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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new combination of treatments for melanoma that has spread to the brain. Researchers are testing whether combining precise radiation therapy, known as stereotactic radiosurgery, with immunotherapy drugs (pembrolizumab, nivolumab, and ipilimumab) and a device called NovoTTF-100M can be more effective. The NovoTTF-100M uses electric fields to disrupt cancer cell division. People with melanoma that has spread to the brain who have not yet received immunotherapy or have limited disease progression might be a good fit.

As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants a chance to be among the first to receive this innovative combination.

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.

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

Research has shown that using pembrolizumab with stereotactic radiosurgery (SRS) is generally safe for people with melanoma that has spread to the brain. Studies have found that this combination works without causing unexpected side effects. SRS is a precise type of radiation treatment, and pembrolizumab is an immunotherapy drug that helps the immune system fight cancer.

Research suggests that the combination of nivolumab and ipilimumab with SRS is also well-tolerated. Patients receiving this treatment did not experience higher risks of side effects and completed their cancer treatments as planned. Nivolumab and ipilimumab are drugs that help the body's defenses target cancer cells.

The NovoTTF-100M device, part of these treatments, uses electric fields to disrupt cancer cell division. While its safety in this specific setup is still under study, it is generally used with other treatments without significant issues.

Overall, the treatments under study have been manageable for patients in similar situations. This trial is the first step in understanding any new side effects when these treatments are used together for melanoma that has spread to the brain. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Most treatments for melanoma brain metastasis focus on either surgery or traditional radiation. However, these investigational treatments are unique because they combine immunotherapy with stereotactic radiosurgery (SRS) and Tumor Treating Fields (TTFields). TTFields represent a novel approach, using electric fields to disrupt cancer cell division. This combination aims to enhance the effectiveness of immune checkpoint inhibitors like pembrolizumab, nivolumab, and ipilimumab, potentially offering a more comprehensive attack on cancer cells. Researchers are excited about this approach because it could lead to improved outcomes by simultaneously targeting cancer through multiple mechanisms.

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

Research has shown that combining stereotactic radiosurgery, a precise type of radiation therapy, with the drug pembrolizumab is safe and effective for treating melanoma that has spread to the brain. This combination effectively controls tumor growth and is one of the treatment options in this trial. Another treatment arm involves using the drugs nivolumab and ipilimumab with stereotactic radiosurgery, which significantly helps manage melanoma that has spread to the brain without causing additional side effects. Both arms also incorporate Tumor Treating Fields (TTFields), low-intensity electric fields that may enhance these treatments by interfering with cancer cell division. Overall, these combinations have shown promising results in controlling tumor growth and improving outcomes for patients with melanoma that has spread to the brain. ^{1 2 3 4 6}

Who Is on the Research Team?

Mohammad K Khan, MD, PhD

Principal Investigator

Emory University Hospital/Winship Cancer Institute

Are You a Good Fit for This Trial?

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

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

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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 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 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]

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]

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]

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 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]

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