PROSECCO: A Phase 2, Single Arm, Neoadjuvant Study Evaluating Combination Cemiplimab, Fianlimab, And Ipilimumab In Patients With Surgically Resectable Melanoma

Inclusion Criteria: 1. At least 18 years of age on the date of providing informed consent 2. All patients must be either stage III (stage IIIB, IIIC, IIID) or stage IV (M1a, M1b, M1c) per ATJCC 8th edition and have histologically confirmed cutaneous melanoma (including acral melanoma) that is clinically detectable and deemed completely surgically resectable 1. Patients with stage IIIA and Stage IV M1d disease are excluded 2. Mucosal melanoma patients are allowed but capped at 10% of the total study population 3. Patients with melanoma of unknown primary are allowed, provided that complete surgical resection is planned 4. Resectable in-transit metastases (up to 3 lesions) with or without nodal involvement are eligible 3. Clinically detectable is defined as disease which is clinically apparent and measurable according to Response Evaluation Criteria in Solid Tumors. Resectable nodal metastases should be a minimum short-axis diameter of 1.5cm, whereas the minimum size for other metastases should be 1cm. 4. Eastern Cooperative Oncology Group (ECOG) PS 0-1 5. Adequate bone marrow function as determined by: 1. Absolute Neutrophil Count ≥ 1.5 x 109 2. Hemoglobin ≥ 9.0 g/dL 3. Platelet count ≥ 75,000/mm3 6. Adequate hepatic function as determined by: 1. AST (aspartate aminotransferase)/ALT (alanine aminotransferase) ≤ 3x upper limit of normal (ULN) 2. Alkaline phosphatase ≤2.5 x ULN 3. Serum bilirubin ≤ 1.5 x ULN except in patients with clinically documented Gilbert's Syndrome 7. Adequate kidney function as determined by creatine clearance ≥ 30 ml/min using the Cockcroft-Gault equation 8. WOCBP\* must have a negative serum (beta-hCG) at screening. 1. Male study participants with WOCBP partners are required to use condoms during the study and until 6 months after the last dose of study treatment unless they are vasectomized or practice sexual abstinence. 2. Vasectomized partner or vasectomized study participant must have received medical assessment of the surgical success. 3. Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and LAM are not acceptable methods of contraception. Female condom and male condom should not be used together. 9. Women of childbearing potential (WOCBP)\* must be willing to practice highly effective contraception prior to the initial dose/start of the first treatment, during the study, and for at least 6 months after the last dose. Highly effective contraceptive measures include: 1. stable use of combined (estrogen and progestogen containing) hormonal contraception (oral, intravaginal, transdermal) or progestogen-only hormonal contraception (oral, injectable, implantable) associated with inhibition of ovulation initiated 2 or more menstrual cycles prior to screening; 2. intrauterine device; intrauterine hormone-releasing system; 3. bilateral tubal occlusion/ligation; 4. vasectomized partner (provided that the male vasectomized partner is the sole sexual partner of the WOCBP study participant and that the vasectomized partner has obtained medical assessment of surgical success for the procedure); and/or 5. sexual abstinence†, ‡. * Pregnancy testing and contraception are required for WOCBP. * Pregnancy testing and contraception are not required for women who are post-menopausal or permanently sterile. * Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study drugs. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the subject. * Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and LAM are not acceptable methods of contraception. Female condom and male condom should not be used together. 10. WOCPB must not agree to donate eggs for purposes of assisted reproduction during the entire study and until 6 months after last treatment 11. All men must agree not to donate sperm during the trial and for 6 months after receiving the last therapy dose 12. Willing and able to comply with clinic visits and study-related procedures 13. Provide informed consent signed by study patient or legally acceptable representative Exclusion Criteria: 14. Primary uveal melanoma 15. Ongoing or recent (within 2 years) of active autoimmune disease that required systemic treatment with immunosuppressive agents. The following are non-exclusionary: vitiligo, childhood asthma that has resolved, residual hypothyroidism that requires only hormone replacement, and psoriasis not requiring systemic treatment. 16. Patients must not have received any prior systemic anti-cancer therapy for melanoma. Prior radiotherapy for melanoma is allowed if not given to a target lesion, or if given to a target lesion there is pathological evidence of disease progression in the same lesion. 17. Uncontrolled infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV) infection; or diagnosis of immunodeficiency that is related to, or results in chronic infection. Notes: 1. Patients with known HIV who have controlled infection (undetectable viral load and CD4 count above 350 either spontaneously or on a stable antiviral regimen) are permitted. For patients with controlled HIV infection, monitoring will be performed per local standards. 2. Patients with known hepatitis B (HepBsAg+) who have controlled infection (serum hepatitis B virus DNA PCR that is below the limit of detection AND receiving anti-viral therapy for hepatitis B) are permitted. Patients with controlled infections must undergo periodic monitoring of HBV DNA per local standards and must remain on anti-viral therapy for at least 6 months beyond the last dose of investigational study drug. 3. Patients who are known hepatitis C virus antibody positive (HCV Ab+) who have controlled infection (undetectable HCV RNA by PCR either spontaneously or in response to a successful prior course of anti-HCV therapy) are permitted. 4. Patients with HIV or hepatitis must be reviewed by a qualified specialist (eg, infectious disease or hepatologist) managing this disease prior to commencing and regularly throughout the duration of their participation in the trial. 18. Concurrent malignancy that is currently progressing or requiring active treatment within the past 2 years except for cancers will a negligible risk of metastasis or death (adequately treated carcinoma in situ of the cervix, basal or squamous cell skin cancer, localized early-stage prostate cancer or ductal carcinoma in situ of the breast). 19. Use of immunosuppressive dose of corticosteroids (≥ 10mg of prednisone or equivalent) within 14 days of the first dose of study medication. Inhaled or topical steroids are permitted, provided that they are not for treatment of an active autoimmune disorder. 20. Pregnant or breastfeeding women. 21. Received a live vaccine within 30 days of planned start of study medication. a. Live or live attenuated vaccination with replicating potential. If a patient intends to receive a COVID-19 vaccine before the start of study drug, participation in the study should be delayed at least 1 week after any COVID-19 vaccination. During the treatment period, it is recommended to delay COVID-19 vaccination until patients are receiving and tolerating a steady dose of study drug. A vaccine dose should not be less than 48 hours before or after study drug dosing. 22. Participants with a history of myocarditis. 23. Troponin T (TnT) or troponin I (TnI) \> 2x institutional ULN at baseline. a. Patients with TnT or TnI levels between \> 1 to 2x ULN are permitted if repeat levels within 24 hours are ≤ 1x ULN. If TnT or TnI levels are \> 1 to 2x ULN within 24 hours, the subject may undergo a cardiac evaluation and be considered for treatment by the investigator based on the medical judgement in the patient's best interest. 24. History or current evidence of significant (NCI-CTCAE grade ≥2) local or systemic infection (e.g., cellulitis, pneumonia, septicemia) requiring systemic antibiotic treatment within 2 weeks prior to the first dose of trial medication. 25. Active infection requiring therapy. 26. Known hypersensitivity to the active substances or to any of the excipients. 27. Presence of a severe concurrent illness or other condition (e.g., psychological, family, sociological, or geographical circumstances) that does not permit adequate follow-up and compliance with the protocol. 28. Prior allogeneic stem cell transplant or solid organ transplant. 29. Any medical condition that in the opinion of the investigator would make participation in the study not in the best interest of the patient.