Ipilimumab + Pembrolizumab for Brain Metastasis from Melanoma

Overseen By Isabella C Glitza

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Corticosteroids, Immunosuppressants

Disqualifiers: Autoimmune disease, Hepatitis B/C, HIV, 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

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

Compensation: Varies

Number of Visits: 9

Duration: Up to 105 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores the effectiveness of two immunotherapy drugs, ipilimumab (Yervoy) and pembrolizumab (KEYTRUDA), in treating melanoma that has spread to the brain. The goal is to determine if these drugs can help the immune system attack the cancer and halt its growth. It targets patients with a confirmed diagnosis of melanoma and measurable brain metastases. This trial may suit individuals with brain-spread melanoma who have not received certain local therapies. As a Phase 2 trial, the research measures the treatment's effectiveness in an initial, smaller group, offering participants a chance to contribute to significant findings.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, you cannot take corticosteroids or other immunosuppressive medications within 14 days before starting the study, unless they are for physiological replacement.

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

Previous studies have safely used ipilimumab and pembrolizumab to treat advanced melanoma. Research shows that pembrolizumab has extended patient survival and is generally well-tolerated, with mostly manageable side effects. Common side effects include fatigue and skin reactions.

Ipilimumab has provided lasting benefits for patients with melanoma that has spread to the brain. Its safety profile aligns with past findings, showing no new or unexpected side effects. Some patients might experience side effects like diarrhea or skin rash, but these are usually treatable.

The combination of these two drugs has been studied for efficacy and safety. Data suggest that using these treatments together does not cause unexpected side effects beyond those already known for each drug. This indicates that the treatment should be fairly well-tolerated, though some side effects remain possible. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about combining ipilimumab and pembrolizumab for treating brain metastases from melanoma because these drugs work together to boost the immune system in a unique way. Unlike traditional treatments like radiation or chemotherapy, which directly target cancer cells, this combo enhances the body's immune response. Ipilimumab blocks CTLA-4, while pembrolizumab blocks PD-1, both of which are proteins that normally help keep the immune system in check. By inhibiting these proteins, the treatment allows the immune system to attack cancer cells more aggressively. This approach offers hope for more effective treatment by potentially overcoming the limitations of current therapies.

What evidence suggests that this treatment might be an effective treatment for brain metastasis from melanoma?

This trial will evaluate the combination of ipilimumab and pembrolizumab for treating melanoma that has spread to the brain. Studies have shown that using these drugs together can help treat melanoma with brain metastases. In one study, patients with stable brain metastases who took pembrolizumab had a 40% chance of surviving for 10 years, compared to 27.6% for those who took only ipilimumab. Another study found that patients with brain metastases treated with ipilimumab lived an average of 4.3 months, with about 20% living for at least a year. Additionally, research showed that 31.4% of patients with brain metastases had their tumors respond to this combination treatment. These findings suggest that these drugs may help control melanoma that has spread to the brain. ^{1 2 3 4 6}

Who Is on the Research Team?

Isabella C. Glitza, MD

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

This trial is for melanoma patients with brain metastases who can follow the study plan, have a measurable brain lesion not previously treated locally, normal blood clotting levels unless on anticoagulants, good organ function, and no severe medical conditions. Pregnant or breastfeeding women and those with certain autoimmune diseases or recent corticosteroid use are excluded.

Inclusion Criteria

My blood clotting tests are within normal limits, or if I'm on blood thinners, they're in the therapeutic range.

I am not breastfeeding and have a recent negative pregnancy test.

Any side effects from my past cancer treatments have mostly gone away.

Exclusion Criteria

I haven't taken high-dose steroids or other immune-weakening drugs in the last 2 weeks.

I have previously received checkpoint inhibitor therapy.

Subjects with major medical, neurologic or psychiatric condition who are judged as unable to fully comply with study therapy or assessments should not be enrolled

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Patients receive ipilimumab IV over 90 minutes and pembrolizumab IV over 30 minutes on day 1. Treatment repeats every 3 weeks for up to 4 cycles for ipilimumab and up to 35 cycles for pembrolizumab in the absence of disease progression or unacceptable toxicity.

Up to 105 weeks

Every 3 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment. Follow-up occurs at 30 days post-treatment, every 6 weeks for the first year, and then every 12 weeks thereafter.

Up to 1 year

Every 6 weeks for the first year, then every 12 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Ipilimumab
• Pembrolizumab

Trial Overview The trial tests low dose ipilimumab combined with pembrolizumab in melanoma that has spread to the brain. It aims to see how well these immunotherapy drugs work together by enabling the immune system to target cancer cells more effectively.

How Is the Trial Designed?

Group I: Treatment (ipilimumab, pembrolizumab) Experimental Treatment 2 Interventions

Patients receive ipilimumab IV over 90 minutes and pembrolizumab IV over 30 minutes on day 1. Treatment repeats every 3 weeks for up to 4 cycles for ipilimumab and up to 35 cycles for pembrolizumab 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?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

In a phase II clinical trial involving 23 melanoma patients with untreated brain metastases, pembrolizumab demonstrated a 26% response rate in brain metastases, indicating its potential efficacy in this challenging patient population.

The treatment was associated with acceptable toxicity, as 65% of patients experienced neurologic adverse events, mostly mild (grade 1 or 2), and nearly half of the patients (48%) were alive at 24 months, suggesting durable responses and a need for careful management of brain metastases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-Term Survival of Patients With Melanoma With Active Brain Metastases Treated With Pembrolizumab on a Phase II Trial. Kluger, HM., Chiang, V., Mahajan, A., et al.[2020]

In a phase 2 trial involving 36 patients with untreated brain metastases from melanoma or non-small-cell lung cancer (NSCLC), pembrolizumab demonstrated activity, achieving a brain metastasis response in 22% of melanoma patients and 33% of NSCLC patients, with responses being durable for most.

The treatment had an acceptable safety profile, with serious adverse events occurring in a small percentage of patients, indicating that systemic immunotherapy could be a viable option for those with untreated or progressive brain metastases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab for patients with melanoma or non-small-cell lung cancer and untreated brain metastases: early analysis of a non-randomised, open-label, phase 2 trial. Goldberg, SB., Gettinger, SN., Mahajan, A., et al.[2022]

In a study of 21 melanoma patients with brain metastases treated with concurrent pembrolizumab and radiation therapy, the treatment was found to be safe, with no severe toxicities reported, although one patient experienced Grade 3 side effects.

The use of stereotactic radiosurgery (SRS) alongside pembrolizumab resulted in a high response rate, with 70% of patients showing complete or partial responses at the first follow-up MRI, which is significantly better than response rates seen with SRS combined with other treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Melanoma brain metastases treated with stereotactic radiosurgery and concurrent pembrolizumab display marked regression; efficacy and safety of combined treatment. Anderson, ES., Postow, MA., Wolchok, JD., et al.[2022]

Pembrolizumab, a PD-1 inhibitor, has demonstrated clinical effectiveness in treating various solid tumors, particularly in patients with PD-L1-positive non-small-cell lung cancer and unresectable/metastatic melanoma.

Early-phase trials and ongoing studies are focused on further confirming the clinical benefits of pembrolizumab in thoracic malignancies, highlighting its potential as a significant treatment option in cancer therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab for the treatment of thoracic malignancies: current landscape and future directions. Karim, S., Leighl, N.[2017]

Pembrolizumab (KEYTRUDA) was approved by the FDA for treating unresectable or metastatic melanoma based on two clinical trials involving 1,374 patients, showing significant improvements in overall survival compared to ipilimumab, with hazard ratios indicating a reduced risk of death.

Patients receiving pembrolizumab also experienced significant improvements in progression-free survival, although some immune-mediated adverse reactions like hypothyroidism and pneumonitis were noted, highlighting the importance of monitoring for side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Pembrolizumab for the Treatment of Patients with Unresectable or Metastatic Melanoma. Barone, A., Hazarika, M., Theoret, MR., et al.[2022]

Pembrolizumab, an anti-PD-1 antibody, has shown a rapid and sustained response in a patient with symptomatic brain metastases from melanoma, achieving complete remission for over a year without the need for additional radiotherapy.

This case suggests that pembrolizumab may be effective for treating brain metastases in melanoma patients, highlighting the importance of conducting further clinical studies to explore its potential in this specific patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rapid remission of symptomatic brain metastases in melanoma by programmed-death-receptor-1 inhibition. Lüttmann, N., Grätz, V., Haase, O., et al.[2018]

In a phase 2 trial involving 42 patients with untreated brain metastases from non-small-cell lung cancer (NSCLC), pembrolizumab showed a 29.7% response rate in patients with PD-L1 expression of at least 1%, indicating its efficacy in treating brain metastases.

The treatment was generally safe, with serious adverse events occurring in 14% of patients, but no treatment-related deaths were reported, suggesting that pembrolizumab can be a viable option for selected patients with CNS involvement.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab for management of patients with NSCLC and brain metastases: long-term results and biomarker analysis from a non-randomised, open-label, phase 2 trial. Goldberg, SB., Schalper, KA., Gettinger, SN., et al.[2021]

Citations

1. annalsofoncology.org annalsofoncology.org/article/S0923-7534%2824%2903910-3/fulltext

10-year follow-up of the phase III KEYNOTE-006 study The 10-year OS rate in patients with previously treated and stable brain metastases was 40.0% with pembrolizumab versus 27.6% with ipilimumab; ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4023079/

Efficacy and safety of ipilimumab in patients with advanced ... Median OS for patients with melanoma and asymptomatic brain metastases was 4.3 months and approximately 20 % of patients were alive at 1 year. A similar ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT03873818

Low Dose Ipilimumab With Pembrolizumab in Treating ... This phase II trial studies the side effects and how well low dose ipilimumab works in combination with pembrolizumab in treating patients with melanoma ...

4. nejm.org nejm.org/doi/full/10.1056/NEJMoa1503093

Pembrolizumab versus Ipilimumab in Advanced Melanoma The response rate was improved with pembrolizumab administered every 2 weeks (33.7%) and every 3 weeks (32.9%), as compared with ipilimumab ( ...

5. frontiersin.org frontiersin.org/journals/oncology/articles/10.3389/fonc.2024.1485532/full

Progress in immunotherapy for brain metastatic melanoma The study, which included 153 patients, including those with brain metastases, demonstrated an objective remission rate (ORR) of 31.4%, a median ...

6. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0923753424039103

10-year follow-up of the phase III KEYNOTE-006 study Results from the primary analysis showed that pembrolizumab significantly improved overall survival (OS) and progression-free survival (PFS) compared with ...