Rituximab and Hyaluronidase Human in Patients With Advanced Melanoma Undergoing Nivolumab and Ipilimumab Therapy

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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A Randomized Phase 2 Study of Rituxan Hycela in Patients With Advanced Melanoma Undergoing Combination Immune Checkpoint Blockade With Nivolumab and Ipilimumab

Conditions
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Cutaneous Melanoma, Stage III, Cutaneous Melanoma, Stage IV, Stage III Melanoma, Stage IIIA Skin Melanoma, Stage IIIB Skin Melanoma, Stage IIIC Skin Melanoma, Stage IV Skin Melanoma, Unresectable Melanoma

Intervention / Treatment
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* Drug: Nivolumab
* Biological: Rituximab and Hyaluronidase Human
* Drug: Ipilimumab


Participation Criteria
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Eligibility Criteria
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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).

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm A (standard of care)<br>This is standard of care arm: induction with 4 cycles (21 days each) of Ipilimumab and nivolumab followed by continuation with nivolumab alone every month X1 year (13 doses). | Drug: Nivolumab<br>* Receive standard of care nivolumab therapy<br>* Other names: Opdivo;Drug: Ipilimumab<br>* Receive standard of care ipilimumab therapy<br>* Other names: Yervoy;|
| Experimental: Arm B (rituximab, hyaluronidase human)<br>This includes induction with 4 cycles of ipilimumab and nivolumab X 4 cycles followed by continuation with nivolumab alone every month for 1 year as in standard of care arm. Each induction cycle is 21 days and includes ipilimumab on day 1 plus nivolumab on day 1. In addition, patients will receive 4 weekly doses of Rituxan (first dose intravenously and then 3 weekly doses subcutaneously). First dose of Rituxan will be administered one week following the start of cycle 1 of ipilimumab and nivolumab. All treatments will have a +/-3 business day window for administration. | Drug: Nivolumab<br>* Receive standard of care nivolumab therapy<br>* Other names: Opdivo;Biological: Rituximab and Hyaluronidase Human<br>* Given IV or SC<br>* Other names: Rituxan Hycela;Drug: Ipilimumab<br>* Receive standard of care ipilimumab therapy<br>* Other names: Yervoy;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of Common Terminology Criteria (CTC) (version [v]5.0) grade 3 or greater immune-related adverse events | All patients will be evaluable for toxicity from the time of their first treatment with ipilimumab/nivolumab. Investigators will review the toxicities, grade, and attribute each toxicity. | At 6 months after study start | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of CTC (v5.0) toxicity related to rituximab and hyaluronidase human | All patients will be evaluable for toxicity from the time of their first treatment with ipilimumab/nivolumab. Investigators will review the toxicities, grade, and attribute each toxicity. | Up to 4 weeks after study start | 
| Objective tumor response | Will be assessed by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 and immune-related (ir)RECIST. Only those patients who have measurable disease present at baseline, have received at least one cycle of therapy, and have had their disease re-evaluated will be considered evaluable for response. Patients who exhibit objective disease progression prior to the end of cycle 1 will also be considered evaluable. | At 12 weeks and every 12 weeks thereafter up to 1 year | 
| Rate of overall survival | Overall survival is defined as the duration of time from start of treatment to time of death or last follow-up, whichever occurs first. | From start of treatment up to 1 year | 
| Rate of progression-free survival (PFS) | PFS is defined as the duration of time from start of treatment to time of progression or death or last follow-up, whichever occurs first. | From start of treatment up to 1 year |