcontinuous use of topical steroid creams or ointments or ophthalmologic steroids orsteroid inhalers. If a patient had been taking steroids, at least 2 weeks must havepassed since the last dose.