This phase II trial studies whether rituximab and hyaluronidase human (Rituxan Hycela) can prevent immune related adverse events in participants with stage III-IV melanoma that cannot be removed by surgery who are undergoing nivolumab and ipilimumab therapy.

PRIMARY OBJECTIVE:

I. To compare rates for grade 3-4 immune-related adverse event (IRAE)s in the first 6 months in patients treated with combination checkpoint blockade (CCB) therapy (anti-CTLA4 and anti-PD1) as a part of standard of care for advanced melanoma who are treated with a single course of 4 weekly doses of rituximab and hyaluronidase human (Rituxan) therapy versus those who are not treated with Rituxan.

SECONDARY OBJECTIVES:

I. To evaluate the safety and tolerability (in terms of Rituxan-related adverse events) in patients with melanoma receiving CCB.

II. To compare objective response rate in patients receiving CCB therapy + Rituxan versus CCB therapy alone.

III. To compare 1 year overall and progression-free survival in patients receiving CCB therapy + Rituxan versus CCB therapy alone.

IV. To compare changes in cluster of differentiation 21lo (CD21lo) B cells in patients receiving CCB therapy + Rituxan versus CCB therapy alone.

V. To compare changes in T cells in patients receiving CCB therapy + Rituxan versus CCB therapy alone.

OUTLINE: Participants are randomized to 1 of 2 arms.

ARM A: Participants receive standard of care ipilimumab and nivolumab therapy.

ARM B: Participants receive standard of care ipilimumab and nivolumab therapy. On day 2 of each cycle, participants also receive rituximab and hyaluronidase human intravenously (IV) or subcutaneously (SC) weekly starting week 1 for 4 doses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, participants are followed up for 4 weeks.

Inclusion Criteria:

• Clinically eligible to receive Food and Drug Administration (FDA) approved standard of care combination immune checkpoint therapy with ipilimumab and nivolumab for unresectable stage III or stage IV melanoma.

• No therapy with immune checkpoint inhibitors within 1 year prior to starting combination checkpoint therapy. Prior adjuvant ipilimumab, nivolumab, or pembrolizumab as single agent is allowed if greater than 1 year since last treatment and patient had no grade 3 or 4 toxicities from the checkpoint inhibitors. History of adjuvant interferon is allowed.

• Obtained within one week prior to randomization:

  • White blood count ≥ 3,000/µL
  • Absolute neutrophil count (ANC) ≥ 1,500/µL
  • Platelet count ≥ 100,000/µL
  • Hemoglobin ≥ 9 g/dL
  • Serum creatinine ≤ 1.5 x institutional upper limit of normal (ULN) or serum creatinine clearance (CrCl) ≥ 40 ml/min
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 x ULN (≤ 5 x ULN for patients with documented liver metastases)
  • Alkaline phosphatase ≤ 2 X ULN (≤ 5 X ULN for those with bone metastasis)
  • Total bilirubin ≤ 1.5 X ULN except those with direct bilirubin or Gilbert's syndrome
  • Serum lactate dehydrogenase (LDH) ≤ 10 X ULN

Exclusion Criteria:

• Allergy to rituximab, or any of the ingredients in rituximab injection or rituximab and hyaluronidase human injection.
• Patients with active central nervous system (CNS) metastatic disease or leptomeningeal disease. Patients with CNS metastatic disease that has been treated with surgical resection or stereotactic radiosurgery are eligible if lesions are stable for at least 4 weeks following therapy as determined by magnetic resonance imaging (MRI) scan done within one week of randomization.
• Prior therapy with immune checkpoint blocking antibodies (unless monotherapy given at least 1 year prior to starting combination therapy and no grade 3-4 toxicities while on monotherapy), vaccines or interleukin-2 (IL-2).
• Patients may have had prior systemic therapy in the adjuvant setting (e.g. interferon, proto-oncogene B-Raf [BRAF], or mitogen-activated protein-extracellular signal-regulated kinase [MEK] agents). Adjuvant ipilimumab, nivolumab, or pembrolizumab as single agent is allowed if greater than 1 year since last treatment and patient had no grade 3 or 4 toxicities from the checkpoint inhibitors.
• Women must not be pregnant or lactating. Must have negative urine or blood pregnancy test within 1 week of starting therapy.
• Patients with known human immunodeficiency virus (HIV) are ineligible.
• Patients with active Hepatitis B Virus (HBV) or Hepatitis C virus (HCV) are ineligible. -- ----Patients with prior history of, or serology suggestive of prior infection with Hepatitis B Virus (HBV) or Hepatitis C virus (HCV) are also ineligible.
• Patients with active, known or suspected autoimmune disorders including lupus and type I diabetes are ineligible. Patients with history of vitiligo, thyroiditis are eligible.
• Patients with active disease or history of inflammatory bowel disease are ineligible.
• Patients cannot be on corticosteroid therapy except as physiologic replacement therapy.
• Patients receiving ongoing corticosteroid therapy for autoimmune disorders are ineligible. Occasional steroid inhaler use or nasal spray are allowed. Patients receiving replacement doses of steroids for adrenal insufficiency are eligible.
• Patients must not have any serious underlying medical conditions or take medications that in the investigators opinion may interfere with compliance or interpretation of Immune-related adverse events (IRAEs).