Inclusion Criteria:
* Histologic diagnosis of unresectable or advanced mucosal melanoma arising from the head/neck (e.g. sinonasal, oral cavity, conjunctival), gastrointestinal (e.g. anorectal, esophageal), or genitourinary (e.g. vulvovaginal, urethral) sites.
* Measurable disease
1. Initial study entry: Subjects must have at least 1 extracranial, unresectable, non-bony lesion that is measurable radiographically (based on RECIST 1.1).
2. Triplet arms: assessable disease required. RECIST 1.1 measurable disease is not required.
* Prior therapy
1. Initial study entry: No prior systemic therapy (adjuvant or metastatic).
2. Triplet arms: Only prior systemic therapy is nivolumab + axitinib on this trial.
* ECOG performance status of 0-2.
* Asymptomatic untreated brain metastases are allowed. Symptomatic brain metastases that have undergone local therapy with RT or surgery and have not required an increase in steroid dose in prior 2 weeks are allowed.
* Screening laboratory parameters:
1. White blood cell (WBC) count ≥ 2000/μL;
2. Absolute neutrophil count (ANC) ≥ 1500/μL;
3. Platelets ≥ 100,000/μL;
4. Hemoglobin (Hgb) ≥ 9 g/dL;
5. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 × upper limit of normal (ULN);
6. Total bilirubin ≤ 1.5 × ULN (\< 3 mg/dL for subjects with Gilbert's disease);
7. Estimated glomerular filtration rate (GFR) ≥ 30 mL/min;either Cockcroft Gault or a cancer-specific GFR Model such as the camGFR version 2 can be used;
* Age ≥ 18 years.
* Females of childbearing potential who are sexually active with a nonsterilized male partner must use 2 methods of effective contraception from screening, and must agree to continue using such precautions for 23 weeks after the final dose of investigational product; cessation of birth control after this point should be discussed with a responsible physician. Periodic abstinence, the rhythm method, and the withdrawal method are not acceptable methods of birth control. \[Females of childbearing potential are defined as those who are not surgically sterile (i.e., bilateral tubal ligation, bilateral oophorectomy, or complete hysterectomy) or postmenopausal (defined as 12 months with no menses without an alternative medical cause).\] Nonsterilized males who are sexually active with a female partner of childbearing potential must use 2 acceptable methods of effective contraception from Day 1 and for 31 weeks after receipt of the final dose of investigational product.
Acceptable methods of effective contraception are described in the following:
* Barrier Methods (Male condom plus spermicide, cap plus spermicide, or diaphragm plus spermicide).
* Intrauterine Device Methods (Copper T, or Levonorgestrelreleasing intrauterine system (e.g., Mirena®), also considered a hormonal method).
* Hormonal Methods (Implants, hormone shot or injection, combined pill, mini pill, or Patch).
Exclusion Criteria:
* Active autoimmune disease or any condition requiring systemic treatment with either corticosteroids (\>10 mg daily of prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement doses \> 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.
* History of motor neuropathy considered to be of autoimmune origin (e.g., Guillain- Barre Syndrome, Myasthenia Gravis).
* History of myocarditis.
* History of, or any active evidence of non-infectious pneumonitis
* Other active, concurrent malignancy that requires ongoing systemic treatment or interferes with radiographic assessment of melanoma response as determined by the investigator.
* Cardiovascular disease, including:
* History of acute coronary syndromes (including myocardial infarction and unstable angina), coronary artery bypass graft (CABG) coronary angioplasty, or stenting within 6 months prior to study entry.
* Current Class II or higher congestive heart failure as defined by the New York Heart Association (NYHA) functional classification system.
* Treatment-refractory hypertension defined as a blood pressure of systolic \>150 mmHg and/or diastolic \>90 mmHg despite adequate attempts at antihypertensive therapy.
* Underlying hematologic issues including:
* Congenital bleeding diathesis
* GI bleeding requiring intervention within the past 6 months
* Active hemoptysis within 42 days prior to study enrollment
* Pulmonary emboli or deep vein thromboses (DVT) that are not stable on anticoagulation regimen.
* History of severe allergic reactions to an unknown allergen or any components of the study drugs.
* Other serious infectious illnesses (e.g., active symptoms of COVID-19 infection or a post-infectious symptomatic autoimmune syndrome, serious bacterial infections requiring antibiotics).
* Women who are breastfeeding or who are pregnant as evidenced by a positive serum pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) performed within 14 days of the first dose of study drug and by a urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours of the first dose of study drug(s).
* Genetic or autoimmune condition causing heightened radio sensitivity.
