Rituximab + Hyaluronidase with Immunotherapy for Melanoma

Overseen By Kavita Dhodapkar, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Emory University

Must not be taking: Corticosteroids, IL-2

Disqualifiers: CNS metastases, Autoimmune disorders, HIV, Hepatitis, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: Unknown

15 Participants Needed

Trial Summary

What is the purpose of this trial?

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.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot be on corticosteroid therapy unless it's for adrenal insufficiency or occasional use like inhalers or nasal sprays. It's best to discuss your specific medications with the trial team.

What data supports the effectiveness of the drug combination of Rituximab + Hyaluronidase with Immunotherapy for Melanoma?

Research shows that combining nivolumab and ipilimumab, which are part of the treatment, significantly improves survival and response rates in patients with advanced melanoma compared to using ipilimumab alone. ^{1 2 3 4 5}

Is the combination of Rituximab, Hyaluronidase, and Immunotherapy safe for humans?

Ipilimumab and Nivolumab, used in combination for melanoma, can cause immune-related side effects, which are often mild but can be serious and life-threatening if not managed properly. These side effects can affect the skin, digestive system, liver, and other organs, but with proper management, they usually resolve. It's important for patients to be educated and monitored closely to manage these potential side effects effectively. ^{6 7 8 9 10}

How is the drug Rituximab + Hyaluronidase with Immunotherapy for Melanoma different from other treatments?

This treatment combines rituximab and hyaluronidase with immunotherapy drugs ipilimumab and nivolumab, which work by targeting different immune checkpoints to enhance the body's immune response against melanoma. The combination of these drugs is unique because it leverages multiple mechanisms to potentially improve treatment outcomes compared to using ipilimumab or nivolumab alone. ^{1 3 4 5 11}

Research Team

Kavita Dhodapkar, MD

Principal Investigator

Emory University

Eligibility Criteria

This trial is for adults with advanced melanoma that can't be surgically removed, who are about to start treatment with nivolumab and ipilimumab. They must have certain blood test levels within normal ranges and no severe side effects from previous similar treatments. Excluded are those with inflammatory bowel disease, active CNS metastases, hepatitis B or C, HIV, autoimmune disorders like lupus or type I diabetes, or on corticosteroids.

Inclusion Criteria

My liver function tests are within the required range.

Your LDH blood test result is not more than 10 times the upper limit of normal.

I had ipilimumab, nivolumab, or pembrolizumab over a year ago without severe side effects.

Exclusion Criteria

I am not on steroids for an autoimmune disease.

My cancer has spread to my brain or spinal cord.

I have had treatments like immune therapies or vaccines before.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Induction Treatment

Participants receive 4 cycles of ipilimumab and nivolumab, with rituximab and hyaluronidase human administered weekly for 4 doses in Arm B

12 weeks

Weekly visits for rituximab administration in Arm B

Continuation Treatment

Participants continue with nivolumab alone every month for 1 year

12 months

Monthly visits

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Hyaluronidase Human
• Ipilimumab
• Nivolumab
• Rituximab

Trial Overview The study is testing if Rituxan Hycela (rituximab and hyaluronidase human) can prevent serious immune-related side effects in patients receiving standard care therapy with nivolumab and ipilimumab for unresectable stage III-IV melanoma.

Participant Groups

Group I: Arm B (rituximab, hyaluronidase human) Experimental Treatment 3 Interventions

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.

Group II: Arm A (standard of care) Active Control 2 Interventions

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).

Ipilimumab is already approved in United States, European Union for the following indications:

Approved in United States as Yervoy for:

• Advanced melanoma
• Stage III unresectable melanoma
• Stage IV metastatic melanoma

Approved in European Union as Yervoy for:

• Advanced melanoma
• Stage III unresectable melanoma
• Stage IV metastatic melanoma

Who Is Running the Clinical Trial?

Emory University

Lead Sponsor

Trials

1,735

Recruited

2,605,000+

Genentech, Inc.

Industry Sponsor

Trials

1,578

Recruited

569,000+

Ashley Magargee

Genentech, Inc.

Chief Executive Officer since 2024

MBA from Harvard University, BA from Princeton University

Levi Garraway

Genentech, Inc.

Chief Medical Officer since 2021

MD, PhD

Findings from Research

Nivolumab (Opdivo) monotherapy led to complete regression of local recurrence and multiple lung metastases in a patient with recurrent skin melanoma and a positive BRAF mutation, demonstrating its efficacy as a treatment option.

After 5 courses of nivolumab, the patient experienced significant improvement in her condition, achieving an ECOG performance status of 0, indicating a return to an active lifestyle without pain, and normal serum LDH levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[EVALUATION OF THE EFFICASY OF THE DRUG OPDIVO (NIVOLUMAB) IN A PATIENT DIAGNOSED WITH UNRESECTABLE SKIN MELANOMA, POSITIVE BRAF MUTATION AND DISEASE DISSEMINATION (CASE REPORT)]. Samsonia, M., Kandelaki, M., Gibradze, O., et al.[2021]

In a study of 142 patients with advanced melanoma, the combination of nivolumab and ipilimumab resulted in a significantly higher objective response rate of 61% compared to 11% for ipilimumab alone, indicating that the combination therapy is much more effective for treating this type of cancer.

While the combination therapy showed promising efficacy, it also had a higher incidence of severe adverse events (54% vs. 24% for monotherapy), but most of these side effects were manageable with immune-modulating medications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. Postow, MA., Chesney, J., Pavlick, AC., et al.[2022]

In a phase 1 trial involving 53 patients with advanced melanoma, the combination of nivolumab and ipilimumab resulted in a 40% objective response rate, with 65% of patients showing clinical activity, indicating significant effectiveness in tumor reduction.

The concurrent treatment had a manageable safety profile, with 53% of patients experiencing grade 3 or 4 adverse events, which were similar to those seen with monotherapy and generally reversible, suggesting that this combination therapy is a viable option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab plus ipilimumab in advanced melanoma. Wolchok, JD., Kluger, H., Callahan, MK., et al.[2022]

In a study of 40 patients with metastatic melanoma who progressed after anti-PD-1 therapy, 10% achieved an objective response to subsequent treatment with ipilimumab, and 8% experienced prolonged stable disease for over 6 months.

However, 35% of patients developed severe immune-related toxicities, with the most common being diarrhea, and 7% experienced life-threatening pneumonitis, highlighting the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and toxicity of treatment with the anti-CTLA-4 antibody ipilimumab in patients with metastatic melanoma after prior anti-PD-1 therapy. Bowyer, S., Prithviraj, P., Lorigan, P., et al.[2021]

In a phase 2 trial involving 142 patients with untreated advanced melanoma, the combination of nivolumab and ipilimumab resulted in a 2-year overall survival rate of 63.8%, compared to 53.6% for those receiving ipilimumab alone, suggesting improved survival outcomes with the combination therapy.

However, the combination treatment was associated with a higher incidence of severe side effects, with 54% of patients experiencing grade 3-4 adverse events compared to 20% in the ipilimumab-only group, indicating a trade-off between efficacy and safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combined nivolumab and ipilimumab versus ipilimumab alone in patients with advanced melanoma: 2-year overall survival outcomes in a multicentre, randomised, controlled, phase 2 trial. Hodi, FS., Chesney, J., Pavlick, AC., et al.[2022]

Ipilimumab, an anti-CTLA-4 monoclonal antibody, significantly extends overall survival in patients with unresectable stage III or IV melanoma by enhancing T-cell activation and immune response against tumors.

While ipilimumab can lead to immune-related adverse events (irAEs), which are often manageable, proper management strategies are crucial to ensure patients can safely benefit from the treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immune-mediated adverse events associated with ipilimumab ctla-4 blockade therapy: the underlying mechanisms and clinical management. Tarhini, A.[2022]

Combining nivolumab and ipilimumab shows improved effectiveness in treating metastatic melanoma compared to using either drug alone, based on a retrospective analysis of approximately 7700 patients.

The combination therapy presents a safety profile that includes immune-related adverse events from both drugs, indicating that while the combination is effective, it also carries a heightened risk of toxicity that needs further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Retrospective Side Effect Profiling of the Metastatic Melanoma Combination Therapy Ipilimumab-Nivolumab Using Adverse Event Data. Soldatos, TG., Dimitrakopoulou-Strauss, A., Larribere, L., et al.[2022]

Ipilimumab, an anti-CTLA-4 antibody, has been shown to improve survival in patients with unresectable or metastatic melanoma, with a standard dosing of 3 mg/kg every 3 weeks for a total of 4 doses.

While ipilimumab can cause immune-related adverse events in 15% of patients, most are mild and manageable; however, high-grade events can be serious and require careful monitoring and treatment with corticosteroids.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ipilimumab for advanced melanoma: a pharmacologic perspective. Trinh, VA., Hagen, B.[2021]

Ipilimumab, an FDA-approved immunotherapy for advanced melanoma, effectively blocks CTLA-4 to enhance anti-tumor immune responses, but it is associated with a range of immune-related adverse events (irAEs) such as colitis, dermatologic issues, and endocrine dysfunction.

The article discusses the potential for combination therapies to mitigate these irAEs and emphasizes the need for further research to identify biomarkers that could predict patient responses to ipilimumab treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immune-mediated adverse events of anticytotoxic T lymphocyte-associated antigen 4 antibody therapy in metastatic melanoma. Quirk, SK., Shure, AK., Agrawal, DK.[2019]

Nivolumab, administered at 3 mg/kg with or without a peptide vaccine, was well tolerated and demonstrated a 25% response rate in patients with advanced melanoma, regardless of prior ipilimumab treatment.

The study suggests that nivolumab can induce long-lasting responses, with some patients responding for up to 140 weeks, and highlights the potential for combining or sequencing nivolumab with ipilimumab for better treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety, efficacy, and biomarkers of nivolumab with vaccine in ipilimumab-refractory or -naive melanoma. Weber, JS., Kudchadkar, RR., Yu, B., et al.[2022]

References

1. Georgia (Republic) pubmed.ncbi.nlm.nih.gov

[EVALUATION OF THE EFFICASY OF THE DRUG OPDIVO (NIVOLUMAB) IN A PATIENT DIAGNOSED WITH UNRESECTABLE SKIN MELANOMA, POSITIVE BRAF MUTATION AND DISEASE DISSEMINATION (CASE REPORT)]. [2021]

2. United States pubmed.ncbi.nlm.nih.gov

Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. [2022]

3. United States pubmed.ncbi.nlm.nih.gov

Nivolumab plus ipilimumab in advanced melanoma. [2022]

4. England pubmed.ncbi.nlm.nih.gov

Efficacy and toxicity of treatment with the anti-CTLA-4 antibody ipilimumab in patients with metastatic melanoma after prior anti-PD-1 therapy. [2021]

5. England pubmed.ncbi.nlm.nih.gov

Combined nivolumab and ipilimumab versus ipilimumab alone in patients with advanced melanoma: 2-year overall survival outcomes in a multicentre, randomised, controlled, phase 2 trial. [2022]

6. Egypt pubmed.ncbi.nlm.nih.gov

Immune-mediated adverse events associated with ipilimumab ctla-4 blockade therapy: the underlying mechanisms and clinical management. [2022]

7. England pubmed.ncbi.nlm.nih.gov

Prevalence of immune-related systemic adverse events in patients treated with anti-Programmed cell Death 1/anti-Programmed cell Death-Ligand 1 agents: A single-centre pharmacovigilance database analysis. [2017]

8. Switzerland pubmed.ncbi.nlm.nih.gov

Retrospective Side Effect Profiling of the Metastatic Melanoma Combination Therapy Ipilimumab-Nivolumab Using Adverse Event Data. [2022]

9. England pubmed.ncbi.nlm.nih.gov

Ipilimumab for advanced melanoma: a pharmacologic perspective. [2021]

10. United States pubmed.ncbi.nlm.nih.gov

Immune-mediated adverse events of anticytotoxic T lymphocyte-associated antigen 4 antibody therapy in metastatic melanoma. [2019]

11. United States pubmed.ncbi.nlm.nih.gov

Safety, efficacy, and biomarkers of nivolumab with vaccine in ipilimumab-refractory or -naive melanoma. [2022]