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

NCT03719131 | Active Not Recruiting Phase 2 Results DMC FDA Drug

• 3 other identifiers: IRB00105605NCI-2018-01804Winship4457-18
• Study Type: interventional
• Target: 15
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

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

Outcome Measures

Primary Outcomes (1)

• Number of Participants With 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 Outcomes (4)

• Rate of CTC (v5.0) Toxicity Related to Rituximab and Hyaluronidase Human

  Up to 4 weeks after study start

• Objective Tumor Response

  At 12 weeks and every 12 weeks thereafter up to 1 year

• Rate of Overall Survival

  From start of treatment up to 1 year

• Rate of Progression-free Survival (PFS)

  From start of treatment up to 1 year

Study Arms (2)

Arm A (standard of care)

ACTIVE COMPARATOR

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; Drug: Ipilimumab

Arm B (rituximab, hyaluronidase human)

EXPERIMENTAL

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; Biological: Rituximab and Hyaluronidase Human; Drug: Ipilimumab

Interventions

Nivolumab DRUG

Receive standard of care nivolumab therapy

Also known as: Opdivo

Arm A (standard of care); Arm B (rituximab, hyaluronidase human)

Rituximab and Hyaluronidase Human BIOLOGICAL

Given IV or SC

Also known as: Rituxan Hycela

Arm B (rituximab, hyaluronidase human)

Ipilimumab DRUG

Receive standard of care ipilimumab therapy

Also known as: Yervoy

Arm A (standard of care); Arm B (rituximab, hyaluronidase human)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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).

Sponsors & Collaborators

• Emory University: lead
• Genentech, Inc.: collaborator

Study Sites (1)

Emory University Hospital/Winship Cancer Institute

Atlanta, Georgia, 30322, United States

Location

MeSH Terms

Conditions

Melanoma

Interventions

Nivolumab; Rituximab; Ipilimumab

Condition Hierarchy (Ancestors)

Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Neoplasms by Site; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Antibodies, Monoclonal, Murine-Derived

Limitations and Caveats

Study was closed prematurely due to study supporter decision.

Results Point of Contact

• Title: Kavita Dhodapkar, MD
• Organization: Emory University

kavita.dhodapkar@emory.edu

404-785-1112

Study Officials

• Kavita Dhodapkar, MD

  Emory University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: October 23, 2018
• First Posted: October 25, 2018
• Study Start: June 5, 2019
• Primary Completion: September 27, 2022
• Study Completion (Estimated): June 30, 2026
• Last Updated: April 22, 2025
• Results First Posted: April 22, 2025

Record last verified: 2025-04

Locations

US (1)