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

8 Participants Needed

Trial Summary

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.

What data supports the effectiveness of the treatment hu14.18-IL2 + Nivolumab + Ipilimumab + Radiation for Melanoma?

Research shows that combining immune checkpoint inhibitors like nivolumab and ipilimumab with radiation therapy can enhance the antitumor effects in melanoma patients, leading to successful treatment outcomes in some cases. ^{1 2 3 4 5}

Is the combination of hu14.18-IL2, Nivolumab, Ipilimumab, and Radiation safe for humans?

The combination of Ipilimumab and radiation therapy has been studied for safety in patients with melanoma, showing that it can cause immune-related side effects like skin rash, inflammation of the colon (colitis), liver (hepatitis), and pituitary gland (hypophysitis). These side effects are usually treated with high-dose steroids and often improve. Safety data for Nivolumab and radiation therapy also exist, but specific safety information for the exact combination with hu14.18-IL2 is not detailed in the available studies. ^{1 3 6 7 8}

What makes the hu14.18-IL2 + Nivolumab + Ipilimumab + Radiation treatment unique for melanoma?

This treatment is unique because it combines immune system-boosting drugs (Nivolumab and Ipilimumab) with a targeted therapy (hu14.18-IL2) and radiation, aiming to enhance the body's ability to fight melanoma more effectively than using these components separately. ^{1 2 4 9 10}

What is the purpose of this trial?

This phase I/II trial is designed to determine the maximum tolerated dose or the maximum administered dose of intratumoral administration of hu14.18-IL2 and to evaluate side effects of intratumoral hu14.18-IL2 when given alone, after radiation therapy, after radiation therapy and in combination with nivolumab, and after radiation therapy and in combination with nivolumab and ipilimumab in patients with melanoma that is advanced (stage IV) or with melanoma that cannot be removed by surgery and is considered surgically incurable. Hu14.18-IL2 is a molecule called a fusion protein that can bind to some tumor cells and cause immune cells to become activated to kill tumor cells. Radiation therapy is a type of cancer treatment that uses beams of high energy x-rays to kill tumor cells and shrink tumors. Immunotherapy with immune checkpoint inhibitors, such as nivolumab and ipilimumab, can help the body's immune system attack cancer by releasing the "brakes" on the immune system to allow cancer fighting immune cells to remain activated. This study will evaluate whether giving intratumoral hu14.18-IL2 with radiation therapy, nivolumab and ipilimumab has antitumor activity for participants with advanced melanoma. After completion of study treatment, participants are followed up at 30 days, every 12 weeks for up to 2 years, and then every 6 months thereafter.

Research Team

Mark R Albertini, MD

Principal Investigator

University of Wisconsin, Madison

Paul Sondel, MD, PhD

Principal Investigator

University of Wisconsin, Madison

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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 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]

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]

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]

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]

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]

References

1. Germany pubmed.ncbi.nlm.nih.gov

Efficacy and safety of concurrent immunoradiotherapy in patients with metastatic melanoma after progression on nivolumab. [2019]

2. England 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. [2018]

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

Phase 1 Dose Escalation Trial of Ipilimumab and Stereotactic Body Radiation Therapy in Metastatic Melanoma. [2019]

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

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

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

Ipilimumab and Radiation in Patients with High-risk Resected or Regionally Advanced Melanoma. [2022]

6. England pubmed.ncbi.nlm.nih.gov

Ipilimumab may increase the severity of cutenaous toxicity related to radiotherapy. [2018]

7. Netherlands pubmed.ncbi.nlm.nih.gov

Effectiveness and safety of immune checkpoint inhibitors in combination with palliative radiotherapy in advanced melanoma: A systematic review. [2021]

8. England pubmed.ncbi.nlm.nih.gov

Efficacy and safety of ipilimumab monotherapy in patients with pretreated advanced melanoma: a multicenter single-arm phase II study. [2022]

9. 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]

10. Japan pubmed.ncbi.nlm.nih.gov

Combined radiotherapy with nivolumab for extracranial metastatic malignant melanoma. [2019]