Rituximab and Hyaluronidase Human in Patients With Advanced Melanoma 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. 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. 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 human immunodeficiency virus (HIV) are ineligible.

- Patients with active hepatitis B virus (HBV) or hepatitis C virus (HCV) are
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).