Rituximab and Hyaluronidase Human in Treating Patients with Unresectable Stage III-IV Melanoma Undergoing Nivolumab and Ipilimumab Therapy

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.
• Patients with progression on anti-PD-1 as a single agent are allowed to enroll on the study.
• No therapy with immune checkpoint inhibitors other than anti-PD-1 within 1 year prior to starting combination checkpoint therapy. Prior adjuvant ipilimumab as single agent is allowed if greater than 1 year since last treatment. Patient had no grade 3 or 4 toxicities from the checkpoint inhibitors including prior single agent PD-1 or anti CTLA4 therapy. History of adjuvant interferon is allowed.
• White blood count >= 3,000/uL (obtained within three weeks prior to randomization)
• Absolute neutrophil count (ANC) >= 1,500/uL (obtained within three weeks prior to randomization)
• Platelet count >= 100,000/uL (obtained within three weeks prior to randomization)
• Hemoglobin >= 9 g/dL (obtained within three weeks prior to randomization)
• Serum creatinine =< 1.5 x institutional upper limit of normal (ULN) or serum creatinine clearance (CrCl) >= 40 ml/min (obtained within three weeks prior to randomization)
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3 x ULN (=< 5 x ULN for patients with documented liver metastases) (obtained within three weeks prior to randomization)
• Alkaline phosphatase =< 2 X ULN (=< 5 X ULN for those with bone metastasis) (obtained within three weeks prior to randomization)
• Total bilirubin =< 1.5 X ULN except those with direct bilirubin or Gilbert's syndrome (obtained within three weeks prior to randomization)
• Serum lactate dehydrogenase (LDH) =< 10 X ULN (obtained within three weeks prior to randomization)

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. If patient required steroid therapy for his CNS metastatic disease, the patient maybe enrolled 2 weeks after stopping steroids.
• Prior therapy with immune checkpoint blocking antibodies (monotherapy given at least 1 year prior to starting combination therapy and no grade 3-4 toxicities while on monotherapy are allowed, prior vaccines or IL2 given at least one year prior is also allowed).
• Patients may have had prior systemic therapy in the adjuvant setting (e.g. interferon, BRAF, or MEK agents). Adjuvant ipilimumab 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. Prior anti-PD-1 therapy is allowed if patients progress and have had no grade 3 or 4 toxicities related to anti-PD-1 therapy.
• 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 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 IRAEs.