LDR Brachytherapy + Immunotherapy for Melanoma

Overseen By Jay Ciezki, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Case Comprehensive Cancer Center

Must not be taking: Systemic corticosteroids

Disqualifiers: Uveal melanoma, Uncontrolled illness, Others

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

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Approved in 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 15

5 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot have had prior anti-cancer therapy for melanoma, renal cell cancer, or urothelial cancer less than 14 days before starting the study treatment. Also, you cannot be on high doses of systemic corticosteroids.

What data supports the effectiveness of the treatment LDR Brachytherapy + Immunotherapy for Melanoma?

Research shows that Nivolumab, a drug used in this treatment, has demonstrated long-term survival benefits and durable responses in patients with advanced melanoma, especially after other treatments have failed. ^{1 2 3 4 5}

Is the combination of LDR Brachytherapy and Nivolumab safe for treating melanoma?

Nivolumab, also known as Opdivo, is generally considered safe for treating melanoma, but it can cause side effects like fatigue, diarrhea, and rash. In some cases, more serious side effects may occur, and about half of the patients in certain studies experienced severe reactions requiring hospital care. ^{6 7 8 9 10}

How is the treatment of LDR Brachytherapy + Nivolumab for melanoma different from other treatments?

This treatment combines LDR Brachytherapy, a type of radiation therapy that places radioactive material inside the body, with Nivolumab, an immunotherapy drug that helps the immune system attack cancer cells. This combination is unique because it uses both radiation and immune system activation to target melanoma, potentially offering a more comprehensive approach than using either method alone. ^{1 2 6 11 12}

What is the purpose of this trial?

This is a pilot study of combination low dose rate brachytherapy (LDR) added to standard of care (SOC) immunotherapy in stage III and IV melanoma, stage IV renal call cancer, and stage IV urothelial cancer.

Research Team

Jay Ciezki

Principal Investigator

Cleveland Clinic, Case Comprehensive Cancer Center

Eligibility Criteria

This trial is for adults with certain advanced cancers (stage III/IV melanoma, stage IV kidney or urothelial cancer) who are in fair to good health and not pregnant. They must have measurable disease, meet specific lab value criteria, and agree to use contraception if applicable. It's not for those with other active metastatic cancers needing treatment, recent anti-cancer therapy, high-dose steroid use, uncontrolled HIV/hepatitis, certain types of melanoma or brain radiation history.

Inclusion Criteria

Your blood test results need to be within certain ranges.

My cancer is advanced and cannot be removed by surgery.

I am a woman who is either postmenopausal, surgically sterile, or using contraception.

Exclusion Criteria

Unwilling or unable to follow protocol requirements

I do not have active cancer needing treatment, except for skin, kidney, or bladder cancer.

Any condition which in the Investigator's opinion deems the participant an unsuitable candidate to receive study treatment

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Brachytherapy

Participants receive one treatment of low-dose-rate brachytherapy on treatment day 1

1 day

1 visit (in-person)

Immunotherapy

Participants begin standard of care immunotherapy after brachytherapy, administered on day 1 of each cycle

Up to 12 months

Every 14, 21, 28, or 42 days (in-person)

Follow-up

Participants are monitored for tumor response and overall survival

12 months after brachytherapy

Treatment Details

Interventions

• Low Dose Rate Brachytherapy (LDR)
• Nivolumab

Trial Overview The study tests adding low dose rate brachytherapy (LDR), a type of internal radiation therapy, to the standard immune checkpoint inhibitors used in treating advanced skin cancer (melanoma), kidney cancer (renal cell carcinoma), and bladder cancer (urothelial). The goal is to see how well they work together.

Participant Groups

Group I: LDR + SOC Immunotherapy Experimental Treatment 2 Interventions

Participants will receive one treatment of brachytherapy on treatment day 1 (LDRD1). After a minimum of 7 days but no more than 30 days to allow antigenic release, participants will then begin immunotherapy treatment with SOC immunotherapy at the standard FDA-approved dose. Standard immunotherapy will be administered on D1 of every standard of care cycle (either 14, 21, 28, or 42 day cycle) at the standard dose. Participants can receive up to 1 year of SOC immunotherapy.

Nivolumab is already approved in United States, European Union, Canada, Switzerland for the following indications:

Approved in United States as Opdivo for:

• Advanced or metastatic gastric cancer
• Gastroesophageal junction cancer
• Esophageal adenocarcinoma
• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Hodgkin lymphoma
• Head and neck squamous cell carcinoma
• Urothelial carcinoma
• Colorectal cancer
• Hepatocellular carcinoma
• Esophageal squamous cell carcinoma

Approved in European Union as Opdivo for:

• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Hodgkin lymphoma
• Head and neck squamous cell carcinoma
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Gastroesophageal junction cancer
• Esophageal adenocarcinoma

Approved in Canada as Opdivo for:

• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Hodgkin lymphoma
• Head and neck squamous cell carcinoma
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Gastroesophageal junction cancer
• Esophageal adenocarcinoma

Approved in Switzerland as Opdivo for:

• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Hodgkin lymphoma
• Head and neck squamous cell carcinoma
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Gastroesophageal junction cancer
• Esophageal adenocarcinoma

Who Is Running the Clinical Trial?

Case Comprehensive Cancer Center

Lead Sponsor

Trials

472

Recruited

33,400+

Findings from Research

In a study of 37 patients with stage IV metastatic melanoma, high levels of soluble CD73 (sCD73) enzyme activity in the serum were linked to significantly poorer overall survival and progression-free survival when treated with nivolumab.

Patients with high sCD73 activity had a median progression-free survival of only 2.6 months compared to 14.2 months for those with lower activity, suggesting that measuring sCD73 could help predict how well patients will respond to nivolumab therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Soluble CD73 as biomarker in patients with metastatic melanoma patients treated with nivolumab. Morello, S., Capone, M., Sorrentino, C., et al.[2018]

Nivolumab is shown to be the most cost-effective treatment option for advanced melanoma patients in England, with incremental cost-effectiveness ratios of £24,483 for BRAF mutation-negative and £17,362 for mutation-positive patients.

The analysis utilized a Markov state-transition model based on patient-level data from clinical trials, indicating that nivolumab provides long-term survival benefits while being economically favorable compared to other treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The cost-effectiveness of nivolumab monotherapy for the treatment of advanced melanoma patients in England. Meng, Y., Hertel, N., Ellis, J., et al.[2020]

In a phase 3 trial involving 405 patients with advanced melanoma, nivolumab resulted in a significantly higher objective response rate (31.7%) compared to investigator's choice of chemotherapy (10.6%), indicating its superior efficacy as a treatment option.

Nivolumab was associated with fewer severe adverse effects compared to chemotherapy, with only 5% of patients experiencing serious drug-related side effects, suggesting it is a safer alternative for patients who have progressed after previous treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. Weber, JS., D'Angelo, SP., Minor, D., et al.[2022]

Combining nivolumab with ipilimumab results in higher response rates in cancer treatment compared to using nivolumab alone, indicating a potentially more effective therapeutic strategy.

This combination therapy may enhance the immune response against cancer, but specific details on the number of subjects or study duration are not provided in the abstract.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab plus Ipilimumab Achieves Responses in dMMR/MSI-H Tumors. [2019]

In a randomized trial comparing FDA-approved immune checkpoint inhibitors for advanced melanoma, pembrolizumab showed significantly better treatment outcomes than ipilimumab.

This study is notable as it is the first to directly compare these two therapies as first-line treatments, highlighting pembrolizumab's potential as a more effective option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab superior to ipilimumab in melanoma. [2017]

Nivolumab significantly improved overall survival and progression-free survival in patients with unresectable or metastatic melanoma compared to dacarbazine, with hazard ratios of 0.42 and 0.43 respectively, based on a trial involving 418 patients.

The most common side effects of nivolumab included fatigue, diarrhea, and rash, but it was still considered to have a favorable benefit-risk profile compared to dacarbazine.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval of Nivolumab for the First-Line Treatment of Patients with BRAFV600 Wild-Type Unresectable or Metastatic Melanoma. Beaver, JA., Theoret, MR., Mushti, S., et al.[2018]

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]

In the phase III CheckMate 238 trial, 67.7% of patients receiving nivolumab experienced treatment-related adverse events (TRAEs), with the most common being pruritus and diarrhea, primarily occurring within the first 3 months of treatment.

Despite the high incidence of TRAEs, there was no significant association found between these adverse events and recurrence-free survival (RFS), indicating that the safety profile of nivolumab remains consistent and does not negatively impact long-term outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adjuvant nivolumab for stage III/IV melanoma: evaluation of safety outcomes and association with recurrence-free survival. Mandala, M., Larkin, J., Ascierto, PA., et al.[2022]

In a real-world study of 709 patients with advanced melanoma treated with ipilimumab plus nivolumab, 50.7% experienced severe treatment-related adverse events, highlighting the need for careful monitoring during therapy.

Despite the high rate of adverse events, the combination therapy showed promising long-term survival outcomes, with a median overall survival of 28.7 months and a 4-year overall survival rate of 50% for patients similar to those in the CheckMate-067 trial.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-world Outcomes of Ipilimumab Plus Nivolumab Combination Therapy in a Nation-wide Cohort of Advanced Melanoma Patients in the Netherlands. van Zeijl, MCT., van Breeschoten, J., de Wreede, LC., et al.[2023]

Nivolumab, an immune checkpoint inhibitor, shows strong antitumor activity but is associated with immune-related adverse events that can affect patient safety and treatment continuation, necessitating careful monitoring.

Long-term safety data, including a 5-year follow-up, suggests that nivolumab can be safely administered to various challenging patient subgroups, but identifying biomarkers for severe toxicity could improve patient selection for this therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An update on the safety of nivolumab for the treatment of advanced melanoma. Czarnecka, AM., Rutkowski, P.[2021]

Nivolumab, a monoclonal antibody targeting the programmed death receptor-1, has shown promising efficacy in treating advanced malignant melanoma, with nearly 25% of patients achieving a partial tumor response in a phase II trial involving previously treated stage III/IV patients.

The treatment demonstrated a durable clinical benefit, with a median progression-free survival of 172 days and an acceptable safety profile, as less than 18% of patients experienced severe adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab: a review of its use in patients with malignant melanoma. Deeks, ED.[2021]

In mouse models of BRAF- and NRAS-mutant melanoma, the sequence of immunotherapy (IT) followed by targeted therapy (TT) significantly improved antitumor responses compared to either treatment alone.

The IT→TT sequence enhanced the immune environment by increasing T cell and natural killer cell infiltration while reducing suppressive immune cells, leading to durable responses that depended on T-cell activity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeted Therapy Given after Anti-PD-1 Leads to Prolonged Responses in Mouse Melanoma Models through Sustained Antitumor Immunity. Phadke, MS., Chen, Z., Li, J., et al.[2022]

References

1. England pubmed.ncbi.nlm.nih.gov

Soluble CD73 as biomarker in patients with metastatic melanoma patients treated with nivolumab. [2018]

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

The cost-effectiveness of nivolumab monotherapy for the treatment of advanced melanoma patients in England. [2020]

3. England pubmed.ncbi.nlm.nih.gov

Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. [2022]

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

Nivolumab plus Ipilimumab Achieves Responses in dMMR/MSI-H Tumors. [2019]

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

Pembrolizumab superior to ipilimumab in melanoma. [2017]

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

FDA Approval of Nivolumab for the First-Line Treatment of Patients with BRAFV600 Wild-Type Unresectable or Metastatic Melanoma. [2018]

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

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

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

Adjuvant nivolumab for stage III/IV melanoma: evaluation of safety outcomes and association with recurrence-free survival. [2022]

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

Real-world Outcomes of Ipilimumab Plus Nivolumab Combination Therapy in a Nation-wide Cohort of Advanced Melanoma Patients in the Netherlands. [2023]

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

An update on the safety of nivolumab for the treatment of advanced melanoma. [2021]

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

Nivolumab: a review of its use in patients with malignant melanoma. [2021]

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

Targeted Therapy Given after Anti-PD-1 Leads to Prolonged Responses in Mouse Melanoma Models through Sustained Antitumor Immunity. [2022]