Immunotherapy + Radiotherapy for Uveal Melanoma

Overseen By Madeline Decker

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: California Pacific Medical Center Research Institute

Must not be taking: Systemic steroids

Disqualifiers: Active CNS metastases, Pregnancy, Autoimmune diseases, 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

Compensation: Varies

Number of Visits: Unknown

Duration: 104 weeks

40 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a phase 2 trial of concurrent stereotactic radiation therapy (SBRT) with immunotherapy with relatlimab and nivolumab for up to two years. SBRT will be given in three doses of 15Gy each to 1-5 separate metastases. Opdualag (nivolumab 480mg and relatlimab 160mg) will be given every 4 weeks for two years

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 mention that you cannot have any other concurrent therapy and cannot use systemic steroids.

What data supports the effectiveness of the treatment Immunotherapy + Radiotherapy for Uveal Melanoma?

A study showed that adding hepatic radiotherapy to anti-PD-1 treatment, like pembrolizumab, helped some patients with metastatic uveal melanoma, with 27.3% achieving partial response and a median overall survival of 21.2 months. This suggests that combining radiotherapy with immunotherapy could be beneficial for treating this type of cancer. ^{1 2 3 4 5}

Is the combination of immunotherapy and radiotherapy safe for treating uveal melanoma?

The combination of nivolumab and relatlimab (Opdualag) has a manageable safety profile in patients with advanced melanoma, although there are immune-related side effects. In a study involving hepatic radiotherapy and anti-PD-1 treatment for metastatic uveal melanoma, no severe radiotherapy-related adverse events were reported. ^{3 6 7 8 9}

How is the treatment of Opdualag and Stereotactic Body Radiotherapy unique for uveal melanoma?

This treatment combines immunotherapy with Opdualag, which targets immune checkpoints to help the body's immune system fight cancer, and Stereotactic Body Radiotherapy, a precise form of radiation therapy. This combination is novel for uveal melanoma, a condition with limited effective treatments, as it aims to enhance the immune response while directly targeting the tumor with radiation. ^{1 4 10 11 12}

Research Team

David R Minor, MD

Principal Investigator

California Pacific Med Center Research Inst.

Eligibility Criteria

This trial is for individuals with metastatic uveal melanoma who have measurable cancer spread, normal liver and kidney function tests, no active hepatitis B or HIV infection, and are generally in good health (performance status 0-1). Pregnant people, those with large liver tumor volumes (>50%), active brain metastases, prior Opdualag/relatlimab treatment, certain autoimmune diseases or previous specific liver treatments are excluded.

Inclusion Criteria

I do not have active Hepatitis B.

I can carry out all my usual activities without help.

Your white blood cell count, absolute neutrophil count, and hemoglobin levels are within specific ranges.

Exclusion Criteria

Pregnancy

More than half of my liver is affected by the tumor.

My cancer has spread to my brain.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Radiation

Participants receive stereotactic body radiotherapy (SBRT) in three doses of 15Gy each to 1-5 separate metastases

3 weeks

Treatment

Participants receive Opdualag (nivolumab 480mg and relatlimab 160mg) every 4 weeks for up to two years

104 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

5 years

Treatment Details

Interventions

• Opdualag
• Stereotactic Body Radiotherapy

Trial Overview The study is testing the combination of stereotactic body radiotherapy (SBRT) given as three doses to target up to five cancer spots along with an immunotherapy drug called Opdualag (nivolumab and relatlimab) every four weeks for two years. The goal is to see how well they work together against metastatic uveal melanoma.

Participant Groups

Group I: one arm Experimental Treatment 2 Interventions

see below

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

Approved in United States as Opdualag for:

• Unresectable or metastatic melanoma

Approved in European Union as Opdualag for:

• Advanced (unresectable or metastatic) melanoma

Who Is Running the Clinical Trial?

California Pacific Medical Center Research Institute

Lead Sponsor

Trials

44

Recruited

10,600+

Findings from Research

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]

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 retrospective study of 22 patients with metastatic uveal melanoma treated with pembrolizumab and hepatic radiotherapy, 27.3% achieved a partial response and the disease control rate was 40.9%, indicating potential efficacy of this combination therapy.

The median overall survival was 21.2 months with no severe adverse events reported, suggesting that adding hepatic radiotherapy to anti-PD-1 treatment is safe and may improve outcomes, especially for certain patient subgroups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hepatic Radiotherapy in Addition to Anti-PD-1 for the Treatment of Metastatic Uveal Melanoma Patients. Rossi, E., Cellini, F., Pagliara, MM., et al.[2023]

Tebentafusp is the first treatment in decades to show improved overall survival in patients with metastatic uveal melanoma (mUM), a condition that has historically had poor treatment outcomes.

Unlike immune checkpoint inhibitors that are less effective in mUM, tebentafusp represents a promising new approach in immuno-oncology, highlighting the need for further research to enhance treatment options for a broader range of uveal melanoma patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immuno-oncology approaches in uveal melanoma: tebentafusp and beyond. Gerard, C., Shum, B., Nathan, P., et al.[2023]

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]

Nivolumab plus relatlimab is a combination immunotherapy that targets immune checkpoints, specifically PD-1 and LAG-3, and has been approved for treating unresectable or metastatic melanoma in adults and adolescents weighing at least 40 kg.

This combination therapy represents a significant advancement in cancer treatment, as it utilizes two different mechanisms to enhance the immune response against cancer cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab Plus Relatlimab: First Approval. Paik, J.[2022]

The combination of nivolumab and relatlimab shows a manageable safety profile for patients with advanced melanoma who have already undergone treatment.

This combination therapy may offer a new option for patients with pretreated melanoma, suggesting potential efficacy in this challenging patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab Plus Relatlimab Is Safe and Efficacious in Pretreated Melanoma. [2023]

Nivolumab is an effective PD1 immune checkpoint inhibitor used to treat various cancers, including non-small cell lung carcinoma and melanoma.

Despite its efficacy as an immunotherapy, nivolumab is associated with a range of immune-related adverse events, which continue to emerge even years after its introduction.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Squamous cell carcinoma or squamous proliferation associated with nivolumab treatment for metastatic melanoma. Vu, M., Chapman, S., Lenz, B., et al.[2022]

A 64-year-old man treated with durvalumab for non-small-cell lung carcinoma developed retinal vasculitis with macular edema, a rare ocular side effect of checkpoint inhibitors.

The condition improved significantly after three doses of methylprednisolone, allowing the patient to continue his durvalumab treatment without interruption.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Retinal Vasculitis Secondary to Durvalumab. R Andrade, A., Moll-Udina, A., Martin, R., et al.[2020]

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 study of 96 patients with metastatic uveal melanoma, treatment with PD-1 inhibitors showed a low response rate of only 4.7%, with median overall survival of 14 months for pembrolizumab and 10 months for nivolumab.

Combined immune checkpoint blockade with PD-1 and CTLA-4 inhibitors resulted in partial responses in 2 out of 15 patients, indicating limited efficacy, while certain blood markers like elevated LDH and CRP levels were identified as predictors of poor survival.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prognostic factors and outcomes in metastatic uveal melanoma treated with programmed cell death-1 or combined PD-1/cytotoxic T-lymphocyte antigen-4 inhibition. Heppt, MV., Heinzerling, L., Kähler, KC., 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]

References

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

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

2. Germany pubmed.ncbi.nlm.nih.gov

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

3. Switzerland pubmed.ncbi.nlm.nih.gov

Hepatic Radiotherapy in Addition to Anti-PD-1 for the Treatment of Metastatic Uveal Melanoma Patients. [2023]

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

Immuno-oncology approaches in uveal melanoma: tebentafusp and beyond. [2023]

5. 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]

6. New Zealand pubmed.ncbi.nlm.nih.gov

Nivolumab Plus Relatlimab: First Approval. [2022]

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

Nivolumab Plus Relatlimab Is Safe and Efficacious in Pretreated Melanoma. [2023]

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

Squamous cell carcinoma or squamous proliferation associated with nivolumab treatment for metastatic melanoma. [2022]

9. Switzerland pubmed.ncbi.nlm.nih.gov

Retinal Vasculitis Secondary to Durvalumab. [2020]

10. England pubmed.ncbi.nlm.nih.gov

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

11. England pubmed.ncbi.nlm.nih.gov

Prognostic factors and outcomes in metastatic uveal melanoma treated with programmed cell death-1 or combined PD-1/cytotoxic T-lymphocyte antigen-4 inhibition. [2022]

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

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