Nivolumab or Expectant Observation Following Ipilimumab, Nivolumab, and Surgery in Treating Patients With High Risk Localized, Locoregionally Advanced, or Recurrent Mucosal Melanoma

Inclusion Criteria:

• STEP 1 ELIGIBILITY CRITERIA

• Documentation of disease:

  • Histologic documentation: histologically proven mucosal melanoma by local pathology
  • Tumor tissue: tumor tissue from the primary site of disease must be available for PD-L1 testing (stratification factor)

• Disease status

  • Tumors must have NOT been completely resected, or must be locoregionally recurrent if previously resected; tumor must be deemed potentially resectable by local surgeon
  • MM arising from the head/neck, genitourinary, or gastrointestinal tract

  • Disease meets any 1 of 4 characteristics:

    • Regional lymph node (LN) involvement; OR
    • Multifocal/satellite primary disease; OR

    • Single localized, primary disease meeting one of the following site-specific requirements:

      • Head/neck - any primary lesion if sinonasal; pT4a or above for nasal or oral cavity
      • Anorectal - any primary lesion
      • Conjunctiva - any primary lesion T2 or T3 stage by American Joint Committee on Cancer (AJCC)
      • Vaginal/cervical - any primary
      • Vulvar (hair bearing surface, labia majora) - AJCC cutaneous stage IIB or higher
      • Esophageal - any primary
    • Locoregionally recurrent following prior resection
  • No evidence of metastatic disease at the time of registration
• No prior medical therapy (chemotherapy, immunotherapy, biologic or targeted therapy) or radiation therapy for MM, unless locoregionally recurrent; if recurrent, no prior medical or radiation therapy is allowed for the latest recurrence

• No history of the following:

  • Active known or suspected autoimmune disease
  • Human immunodeficiency virus (HIV) with CD4+ count < 300 or detectable viral load; patients with HIV, undetectable viral load, and CD4+ count >= 300 are eligible

  • Known active hepatitis B or C

    • Hepatitis B can be defined as:

      • Hepatitis B virus surface antigen (HBsAg) > 6 months
      • Serum hepatitis B virus (HBV) deoxyribonucleic acid (DNA) 20,000 IU/ml (105 copies/ml), lower values 2,000-20,000 IU/ml (104-105 copies/ml) are often seen in hepatitis B virus e antigen (HBeAg)-negative chronic hepatitis B
      • Persistent or intermittent elevation in alanine aminotransferase (ALT)/aspartate aminotransferase (AST) levels
      • Liver biopsy showing chronic hepatitis with moderate or severe necroinflammation

    • Hepatitis C can be defined as:

      • Hepatitis C antibody (AB) positive
      • Presence of hepatitis C virus (HCV) RNA
  • Known active pulmonary disease with hypoxia defined as oxygen saturation < 85% on room air

• Not pregnant and not nursing

  • For women of childbearing potential only, a negative pregnancy test done =< 14 days prior to registration is required
• Eastern Cooperative Oncology Group (ECOG) performance status =< 2
• Absolute neutrophil count (ANC) >= 1,500/mm^3
• Platelet count >= 100,000/mm^3
• Creatinine clearance >= 30 mL/min by Modified Diet in Renal Disease (MDRD) equation or Cockcroft-Gault

• Total bilirubin =< 1.5 x upper limit of normal (ULN)

  • Except in case of Gilbert disease
• AST/ALT =< 2.5 x upper limit of normal (ULN)

• Thyroid-stimulating hormone (TSH) within normal limits (WNL)

  • Supplementation is acceptable to achieve a TSH WNL; in patients with abnormal TSH if free T4 is normal and patient is clinically euthyroid, patient is eligible

• Concomitant medications

  • No systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 7 days of registration (inhaled steroids for patients with underlying chronic pulmonary disease is acceptable as long as they meet other eligibility as listed above)
  • No other planned concurrent investigational agents or other tumor directed therapy (chemotherapy, radiation) while on study
• STEP 2 ELIGIBILITY CRITERIA

• Surgical resection of all gross disease

  • This assessment will be made by the local investigator based on review of the operative report, pathology results, and/or radiology reports; microscopically positive margins (e.g. R1 resection) are permitted

• Completion of PD-L1 testing

  • Patients will be stratified as PD-L1 >= 5% versus (vs) < 5% OR inevaluable; baseline tumor will be utilized; if this returns inevaluable, efforts should be made to utilize the resected specimen

• Randomization within 112 days of completion of surgical

  • The primary region must be included on cross-sectional imaging (e.g. sinus/neck if arising from sinonasal primary; pelvis if genitourinary); radiographic changes considered nonspecific or possibly due to surgery or radiation are not considered evidence of disease

• No significant immune-related adverse event due to the nivolumab plus ipilimumab dose received in the neoadjuvant setting, as follows:

  • Any grade myocarditis, including an asymptomatic troponin elevation felt to be related to nivolumab plus ipilimumab
  • Any grade neurologic complication (e.g. meningitis, encephalitis, neuropathy); study chair should be contacted if there is any question whether an adverse event (AE) was neurologic in nature
  • Grade 2 or higher pneumonitis
  • Grade 2 colitis
  • Grade 2 or higher anemia (due to drug; unrelated anemia is not exclusionary)
  • Thyroid/adrenal AEs regardless of grade that have stabilized or are clinically asymptomatic are eligible
  • Fatigue, regardless of grade, is not a contraindication to randomization
  • Grade 4 AST or ALT elevation
  • Asymptomatic elevated amylase and lipase, regardless of grade, are not contraindications to randomization

  • Grade 4 rash; grade 3 rash is not a contraindication to randomization; any oropharyngeal lesions or bullous skin lesions that are suggestive of toxic epidermal necrolysis or Stevens-Johnson syndrome are contraindications to randomization regardless of the grade of rash

    • If not specified above, other Common Terminology Criteria for Adverse Events (CTCAE) grade 3 or higher AEs deemed possibly related to the nivolumab plus ipilimumab are exclusions to randomization; AEs that were attributable to surgery or adjuvant RT would not be contraindications to randomization