Radiotherapy + Immunotherapy for Melanoma Brain Metastasis

Overseen By Mohammad Khan, MD, PhD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Emory University

Must be taking: Immunotherapy

Must not be taking: Immunosuppressants, Chemotherapy

Disqualifiers: Implanted electrical device, Active infection, Autoimmune disease, 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

Compensation: Varies

Number of Visits: 1

Duration: 3-5 weeks

10 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial tests a new combination of treatments for melanoma that has spread to the brain. It uses precise radiation, immune-boosting drugs, and a device that sends electric fields to disrupt cancer cells. The goal is to see if this combination is safe and more effective than current treatments.

Do I need to stop my current medications to join the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, you must not be on systemic steroids above 20 mg prednisone equivalent or 4 mg dexamethasone per day within 7 days prior to the trial. You also need to have recovered from any prior treatments at least 14 days before enrollment. It's best to discuss your specific medications with the trial team.

What data supports the idea that Radiotherapy + Immunotherapy for Melanoma Brain Metastasis is an effective treatment?

The available research shows that combining radiotherapy with immunotherapy, like ipilimumab or nivolumab, is effective for treating melanoma brain metastases. Studies indicate that this combination improves outcomes compared to using radiotherapy alone. For example, one study found that patients receiving both ipilimumab and stereotactic radiosurgery had better results than those who only received stereotactic radiosurgery. This suggests that the combination treatment can be more effective in controlling the disease in the brain. ^{1 2 3 4 5}

What safety data exists for radiotherapy and immunotherapy in treating melanoma brain metastases?

Several studies have evaluated the safety of combining radiotherapy with immunotherapy for melanoma brain metastases. A Phase 1 study assessed the safety of ipilimumab with stereotactic radiosurgery (SRS) or whole brain radiation therapy (WBRT), focusing on determining the maximum tolerable dose. Another study investigated the safety of concurrent SRS with ipilimumab or nivolumab, highlighting brain control and toxicity. A comparison of ipilimumab and SRS versus SRS alone for newly diagnosed cases also provided safety insights. Additionally, a retrospective review of pembrolizumab combined with SRS reported radiation necrosis in 6.8% of cases, with no other significant adverse events. Lastly, a toxicity analysis of SRS with combined ipilimumab and nivolumab therapy indicated promising results, with a focus on the timing of treatments. ^{1 2 4 6 7}

Is the treatment of radiotherapy combined with the drugs Ipilimumab, Nivolumab, and Pembrolizumab promising for melanoma brain metastasis?

Yes, combining radiotherapy with the drugs Ipilimumab, Nivolumab, and Pembrolizumab shows promise for treating melanoma brain metastasis. Studies suggest that this combination can improve survival rates and control the spread of cancer in the brain. ^{1 2 8 9 10}

Research Team

Mohammad K Khan, MD, PhD

Principal Investigator

Emory University Hospital/Winship Cancer Institute

Eligibility Criteria

This trial is for adults with melanoma that has spread to the brain. Participants must be in good health otherwise, able to consent, and have not received certain treatments recently. They should also agree to use birth control if of childbearing potential and need a caregiver or self-support for device management.

Inclusion Criteria

Female subject of childbearing potential must have a negative urine or serum pregnancy within 2 weeks prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required

I haven't had immunotherapy, or if I did, it was approved by the study leader due to limited disease progression.

I am using two birth control methods or am not having sex to join this study.

Exclusion Criteria

You have signs of high pressure inside your head.

I haven't had cancer treatment in the last 2 weeks or I've recovered from its side effects.

I have only received the flu shot, not the nasal spray vaccine.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive stereotactic radiosurgery (SRS) and immune checkpoint inhibitors (ICI) with NovoTTF-100M device

3-5 weeks

Multiple visits for SRS fractions and device setup

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

1 visit (in-person)

Long-term Follow-up

Participants are monitored for intracranial control and overall survival

Up to 2 years

Treatment Details

Interventions

• Ipilimumab
• Nivolumab
• NovoTTF-100M
• Pembrolizumab
• Stereotactic Radiosurgery

Trial Overview The study tests combining stereotactic radiosurgery (precise radiation therapy) with immune checkpoint inhibitors (drugs like pembrolizumab, nivolumab, ipilimumab) and NovoTTF-100M (a device creating electric fields to disrupt cancer cells). The goal is to see if this combo works better than current methods.

Participant Groups

Group I: Arm II (nivolumab, ipilimumab, SRS, TTFields) Experimental Treatment 4 Interventions

Patients receive standard of care nivolumab and ipilimumab and undergo 3-5 fractions SRS. Patients also undergo TTFields over 8 hours daily using NovoTTF-100M device until intra-cranial progression or until end of immunotherapy treatments at the discretion of the treating physician in the absence of disease progression or unacceptable toxicity.

Group II: Arm I (SRS, pembrolizumab, TTFields) Experimental Treatment 3 Interventions

Patients receive standard of care pembrolizumab and undergo 3-5 fractions SRS. Patients also undergo TTFields over 8 hours daily using NovoTTF-100M device until intra-cranial progression or until end of immunotherapy treatments at the discretion of the treating physician in the absence of disease progression or unacceptable toxicity.

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?

Emory University

Lead Sponsor

Trials

1,735

Recruited

2,605,000+

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

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

In a phase 1 study involving 16 patients with brain metastases from melanoma, ipilimumab combined with stereotactic radiosurgery (SRS) was found to be safe at a maximum dose of 10 mg/kg, with no dose-limiting toxicities reported.

The study showed that while the median progression-free survival was similar for both treatment arms (2.1 months for SRS and 2.5 months for whole brain radiation therapy), the overall survival was not reached for the SRS group, indicating potential benefits of this combination therapy that warrant further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 1 Study of Ipilimumab Combined With Whole Brain Radiation Therapy or Radiosurgery for Melanoma Patients With Brain Metastases. Williams, NL., Wuthrick, EJ., Kim, H., et al.[2022]

In a study of 80 patients with untreated melanoma brain metastases, concurrent stereotactic radiosurgery (SRS) and nivolumab showed significantly better intracranial progression-free survival (PFS) compared to SRS and ipilimumab, with 6-month PFS rates of 69% versus 48%.

While both treatment combinations were effective, 15% of patients experienced radiation-induced brain necrosis, indicating a risk of serious side effects, particularly with ipilimumab.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Stereotactic radiosurgery combined with nivolumab or Ipilimumab for patients with melanoma brain metastases: evaluation of brain control and toxicity. Minniti, G., Anzellini, D., Reverberi, C., et al.[2020]

Patients with melanoma brain metastases who received ipilimumab alongside stereotactic radiosurgery (SRS) had a significantly improved overall survival (OS) of 15.1 months compared to 7.8 months for those who did not receive ipilimumab, indicating its efficacy in enhancing treatment outcomes.

While ipilimumab did not increase the risk of acute toxicity, 5% of patients experienced radiation necrosis, primarily among those treated with ipilimumab, suggesting a need for careful monitoring in this group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Stereotactic radiosurgery and ipilimumab for patients with melanoma brain metastases: clinical outcomes and toxicity. Diao, K., Bian, SX., Routman, DM., et al.[2020]

In a study of 54 patients with newly diagnosed melanoma brain metastases, combining ipilimumab with stereotactic radiosurgery (SRS) did not lead to increased rates of radiation necrosis or hemorrhage, indicating that this combination is safe.

Despite the safety of the combination treatment, there were no significant improvements in overall survival or local control when comparing ipilimumab plus SRS to SRS alone, suggesting that ipilimumab may not enhance treatment outcomes in this context.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ipilimumab and Stereotactic Radiosurgery Versus Stereotactic Radiosurgery Alone for Newly Diagnosed Melanoma Brain Metastases. Patel, KR., Shoukat, S., Oliver, DE., et al.[2022]

In a study of 46 melanoma patients receiving ipilimumab (Ipi) and stereotactic radiosurgery (SRS) for brain metastases, those treated with SRS during or before Ipi showed significantly better overall survival rates compared to those treated after Ipi, with a 1-year overall survival of 65% versus 40%.

The combination of Ipi and SRS was well tolerated, although 20% of patients experienced grade 3 to 4 toxicities; interestingly, treatment during or before Ipi was associated with a temporary increase in tumor size, suggesting a potential immunomodulatory effect.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Stereotactic radiosurgery for melanoma brain metastases in patients receiving ipilimumab: safety profile and efficacy of combined treatment. Kiess, AP., Wolchok, JD., Barker, CA., et al.[2022]

In a study of 25 patients with melanoma brain metastases treated with pembrolizumab (PB) combined with stereotactic radiosurgery (SRS), the treatment was well tolerated, with only a 6.8% incidence of radiation necrosis observed.

The combination therapy achieved local control in 80% of brain metastases and resulted in a median overall survival of 15.3 months, suggesting a promising efficacy for this treatment approach in patients with metastatic melanoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tolerance and outcomes of stereotactic radiosurgery combined with anti-programmed cell death-1 (pembrolizumab) for melanoma brain metastases. Nardin, C., Mateus, C., Texier, M., et al.[2019]

In a study of 31 patients with melanoma brain metastases, the combination of stereotactic radiosurgery (SRS) with immune checkpoint therapy (ipilimumab and nivolumab) showed a concerning increase in neurological grade 3 toxicities, particularly when SRS was administered concurrently with the therapy.

Specifically, patients who received SRS within seven days of starting ipilimumab and nivolumab had a significantly higher risk of severe side effects, suggesting that timing of treatment is crucial for minimizing toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Stereotactic radiosurgery and combined immune checkpoint therapy with ipilimumab and nivolumab in patients with melanoma brain metastases: A retrospective monocentric toxicity analysis. Bodensohn, R., Werner, S., Reis, J., et al.[2023]

In a study of 3,887 patients with metastatic non-small cell lung cancer (NSCLC) and melanoma, adding stereotactic radiosurgery (SRS) to immunotherapy significantly improved overall survival (OS) compared to immunotherapy alone, with hazard ratios of 0.81 for NSCLC and 0.63 for melanoma.

In contrast, the addition of whole-brain radiation therapy (WBRT) to immunotherapy did not show any survival benefit for patients with either melanoma or NSCLC, indicating that SRS may be a more effective combination treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Stereotactic radiosurgery with immunotherapy is associated with improved overall survival in patients with metastatic melanoma or non-small cell lung cancer: a National Cancer Database analysis. Jiang, JM., Kabarriti, R., Brodin, NP., et al.[2022]

A 43-year-old woman with 10 brain metastases from malignant melanoma showed a complete response to stereotactic radiosurgery (SRS) for some lesions, indicating that SRS can effectively treat brain metastases even when multiple are present.

After initial treatment with targeted therapy (dabrafenib/trametinib) and subsequent SRS for new lesions, the patient remained in good health for 20 months, suggesting that combining novel systemic therapies with radiotherapy can lead to improved outcomes in patients with brain metastases from melanoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Systemic therapy augmented by radiotherapy (STAR) effect for brain metastases in a BRAF-mutated melanoma patient with prolonged survival: a case report. Cristaudo, A., Malorgio, A., Medoro, S., et al.[2021]

In a study of 228 melanoma brain metastases patients, those treated with combined nivolumab and ipilimumab (CNI) plus cranial stereotactic radiotherapy (SRT) showed a significant improvement in overall survival (OS) compared to those receiving only CNI, with a median OS not reached in the CNI+SRT group.

The combination of CNI and SRT was associated with a 43% reduction in mortality risk, indicating that adding SRT to CNI treatment can enhance survival outcomes for patients with melanoma brain metastases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of cranial stereotactic radiotherapy associated with immunotherapy with nivolumab and ipilimumab on overall survival in patients with melanoma brain metastases: a real-world evidence. de Castro, DG., Teixeira, CHA., Gondim, GRM., et al.[2022]

References

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

Phase 1 Study of Ipilimumab Combined With Whole Brain Radiation Therapy or Radiosurgery for Melanoma Patients With Brain Metastases. [2022]

2. England pubmed.ncbi.nlm.nih.gov

Stereotactic radiosurgery combined with nivolumab or Ipilimumab for patients with melanoma brain metastases: evaluation of brain control and toxicity. [2020]

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

Stereotactic radiosurgery and ipilimumab for patients with melanoma brain metastases: clinical outcomes and toxicity. [2020]

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

Ipilimumab and Stereotactic Radiosurgery Versus Stereotactic Radiosurgery Alone for Newly Diagnosed Melanoma Brain Metastases. [2022]

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

Stereotactic radiosurgery for melanoma brain metastases in patients receiving ipilimumab: safety profile and efficacy of combined treatment. [2022]

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

Tolerance and outcomes of stereotactic radiosurgery combined with anti-programmed cell death-1 (pembrolizumab) for melanoma brain metastases. [2019]

7. Ireland pubmed.ncbi.nlm.nih.gov

Stereotactic radiosurgery and combined immune checkpoint therapy with ipilimumab and nivolumab in patients with melanoma brain metastases: A retrospective monocentric toxicity analysis. [2023]

8. Italy pubmed.ncbi.nlm.nih.gov

Stereotactic radiosurgery with immunotherapy is associated with improved overall survival in patients with metastatic melanoma or non-small cell lung cancer: a National Cancer Database analysis. [2022]

9. Korea (South) pubmed.ncbi.nlm.nih.gov

Systemic therapy augmented by radiotherapy (STAR) effect for brain metastases in a BRAF-mutated melanoma patient with prolonged survival: a case report. [2021]

10. Italy pubmed.ncbi.nlm.nih.gov

Impact of cranial stereotactic radiotherapy associated with immunotherapy with nivolumab and ipilimumab on overall survival in patients with melanoma brain metastases: a real-world evidence. [2022]