hu14.18-IL2 + Nivolumab + Ipilimumab + Radiation for Melanoma

Overseen By Cancer Connect

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: University of Wisconsin, Madison

Must not be taking: Corticosteroids, Immunosuppressants

Disqualifiers: Auto-immune disease, Cardiac disease, Psychiatric disabilities, Infections, others

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

Compensation: Varies

Number of Visits: Unknown

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new combination of treatments for individuals with advanced melanoma, a type of skin cancer. The goal is to determine the optimal dose and assess the side effects of a fusion protein called hu14.18-IL2, which aids the immune system in attacking cancer cells. Participants will receive this protein alone, with radiation therapy, or possibly with other drugs, such as nivolumab (Opdivo) and ipilimumab (Yervoy), which enhance the immune response. Those with stage IV melanoma or melanoma that cannot be surgically removed, and who have tried or declined at least one other treatment, might be suitable for this trial. As a Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new therapy.

Will I have to stop taking my current medications?

The trial requires a washout period of at least 28 days between any prior systemic anti-cancer therapy and the first dose of the study drugs. Additionally, participants must be willing to stop taking antihypertensive medications on the days they receive hu14.18-IL2.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that hu14.18-IL2 has been tested in adults with melanoma and is generally well-tolerated. In previous studies, patients received doses between 0.8–7.5 mg/m² and found it safe, with no severe side effects commonly observed.

Nivolumab, another treatment for melanoma, has FDA approval, providing extensive safety information. It works effectively alone or with ipilimumab, another treatment. Long-term studies indicate that many patients live for years after treatment, demonstrating a well-understood safety profile.

Ipilimumab has been extensively studied in individuals with advanced melanoma. It has helped some patients live longer and is generally safe. However, like many cancer treatments, it can cause side effects, which are closely monitored in trials.

These treatments are being studied together to evaluate their efficacy and safety when combined. Given their history and approval for treating melanoma, they have been shown to be safe for many people. However, side effects can still occur and remain a key focus of ongoing research. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for melanoma because they combine innovative approaches to tackle the disease more effectively. Unlike traditional treatments like surgery, chemotherapy, or single-agent immunotherapies, this trial explores the synergy of hu14.18-IL2, nivolumab, and ipilimumab. Hu14.18-IL2 is a fusion protein that delivers IL-2 directly to tumor sites, potentially boosting immune response right where it's needed. Nivolumab and ipilimumab are immune checkpoint inhibitors that work by enhancing the body's own immune system to fight cancer cells. By integrating these treatments with radiation, the approach aims to enhance immune activation and potentially improve outcomes for patients with melanoma.

What evidence suggests that this trial's treatments could be effective for advanced melanoma?

This trial will evaluate the combination of hu14.18-IL2, Nivolumab, Ipilimumab, and Radiation Therapy for melanoma. Studies have shown that hu14.18-IL2, a protein that aids the immune system in fighting cancer, is generally safe and can activate the immune system in melanoma patients. Nivolumab and Ipilimumab, drugs that enhance immune function, have been proven to improve survival rates in advanced melanoma. Specifically, research has shown that patients free of disease progression after 3 years had a 96% chance of surviving melanoma for 10 years when treated with both Nivolumab and Ipilimumab. Radiation therapy, which uses high-energy rays to kill cancer cells, has also effectively treated melanoma that has spread. This trial will test the combination of these treatments to potentially enhance their effectiveness, helping the body's immune system attack melanoma more successfully. ^{2 3 6 7 8}

Who Is on the Research Team?

Mark R Albertini, MD

Principal Investigator

University of Wisconsin, Madison

Paul Sondel, MD, PhD

Principal Investigator

University of Wisconsin, Madison

Are You a Good Fit for This Trial?

This trial is for adults with advanced (stage IV) or surgically incurable melanoma. Participants must have measurable disease, accessible tumors for injections and biopsies, and an ECOG performance status of 0 or 1. They should have tried at least one FDA-approved immunotherapy and can't be on high doses of steroids. Those with stable brain metastases may qualify.

Inclusion Criteria

Subjects must be willing and able to provide informed written consent for the study

I need radiation therapy to relieve symptoms from my cancer.

I am willing to stop my blood pressure medicine if recommended.

Exclusion Criteria

Subjects with a diagnosed auto-immune disease

Subjects with significant intercurrent illnesses per physician discretion

Subjects with significant psychiatric disabilities or seizure disorders

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment Phase IA

Participants receive hu14.18-IL2 fusion protein intratumorally once daily on days 1-3, repeating every 21 days for cycles 1-4. Eligible participants may continue maintenance therapy every 28 days for up to 13 cycles.

Up to 13 cycles (21 days for cycles 1-4, 28 days for maintenance)

Treatment Phase IB

Participants undergo palliative radiation therapy on days -8 to -4 of cycle 1 and receive hu14.18-IL2 fusion protein as in Phase IA.

Up to 13 cycles (21 days for cycles 1-4, 28 days for maintenance)

Treatment Phase IC

Participants undergo palliative radiation therapy, receive nivolumab every 2 weeks for up to 1 year, and hu14.18-IL2 fusion protein as in Phase IA.

Up to 1 year for nivolumab, up to 13 cycles for hu14.18-IL2

Treatment Phase ID

Participants undergo palliative radiation therapy, receive nivolumab and ipilimumab every 3 weeks for 4 cycles, followed by maintenance nivolumab for up to 1 year, and hu14.18-IL2 fusion protein as in Phase IA.

4 cycles for ipilimumab, up to 1 year for nivolumab, up to 13 cycles for hu14.18-IL2

Follow-up

Participants are monitored for safety and effectiveness after treatment completion at 30 days, every 12 weeks for up to 2 years, and then every 6 months thereafter.

Up to 5 years

What Are the Treatments Tested in This Trial?

Interventions

• hu14.18-IL2
• Ipilimumab
• Nivolumab
• Radiation Therapy

Trial Overview The study tests the combination of a fusion protein drug hu14.18-IL2, radiation therapy, and immune checkpoint inhibitors nivolumab and ipilimumab in treating advanced melanoma. It aims to find the safest dose of hu14.18-IL2 when used alone or with other treatments, assessing its effectiveness against tumor cells.

How Is the Trial Designed?

Group I: Experimental Groups Experimental Treatment 4 Interventions

PHASE IA: As described above. Participants receive hu14.18-IL2 fusion protein intratumorally (IT). PHASE IB: As described above. Participants undergo palliative RT and hu14.18-IL2 fusion protein IT as in phase IA. PHASE IC: As described above. Participants undergo palliative RT, receive nivolumab, and hu14.18-IL2 fusion protein IT as in phase IA. PHASE ID: As described above. Participants undergo palliative RT, receive nivolumab in combination with ipilimumab, and hu14.18-IL2 fusion protein IT as in phase IA.

Who Is Running the Clinical Trial?

University of Wisconsin, Madison

Lead Sponsor

Trials

1,249

Recruited

3,255,000+

Apeiron Biologics

Industry Sponsor

Trials

5

Recruited

330+

AnYxis Immuno-Oncology GmbH

Collaborator

Trials

1

Recruited

60+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Bristol-Myers Squibb

Industry Sponsor

Trials

2,731

Recruited

4,127,000+

Headquarters

New York City, USA

Known For

Oncology & Cardiovascular

Top Products

Eliquis, Opdivo, Revlimid, Orencia

Christopher Boerner

Bristol-Myers Squibb

Chief Executive Officer since 2023

PhD in Business Administration from the Haas School of Business, University of California, Berkeley; BA in Economics and History from Washington University in St. Louis

Deepak L. Bhatt

Bristol-Myers Squibb

Chief Medical Officer since 2024

MD from Yale University; MSc in Clinical Epidemiology from the University of Pennsylvania

Provenance Biopharmaceuticals

Collaborator

Trials

1

Recruited

60+

Published Research Related to This Trial

Ipilimumab showed a best overall response rate (BORR) of 5.8% and a disease control rate (DCR) of 27% in patients with advanced melanoma, indicating some level of efficacy in this challenging population.

The treatment resulted in promising long-term survival rates, with 1- and 2-year survival rates of 47.2% and 32.8%, respectively, and a median overall survival of 10.2 months, while adverse events were primarily immune-related but manageable.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of ipilimumab monotherapy in patients with pretreated advanced melanoma: a multicenter single-arm phase II study. O'Day, SJ., Maio, M., Chiarion-Sileni, V., et al.[2022]

Concurrent immunoradiotherapy, combining immune checkpoint inhibitors with radiotherapy, showed a 30% overall response rate in 16 patients with metastatic melanoma who had progressed on nivolumab, with a notable 68.8% response rate in lesions within the radiation fields.

Nivolumab combined with radiotherapy demonstrated a 100% response rate inside the radiation fields, suggesting it may be more effective than ipilimumab in this setting, although some patients experienced grade 3 adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of concurrent immunoradiotherapy in patients with metastatic melanoma after progression on nivolumab. Nomura, M., Otsuka, A., Yoshimura, M., et al.[2019]

Two cases of patients with multiple in-transit metastatic melanomas were successfully treated using intensity-modulated radiotherapy (IMRT) combined with immune checkpoint inhibitors ipilimumab or nivolumab.

The combination of IMRT and immune checkpoint inhibitors suggests a potential enhancement of antitumor effects, indicating a promising approach for improving treatment outcomes in melanoma patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Successful treatment of multiple in-transit melanomas on the leg with intensity-modulated radiotherapy and immune checkpoint inhibitors: Report of two cases. Fujimura, T., Kambayashi, Y., Furudate, S., et al.[2018]

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]

In a phase 1 trial with 13 patients suffering from metastatic melanoma, the combination of ipilimumab and high-dose radiation therapy was found to be feasible and safe, with 25% of patients experiencing grade 3 or 4 adverse events.

Local control of the treated lesions was achieved in 11 out of 12 patients, and while only 3 patients showed clinical benefit in non-irradiated lesions, the results suggest that early radiation therapy may enhance the effectiveness of ipilimumab.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 1 Dose Escalation Trial of Ipilimumab and Stereotactic Body Radiation Therapy in Metastatic Melanoma. Sundahl, N., De Wolf, K., Kruse, V., et al.[2019]

Combining palliative radiotherapy (pRT) with immune checkpoint inhibitors (ICI) in melanoma treatment significantly improved objective response rates, complete response rates, and one-year local control, indicating enhanced efficacy of the treatment.

The combination treatment did not lead to a significant increase in adverse events or immune-related adverse events compared to ICI alone, suggesting that it is a safe option for patients with advanced melanoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effectiveness and safety of immune checkpoint inhibitors in combination with palliative radiotherapy in advanced melanoma: A systematic review. Ben Shimol, J., Guzman-Prado, Y., Karlinskaya, M., 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]

Ipilimumab, a monoclonal antibody that enhances the immune response against melanoma, can lead to immune-related adverse effects such as dermatitis, colitis, and hepatitis, which are typically managed with high-dose steroids.

In a reported case, a patient undergoing radiotherapy for metastatic melanoma developed an atypical generalized rash that worsened with concurrent ipilimumab treatment, highlighting the need for careful monitoring of skin reactions during combined therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ipilimumab may increase the severity of cutenaous toxicity related to radiotherapy. Eryılmaz, MK., Mutlu, H., Salim, DK., et al.[2018]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12080919/

Final, 10-Year Outcomes with Nivolumab plus Ipilimumab in ... In patients who were progression-free at 3-years, 10-year melanoma-specific survival rates were 96% with nivolumab-plus-ipilimumab, 97% with ...

2. curemelanoma.org curemelanoma.org/patient-eng/melanoma-treatment/options/yervoy-ipilimumab

Ipilimumab, Yervoy - MRA The results showed that ipilimumab extended the amount of time before cancer returned by an average of 9 months. The clinical trials are ongoing to assess the ...

3. annalsofoncology.org annalsofoncology.org/article/S0923-7534(19)37101-7/fulltext

Efficacy and safety of ipilimumab in metastatic melanoma ... Survival rates at 2 and 3 years were 25% (24 of 95) and 25% (13 of 53) with ipilimumab alone and 19% (54 of 284) and 15% (24 of 156) with ipilimumab plus gp100.

4. news.bms.com news.bms.com/news/details/2016/Yervoy-ipilimumab-Improves-Overall-Survival-in-Fully-Resected-Stage-III-Melanoma-Patients-From-Phase-3-Study/default.aspx

Yervoy (ipilimumab) Improves Overall Survival in Fully ... Yervoy demonstrated a 28% reduction in the risk of death versus placebo in first disclosure of overall survival data from pivotal study ...

5. nejm.org nejm.org/doi/full/10.1056/NEJMoa1910836

Five-Year Survival with Combined Nivolumab and ... Those results showed a median overall survival of 25.9 months (95% CI, 22.6 to 31.5) and a 5-year overall survival of 34% (95% CI, 30 to 38).

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4023079/

Efficacy and safety of ipilimumab in patients with advanced ... Median OS was 7 months for asymptomatic patients, with 1 and 2-year survival rates of 31 and 26 %. Equivalent results for patients with symptomatic brain ...

7. nejm.org nejm.org/doi/full/10.1056/NEJMoa1611299

Prolonged Survival in Stage III Melanoma with Ipilimumab ... At a median follow-up of 2.7 years, adjuvant ipilimumab was associated with significantly prolonged recurrence-free survival, the primary end ...

8. merck.com merck.com/news/ten-year-data-for-mercks-keytruda-pembrolizumab-demonstrates-sustained-overall-survival-benefit-versus-ipilimumab-in-advanced-melanoma/

Ten-Year Data for Merck's KEYTRUDA® (pembrolizumab ... At 10 years, more than one-third (34.0%) of patients with advanced melanoma were alive after treatment with KEYTRUDA, compared to 23.6% of patients treated ...