ctDNA-guided Addition of Ipilimumab to Patients Receiving Nivolumab and Relatlimab

Inclusion Criteria: 1. Patient must be ≥ 18 years old. 2. Patients must have signed and dated an Institutional Review Board (IRB)/Independent Ethics Committee (IEC)-approved written informed consent from (ICF) in accordance with regulatory and institutional guidelines. This must be obtained before the performance of any protocol-related procedures that are not part of normal patient care. 3. Patients must be willing and able to comply with scheduled visits, laboratory tests, and other requirements of the study. 4. Patient must have active advanced melanoma, defined as unresectable stage IIIB-IV by American Joint Committee on Cancer (AJCC) 8th edition. Patients with mucosal melanoma defined as unresectable stage III or regional/distant metastatic disease are eligible. 5. Patient must have melanoma originating from cutaneous, acral-lentiginous, or mucosal primary sites. Patients with melanoma of unknown primary site are eligible. 6. Patient must have at least one lesion for measurable disease per RECIST 1.1 guidelines (refer to section 8.1 for more information). 7. Patients must have specimen required for study procedures, including either archived tumor tissue or fresh tissue and whole blood available, at baseline to send to Natera as part of screening for Signatera testing to be completed. (refer to section 8.2 for more information) 8. Patient must be planned to initiate standard of care first-line therapy for metastatic disease 9. Patients must not have received prior anticancer treatment for metastatic disease (for example, but not limited to, systemic, local, radiation, radiopharmaceutical). Exceptions: Surgery for melanoma and/or post-resection brain radiotherapy (RT) if central nervous system (CNS) metastases and adjuvant RT for locoregional disease after resection. Prior treatment with the following therapies in the adjuvant setting: interferon (IFN)-alpha therapy, BRAF/MEK therapy (e.g. dabrafenib and trametinib), anti-PD-1 therapy (e.g. pembrolizumab or nivolumab), or anti-CTLA-4 therapy (e.g. ipilimumab) is allowed if therapy has been completed for 6 months (see criterion 10). 10. All patients must have their disease status documented by a complete physical examination and imaging studies within 4 weeks prior to the first dose of study drug. Imaging studies must include computerized tomography (CT) scan of chest, abdomen, pelvis, and all known sites of resected disease in the setting of Stage IIIB/C/D or Stage IV disease, and brain magnetic resonance imaging (\[MRI\]; brain CT is allowable if MRI is contraindicated). 11. The complete set of baseline radiographic images must be available before treatment initiation. Prior treatment with adjuvant IFN-alpha, adjuvant ipilimumab and/or nivolumab or pembrolizumab or BRAF/MEK therapy (e.g. dabrafenib and trametinib) are allowed if recurrence of disease occurred more than 6 months from the last dose of adjuvant therapy; that is, a patient must have recurred with unresectable disease at least 6 months or more after finishing adjuvant therapy; combination adjuvant therapies with nivolumab or pembrolizumab are also allowed (vaccines, bempegaldesleukin, relatlimab, etc.). 12. Patients must have detectable ctDNA at baseline. A blood sample will be collected during the screening phase in order to determine if patients are eligible based on presence of ctDNA. Patients are permitted to start treatment with nivolumab/relatlimab cycle 1 while awaiting results. 13. Patient must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1. 14. Patients with prior or concurrent nonmelanoma malignancies whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this study. 15. Asymptomatic brain metastases are permitted. Patients who have received/will receive gamma knife radiotherapy or stereotactic body radiation therapy (SBRT) treated lesions are also eligible. Patients must be on \< 10 mg of prednisone or equivalent at the time of treatment. 16. All baseline laboratory requirements will be assessed and should be obtained within 14 days of C1D1. Screening laboratory values must meet the following criteria: * white blood cells (WBCs) ≥ 2000/μL * Neutrophils ≥ 1500/μL * Platelets ≥ 100 × 10³/μL * Hemoglobin ≥ 9.0 g/dL * Serum creatinine ≤ 1.5 × upper limit of normal (ULN) or creatinine clearance \> 40 mL/minute (using Cockcroft/Gault formula) * Aspartate Aminotransferase (AST) ≤ 1.5 × ULN * Alanine Aminotransferase (ALT) ≤ 1.5 × ULN * Total bilirubin ≤ 1.5 × ULN (except patients with Gilbert Syndrome who must have total bilirubin \< 3.0 mg/dL) * Coagulation : Prothrombin Time (PT), Partial Thromboplastin Time (PTT), International Normalized Ratio (INR) Exclusion Criteria: 1. Patients with carcinomatosis meningitis or a history of current ocular/uveal melanoma are excluded. 2. Patients with a history of myocarditis. 3. Patients with active, known, or suspected autoimmune disease requiring immunosuppression beyond 10 mg daily of prednisone. Patients with type I diabetes mellitus, residual hypothyroidism due to autoimmune thyroiditis only requiring hormone replacement, or skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment are permitted to enroll. For any cases of uncertainty, it is recommended that the Principal Investigator be consulted prior to signing informed consent. 4. Patients with a condition requiring systemic treatment with either corticosteroids (\> 10 mg daily prednisone or equivalent) or other immunosuppressive medications within 14 days of C1D1. Inhaled or topical steroids are permitted in the absence of active autoimmune disease. 5. Patients must not be receiving concurrent anti-tumor therapies in addition to the standard of care anti-PD-1 regimens. Patients who are receiving bisphosphonates and RANKL inhibitors for management of bone metastases are eligible. 6. Any serious or uncontrolled medical disorder or active infection that, in the opinion of the Investigator, may increase the risk associated with or would otherwise affect study participation. 7. Known hypersensitivity to monoclonal antibodies 8. Pregnancy 9. Prior therapy for melanoma with the following exceptions which are allowed: 1) surgery for the melanoma lesion(s), 2) adjuvant RT after neurosurgical resection for CNS lesions or for resected locoregional disease, and 3) prior adjuvant therapy as long as concluded 6 months prior. 10. Any of the following laboratory abnormalities: * Absolute Neutrophil Count (ANC) \< 1,500/μL or WBC \< 2,000 μL * Platelet count \< 100,000/μL * Hematologic growth factors are not allowed at screening or during the first cycle of treatment * Hemoglobin \< 9 g/dL (\< 5.5 mmol/L; previous red blood cell (RBC) transfusion is permitted) * Creatinine \> 1.5 × ULN * AST or ALT \> 1.5 × ULN. For patients with liver metastasis AST or ALT \> 3 × ULN * Serum total bilirubin \> 1.5 mg/dL or \> 3 × ULN for patients with hereditary benign hyperbilirubinemia