Cutaneous Melanoma, Stage IIIPhase 2NCT03719131
Rituximab and Hyaluronidase Human in Patients With Advanced Melanoma Undergoing Nivolumab and Ipilimumab Therapy
A Phase 2 study testing Nivolumab, Rituximab and Hyaluronidase Human and Ipilimumab in people with Cutaneous Melanoma, Stage III and Cutaneous Melanoma, Stage IV, run by Emory University at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Cutaneous Melanoma, Stage III, Cutaneous Melanoma, Stage IV, Stage III Melanoma
- What is being tested?
- Nivolumab, Rituximab and Hyaluronidase Human and Ipilimumab
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 15 participants
- Where
- 1 siteUnited States
- Study dates
- 5 Jun 2019to 9 Apr 2025
- Phase
- Phase 2
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
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- 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
Who cannot join
- 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.
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- 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).
Trial locations and contacts
1 site in 1 country.
United States1 site
Emory University Hospital/Winship Cancer Institute
Atlanta, Georgia, 30322
About this study
Official title: A Randomized Phase 2 Study of Rituxan Hycela in Patients With Advanced Melanoma Undergoing Combination Immune Checkpoint Blockade With Nivolumab and Ipilimumab
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.
Read the detailed description
PRIMARY OBJECTIVE:
- 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:
- 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.
- 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.
- Conditions
- Cutaneous Melanoma, Stage III, Cutaneous Melanoma, Stage IV, Stage III Melanoma, Stage IIIA Skin Melanoma, Stage IIIB Skin Melanoma, Stage IIIC Skin Melanoma
- Being tested
- Nivolumab, Rituximab and Hyaluronidase Human, Ipilimumab
- Medical subject headings
- Melanoma
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
NivolumabDrug
Also called Opdivo
Receive standard of care nivolumab therapy
Rituximab and Hyaluronidase HumanBiological
Also called Rituxan Hycela
Given IV or SC
IpilimumabDrug
Also called Yervoy
Receive standard of care ipilimumab therapy
| Study group | Role | What they receive |
|---|---|---|
| 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). Receives: 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. Receives: Drug: Nivolumab; Biological: Rituximab and Hyaluronidase Human; Drug: Ipilimumab |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: At 6 months after study start
Secondary outcomes (4)
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.
Measured: 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.
Measured: 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.
Measured: up to 2 years from start of treatment
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.
Measured: From start of treatment up to 2 year
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted25 Oct 2018
- Study start5 Jun 2019
- Primary completion27 Sep 2022
- Study completion9 Apr 2025
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Cutaneous Melanoma, Stage IIIStudies of the same condition, open and under way.
- More trials run by Emory UniversityThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 15 participants (actual)
Sponsor and investigators
- Lead sponsor
- Emory University
- Sponsor type
- University, hospital or other
- Collaborators
- Genentech, Inc.
- Responsible party
- Principal investigator, Kavita Dhodapkar, Emory University
- Investigators
- Kavita Dhodapkar, MD, Principal investigator, Emory University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03719131
- Sponsor's protocol ID
- IRB00105605
- Other IDs
- NCI-2018-01804, Winship4457-18
- Status last verified
- Sep 2026
- First submitted
- 23 Oct 2018
- Last updated
- 2 Oct 2026
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
Publications
Dhodapkar KM, Matera A, Duffy AM, Taz A, Manalo RJ, Yushak M, Kuchadkar R, Lawson DH, Dhodapkar MV. B-cell depletion improves therapeutic index of combination checkpoint blockade in patients with advanced melanoma. J Clin Invest. 2026 Aug 25:e205606. doi: 10.1172/JCI205606. Online ahead of print.
PubMed 42640721