Immunotherapy + Radiation for Metastatic Melanoma

(RadVax Trial)

Recruiting at 2 trial locations

Overseen By Tara Mitchell, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Abramson Cancer Center at Penn Medicine

Must not be taking: Immunosuppressants, Chemotherapy

Disqualifiers: CNS metastases, Autoimmune disease, HIV, 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: 7

Duration: 12 weeks

54 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new approach to treating metastatic melanoma (a type of skin cancer that has spread) by combining two immunotherapy drugs, ipilimumab (Yervoy) and nivolumab (Opdivo), with a specific type of radiation therapy called Hypofractionated Radiation Therapy (HFRT). The goal is to determine if adding radiation enhances the safety and effectiveness of the treatment in targeting cancer compared to using the drugs alone. Individuals with metastatic melanoma who have at least two measurable tumors and can undergo radiation therapy may be suitable candidates for this trial. As a Phase 2 trial, this research focuses on evaluating the treatment's effectiveness in an initial, smaller group, offering a chance to contribute to significant advancements in cancer treatment.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but it does exclude those on certain cancer treatments or immunosuppressive medications. It's best to discuss your specific medications with the trial team to see if they are allowed.

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

Research shows that using the drugs ipilimumab and nivolumab together can extend the lives of people with advanced melanoma. Studies have found that up to 86% of patients using this combination survive for 10 years, indicating that these drugs are generally safe and beneficial over time.

For hypofractionated radiation therapy (HFRT), which involves fewer, larger doses of radiation, information is less clear. Some studies have shown that HFRT can be used safely, but it may not be suitable for every patient with metastatic melanoma. While HFRT has worked well for some, it might not be effective for everyone.

Overall, current research considers the combination of ipilimumab, nivolumab, and HFRT safe. However, individual responses may vary, so patients should discuss potential risks and benefits with their healthcare provider. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of immunotherapy with radiation for metastatic melanoma because it offers a potentially more effective approach than current treatments. Unlike standard immunotherapy alone, which utilizes drugs like ipilimumab and nivolumab to boost the immune system, this treatment pairs these drugs with hypofractionated radiation therapy (HFRT). HFRT delivers higher doses of radiation in fewer sessions, which may enhance the immune response against cancer cells. This combination could lead to faster and more robust tumor control, providing hope for improved outcomes in patients with metastatic melanoma.

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

Studies have shown that using ipilimumab and nivolumab together effectively treats advanced skin cancer (metastatic melanoma). Research indicates that this combination can help the immune system attack cancer cells, improving survival rates. In this trial, some participants will receive this combination without additional treatment.

Another group in this trial will receive hypofractionated radiation therapy (HFRT), which has been shown to control tumors for extended periods and relieve symptoms. Early findings suggest that combining HFRT with immunotherapy like ipilimumab and nivolumab can effectively control local tumors. Together, these treatments show promise in managing advanced skin cancer by enhancing the body's ability to fight cancer. ^{1 3 4 6 7}

Who Is on the Research Team?

Tara Mitchell, MD

Principal Investigator

Abramson Cancer Center

Are You a Good Fit for This Trial?

Adults over 18 with metastatic melanoma, not pregnant or breastfeeding, willing to use birth control. They must have good organ function and an index lesion suitable for radiotherapy. Excluded are those with certain autoimmune diseases, brain metastases needing urgent treatment, prior T-cell targeting therapy, recent other cancer treatments or surgeries.

Inclusion Criteria

I have a tumor between 1cm and 7cm suitable for high-focus radiation therapy.

Your hemoglobin level is at least 9 grams per deciliter.

I agree to use or have my partner use effective birth control or abstain from sex.

Exclusion Criteria

I have not had any autoimmune diseases except for stable thyroid issues, vitiligo, alopecia, Grave's disease, or psoriasis not needing strong treatment in the past year.

Concurrent enrollment in another clinical study, unless in a follow-up period or the study is an observational or non-interventional study

Any condition that, in the opinion of the investigator, would interfere with evaluation of the investigational product or interpretation of subject safety or study results

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive ipilimumab and nivolumab with or without hypofractionated radiotherapy

12 weeks

4 visits (in-person) for ipilimumab and nivolumab, additional visits for radiotherapy

Radiation

Participants in the experimental group receive hypofractionated radiotherapy

1 week

3 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Hypofractionated Radiation Therapy (HFRT)
• Ipilimumab
• Nivolumab

Trial Overview The trial is testing the combination of two immunotherapy drugs (Ipilimumab and Nivolumab) with hypofractionated radiotherapy on a single tumor versus just the drugs alone in patients with metastatic melanoma to assess safety and impact on the cancer.

How Is the Trial Designed?

Group I: HFRT Experimental Treatment 3 Interventions

The dose of hypofractionated radiation therapy (HFRT) will be 8 Gy x 3 fractions, given over a maximum of 7 days timespan.

Group II: No HFRT Active Control 2 Interventions

ipilimumab and nivolumab once every 3 weeks for up to 4 doses, followed by nivolumab once every 2 weeks or every 4 weeks until disease progression.

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?

Abramson Cancer Center at Penn Medicine

Lead Sponsor

Trials

425

Recruited

464,000+

Abramson Cancer Center of the University of Pennsylvania

Lead Sponsor

Trials

360

Recruited

108,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

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]

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]

In a long-term follow-up of patients with metastatic melanoma treated with ipilimumab and radiation therapy, two out of three patients who achieved a complete response (CR) remain alive and free of melanoma, although they developed chronic treatment-induced hypophysitis.

The durability of the complete responses appears to be linked to the occurrence of grade 2-3 hypophysitis, suggesting that this side effect may be a marker of effective treatment response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Durability of response in metastatic melanoma patients after combined treatment with radiation therapy and ipilimumab. Sodji, QH., Gutkin, PM., Swetter, SM., et al.[2022]

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, 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]

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 study of 70 melanoma patients with brain metastases, those treated with ipilimumab had a significantly longer median survival of 18.3 months compared to 5.3 months for those who did not receive the treatment, indicating ipilimumab enhances overall survival.

Patients who received ipilimumab before radiotherapy showed a higher partial response rate (40%) to treatment compared to those who did not receive ipilimumab (9.1%), suggesting that the sequence of treatments may influence disease control in the brain.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ipilimumab and radiation therapy for melanoma brain metastases. Silk, AW., Bassetti, MF., West, BT., et al.[2022]

In a review of 16 melanoma patients treated with ipilimumab and cranial radiation, the combination was found to be well tolerated and associated with a median survival of 14 months, suggesting potential benefits for patients with brain metastases.

There was a notable trend indicating that administering ipilimumab within three months of radiation may enhance the likelihood of improved responses in extra-cranial lesions, warranting further investigation into the timing of these treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ipilmumab and cranial radiation in metastatic melanoma patients: a case series and review. Schoenfeld, JD., Mahadevan, A., Floyd, SR., et al.[2022]

Combining anti-PD-L1 immunotherapy with radiation therapy has shown promising results in increasing progression-free survival (PFS) and overall survival (OS) in patients with advanced melanoma and metastatic non-small cell lung cancer (NSCLC), based on several preclinical studies and two early clinical trials.

Low doses of radiation enhance T-cell activity, which is further boosted by anti-PD-L1 therapy, suggesting that this combination can effectively overcome the immune suppression caused by PD-L1, leading to better tumor control and regression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Radiation Therapy Plus Anti-Programmed Death Ligand 1 Immunotherapy: A Review on Overall Survival. Krcik, EM.[2019]

In a phase 2 trial involving 20 patients with metastatic melanoma, combining stereotactic body radiation therapy (SBRT) with nivolumab resulted in an overall response rate of 45%, indicating that this combination may enhance treatment efficacy.

The treatment was generally well tolerated, with most adverse events being mild (grade 1 to 2), and some patients showed delayed responses after SBRT, suggesting that this approach could benefit those who initially do not respond to nivolumab alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 2 Trial of Nivolumab Combined With Stereotactic Body Radiation Therapy in Patients With Metastatic or Locally Advanced Inoperable Melanoma. Sundahl, N., Seremet, T., Van Dorpe, J., et al.[2019]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11415805/

Durable local control with hypofractionated radiation ... HFRT provided durable local control and improved tumor-associated symptoms in patients with limited toxicity. •. HFRT is an effective form of ...

2. redjournal.org redjournal.org/article/S0360-3016(24)03045-1/fulltext

Hypofractionated Radiation Therapy for Unresectable or ... Twenty-six patients died during follow-up (53%) at a median time from HFRT of 8 months. Median follow-up of those alive at last follow-up was 26 ...

3. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0360301624030451

Hypofractionated Radiation Therapy for Unresectable or ... In this study we evaluated if dose-escalated hypofractionated radiation therapy (HFRT) can provide durable local control and improve tumor-associated symptoms

4. spandidos-publications.com spandidos-publications.com/10.3892/ol.2024.14731

Good response of stage IV melanoma to high‑dose ... The present case report demonstrates that high‐dose radiotherapy combined with immunotherapy may be effective for local lesions.

5. tandfonline.com tandfonline.com/doi/full/10.1080/2162402X.2020.1863631

A stratified phase I dose escalation trial of hypofractionated ... Eleven patients had grade 3 AEs (no grade 4/5). There were no dose-limiting toxicities related to the radiation/ipilimumab combination. Five of 22 patients ( ...

6. sciencedirect.com sciencedirect.com/science/article/pii/S0959804925000371

Nivolumab and hypofractionated radiotherapy in patients ... This was a multicenter, non-randomized, phase 2 trial that enrolled patients with treatment-naïve metastatic melanoma. They received nivolumab ( ...

7. nature.com nature.com/articles/s41416-018-0281-9

A phase I trial of pembrolizumab with hypofractionated ... We conducted a phase I trial evaluating pembrolizumab+hypofractionated radiotherapy (HFRT) for patients with metastatic cancers.