Tumor-Treating Fields + Immunotherapy for Uveal Melanoma

Recruiting at1 trial location

Overseen by Justin Moser, MD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

Sponsor: HonorHealth Research Institute

Must not be taking: Corticosteroids, Immunosuppressives

Disqualifiers: Autoimmune disease, Pacemaker, others

No Placebo Group

Breakthrough Therapy

Trial Summary

What is the purpose of this trial?

This trial is testing a new cancer treatment that uses electric fields to stop cancer cell growth. It targets patients with metastatic uveal melanoma, who often do not respond well to current treatments. The treatment works by boosting the immune system to help fight the cancer.

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 require that you haven't had certain cancer treatments recently and that any side effects from past treatments have resolved. It's best to discuss your specific medications with the trial team.

What data supports the effectiveness of the treatment Tumor-Treating Fields + Immunotherapy for Uveal Melanoma?

The use of immune checkpoint inhibitors (ICI) like Ipilimumab and Nivolumab has shown improved survival rates in patients with metastatic uveal melanoma, with a one-year overall survival rate increasing from 25.0% to 41.9% after ICI treatment. Although response rates are lower compared to other melanoma types, these treatments have significantly improved real-world survival outcomes. ^{1 2 3 4 5}

What safety information is available for Tumor-Treating Fields and Immunotherapy in humans?

Immune checkpoint inhibitors like Ipilimumab and Nivolumab can cause rare but serious eye-related side effects, such as uveitis (eye inflammation) and panuveitis, which may require treatment. In a study of Ipilimumab for uveal melanoma, some patients experienced immune-related side effects like diarrhea and liver enzyme changes, which were managed with steroids. ^{6 7 8 9 10}

How is the Tumor-Treating Fields + Immunotherapy treatment for uveal melanoma different from other treatments?

This treatment is unique because it combines Tumor-Treating Fields, a non-invasive therapy that uses electric fields to disrupt cancer cell division, with immunotherapy drugs like Ipilimumab and Nivolumab, which help the immune system attack cancer cells. Unlike other treatments, this combination aims to enhance the body's natural defenses while directly targeting tumor growth. ^{3 4 5 11 12}

Research Team

Justin Moser, MD

Principal Investigator

HonorHealth Research Institute

Eligibility Criteria

This trial is for adults with metastatic uveal melanoma, mainly affecting the liver. Participants must be in good physical condition (ECOG 0-1), have a life expectancy of at least 3 months, and normal organ/marrow function. Women of childbearing potential must test negative for pregnancy and use contraception. Excluded are those with active autoimmune diseases requiring strong medication, recent cancer treatments, or severe reactions to immune checkpoint inhibitors.

Inclusion Criteria

My cancer is a type of eye melanoma that has spread mainly to my liver.

My organs and bone marrow are functioning normally.

I am fully active and can carry on all my pre-disease activities without restriction.

Exclusion Criteria

I had a severe reaction to previous immunotherapy.

My side effects from cancer treatments are mostly mild, except for hormone issues being treated.

I am willing and able to follow the study's procedures.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive Tumor Treating Fields in combination with nivolumab and ipilimumab

up to 1 year

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Long-term follow-up

Participants are monitored for overall survival and progression-free survival

up to 100 months

Treatment Details

Interventions

• Ipilimumab (Checkpoint Inhibitor)
• Nivolumab (Monoclonal Antibodies)
• Novocure Optune (Device)

Trial Overview The study tests Tumor-Treating Fields targeting liver metastases combined with Nivolumab and Ipilimumab—two immunotherapy drugs—in patients with metastatic uveal melanoma. The goal is to see if this combination improves patient outcomes compared to current treatments.

Participant Groups

Group I: TTF Plus Chemotherapy Experimental Treatment 3 Interventions

Novacure Optune with Opdivo and Yervoy

Who Is Running the Clinical Trial?

HonorHealth Research Institute

Lead Sponsor

Trials

26

Recruited

940+

NovoCure Ltd.

Industry Sponsor

Trials

64

Recruited

6,100+

Ashley Cordova

NovoCure Ltd.

Chief Executive Officer

Bachelor of Science in Material Engineering from Ben-Gurion University of the Negev, Israel

Uri Weinberg

NovoCure Ltd.

Chief Medical Officer since 2020

MD from an unspecified institution

Findings from Research

In a nationwide study of patients with metastatic uveal melanoma (UM), the introduction of immune checkpoint inhibitors (ICI) as first-line treatment significantly improved overall survival rates, increasing from 25.0% to 41.9% one year after treatment.

Despite relatively low response rates (7% for anti-PD-1 monotherapy and 21% for combined therapy), median overall survival improved from 7.8 months to 10.0 months, indicating that ICI therapy offers a meaningful benefit for patients with metastatic UM.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-World Impact of Immune Checkpoint Inhibitors in Metastatic Uveal Melanoma. Bol, KF., Ellebaek, E., Hoejberg, L., et al.[2020]

High levels of PD-1 expression in primary uveal melanoma are linked to poorer patient survival and larger tumor size, indicating that PD-1 could serve as a prognostic marker.

Manipulating PD-1 levels in uveal melanoma cell lines showed that increasing PD-1 promotes tumor growth, while reducing PD-1 inhibits it, suggesting that targeting PD-1 may be a promising treatment strategy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

PD-1 expression on uveal melanoma induces tumor proliferation and predicts poor patient survival. Jiang, Z., Yan, Y., Dong, J., et al.[2022]

Uveal melanoma and cutaneous melanoma show significant differences in their immune responses, with cutaneous melanoma having a stronger antitumor T-cell response, particularly with a higher presence of CD8(+) T cells compared to the CD4(+) dominant TIL in uveal melanoma.

However, a subset of uveal melanoma patients exhibited robust antitumor T-cell reactivity, especially in tumors lacking melanin pigmentation, suggesting that these patients may benefit from immunotherapies targeting their unique immune responses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Identification of an Immunogenic Subset of Metastatic Uveal Melanoma. Rothermel, LD., Sabesan, AC., Stephens, DJ., et al.[2023]

In a study of 64 patients with metastatic uveal melanoma treated with a combination of CTLA-4 and PD-1 inhibitors, the overall response rate was 15.6%, with a median overall survival of 16.1 months, indicating that this combination therapy may be the most effective option currently available for this difficult-to-treat cancer.

Despite a significant number of patients experiencing severe treatment-related adverse events (39.1%), the tolerability of this combined therapy appears to be better than that seen in trials for cutaneous melanoma, suggesting a potentially safer profile for patients with uveal melanoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combined immune checkpoint blockade for metastatic uveal melanoma: a retrospective, multi-center study. Heppt, MV., Amaral, T., Kähler, KC., et al.[2023]

In a retrospective review of 15 patients with metastatic uveal melanoma treated with anti-PD-1 antibodies (pembrolizumab or nivolumab), the best response observed was stable disease in four patients, indicating limited efficacy as no objective responses were recorded.

The treatment was generally well tolerated, with manageable toxicity, and the median progression-free survival was 3 months, while the overall survival was 5 months, suggesting that while the therapy may not be highly effective, it can be safely administered.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-PD-1 antibodies in metastatic uveal melanoma: a treatment option? Bender, C., Enk, A., Gutzmer, R., et al.[2021]

In a study of 41,674 cancer patients, only 3.0% reported ocular adverse events (oAEs) related to immune checkpoint inhibitors, with the most common being vision disorders and uveitis.

Uveitis was found to be significantly more common in melanoma patients receiving the combination of anti-PD-1 and anti-CTLA-4 therapies, with a reporting odds ratio (ROR) of 17.1, indicating a strong association.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ocular Adverse Events Induced by Immune Checkpoint Inhibitors: A Comprehensive Pharmacovigilance Analysis. Bomze, D., Meirson, T., Hasan Ali, O., et al.[2022]

Ipilimumab, an immune checkpoint inhibitor used for metastatic melanoma, can lead to severe ophthalmic immune-related adverse events (irAEs) such as uveitis and hypotony, as demonstrated in a case study of a 69-year-old man who experienced significant vision loss after treatment.

The patient's condition required aggressive management with corticosteroids and surgical interventions, highlighting the need for careful monitoring and follow-up for patients on ipilimumab, especially those with prior glaucoma surgeries.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ipilimumab-related uveitis and refractory hypotony with a flat chamber in a trabeculectomized eye with exfoliation glaucoma: A case report. Funagura, N., Fukushima, S., Inoue, T.[2023]

Immune checkpoint inhibitors (ICIs), specifically PD-1/PD-L1 inhibitors, have a lower risk of treatment-related and nonspecific ophthalmic adverse events compared to chemotherapy, with odds ratios of 0.44 and 0.28 respectively, indicating they are safer options for patients.

However, when PD-1 inhibitors are combined with CTLA-4 inhibitors or chemotherapy, the risk of immune-related adverse events significantly increases, suggesting that combination therapies may lead to higher ocular complications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Risk of Ophthalmic Adverse Events in Patients Treated with Immune Checkpoint Inhibitor Regimens: A Systematic Review and Meta-analysis. Hou, YL., Wang, DY., Hu, JX., et al.[2022]

A rare case of panuveitis occurred in a patient receiving Nivolumab and Ipilimumab for recurrent Small Cell Lung Cancer, highlighting the potential for serious immune-related ocular toxicities from checkpoint inhibitors.

The patient successfully managed the panuveitis with an Ozurdex injection, leading to resolution of inflammation and improved vision, allowing her to continue Nivolumab treatment without recurrence of the eye condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Panuveitis in patient on ipilimumab/nivolumab combination for small-cell lung cancer treated with an intravitreal dexamethasone implant. L Hefler, J., M Bailey, L., El Rahi, C., et al.[2021]

In a study involving 13 patients with metastatic uveal melanoma treated with ipilimumab, no objective tumor responses were observed, but some patients achieved stable disease, suggesting potential for further investigation.

The treatment was generally well-tolerated, with no severe non-immune adverse events reported, although 23% of patients experienced grade 3 immune-related adverse events that were manageable with steroids.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ipilimumab in pretreated patients with metastatic uveal melanoma: safety and clinical efficacy. Danielli, R., Ridolfi, R., Chiarion-Sileni, V., et al.[2022]

In a study of 39 patients with uveal melanoma treated with ipilimumab, the overall response rate was low at 2.6%, but the combined response plus stable disease rate was 46% at 12 weeks, indicating some potential for disease stabilization.

Ipilimumab was associated with significant immune-related adverse events in 71.8% of patients, with more severe events occurring in those receiving higher doses, but the treatment was deemed to have manageable toxicity and a median overall survival of 9.6 months.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical activity of ipilimumab for metastatic uveal melanoma: a retrospective review of the Dana-Farber Cancer Institute, Massachusetts General Hospital, Memorial Sloan-Kettering Cancer Center, and University Hospital of Lausanne experience. Luke, JJ., Callahan, MK., Postow, MA., et al.[2022]

A novel immunotherapeutic strategy combining local photodynamic therapy (PDT) with a ROCK inhibitor and PD-1/PD-L1 blockade showed promising results in treating uveal melanoma (UM) by enhancing immune responses and preventing metastasis.

In mouse models, this combination therapy not only reduced primary tumor size but also transformed the tumor microenvironment to promote the infiltration of cytotoxic T cells, leading to improved survival outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

In situ immunogenic clearance induced by a combination of photodynamic therapy and rho-kinase inhibition sensitizes immune checkpoint blockade response to elicit systemic antitumor immunity against intraocular melanoma and its metastasis. Kim, S., Kim, SA., Nam, GH., et al.[2021]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

Real-World Impact of Immune Checkpoint Inhibitors in Metastatic Uveal Melanoma. [2020]

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

PD-1 expression on uveal melanoma induces tumor proliferation and predicts poor patient survival. [2022]

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

Identification of an Immunogenic Subset of Metastatic Uveal Melanoma. [2023]

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

Combined immune checkpoint blockade for metastatic uveal melanoma: a retrospective, multi-center study. [2023]

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

Anti-PD-1 antibodies in metastatic uveal melanoma: a treatment option? [2021]

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

Ocular Adverse Events Induced by Immune Checkpoint Inhibitors: A Comprehensive Pharmacovigilance Analysis. [2022]

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

Ipilimumab-related uveitis and refractory hypotony with a flat chamber in a trabeculectomized eye with exfoliation glaucoma: A case report. [2023]

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

Risk of Ophthalmic Adverse Events in Patients Treated with Immune Checkpoint Inhibitor Regimens: A Systematic Review and Meta-analysis. [2022]

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

Panuveitis in patient on ipilimumab/nivolumab combination for small-cell lung cancer treated with an intravitreal dexamethasone implant. [2021]

10. Germany pubmed.ncbi.nlm.nih.gov

Ipilimumab in pretreated patients with metastatic uveal melanoma: safety and clinical efficacy. [2022]

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

Clinical activity of ipilimumab for metastatic uveal melanoma: a retrospective review of the Dana-Farber Cancer Institute, Massachusetts General Hospital, Memorial Sloan-Kettering Cancer Center, and University Hospital of Lausanne experience. [2022]

12. England pubmed.ncbi.nlm.nih.gov

In situ immunogenic clearance induced by a combination of photodynamic therapy and rho-kinase inhibition sensitizes immune checkpoint blockade response to elicit systemic antitumor immunity against intraocular melanoma and its metastasis. [2021]