Immunotherapy with Steroids for Brain Metastases

(ACT-FAST Trial)

Overseen By John Walker

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: AHS Cancer Control Alberta

Must be taking: Corticosteroids

Must not be taking: Non-steroid immunosuppressants

Disqualifiers: HIV, Hepatitis B, Hepatitis C, 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

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

Compensation: Varies

Number of Visits: 6

Duration: 24 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether immunotherapy, which boosts the body's immune system to fight cancer, is effective for patients also taking steroids. Steroids reduce brain swelling caused by cancer spreading to the brain, which can lead to headaches, nausea, and seizures. The trial compares two types of steroids, prednisone and dexamethasone, to determine which works better with immunotherapy. People with certain cancers, such as melanoma, lung cancer, or kidney cancer, who have cancer spread to the brain and are already on steroid treatment, may be suitable for this study. As a Phase 2 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group of people, offering participants a chance to contribute to important cancer research.

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 require that you are already on corticosteroid therapy. If you are taking non-steroid immunosuppressive agents, you will not be eligible for this study.

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

Research has shown that using nivolumab and ipilimumab together in Accelerated Checkpoint Therapy has been tested in patients with cancer that has spread to the brain. These studies found that 55% of patients experienced noticeable side effects, but only 7% faced serious brain-related issues. Importantly, no new safety problems emerged in patients with brain metastases treated with this combination.

This therapy effectively shrinks or halts the growth of brain tumors. However, serious side effects can occur, so prospective trial participants should discuss potential risks with their healthcare provider. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about accelerated checkpoint therapy with steroids for brain metastases because it combines immunotherapy with steroids like prednisone and dexamethasone in a potentially game-changing way. Unlike traditional treatments that primarily rely on surgery or radiation, this approach aims to harness the body's immune system to target cancer cells more effectively. By using steroids, it may also help reduce inflammation and manage side effects, potentially improving patients' quality of life during treatment. This innovative combination could lead to faster and more effective results compared to existing options.

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

Research has shown that immunotherapy, using the drugs nivolumab and ipilimumab together, effectively treats cancer that has spread to the brain. Studies indicate that more than half of the patients experienced their brain tumors shrinking or stopping growth, with some patients even seeing their tumors disappear completely. This treatment combination has also been linked to longer survival, with more than half of the patients living at least five years after receiving it. In this trial, participants will receive either Prednisone or Dexamethasone as part of the study's active comparator arms. Although the effects of steroids on this treatment remain unknown, current evidence suggests this accelerated therapy holds promise for brain cancer that has spread. ^{1 5 6 7 8}

Are You a Good Fit for This Trial?

This trial is for adults with brain tumors who need steroids to reduce swelling and have started steroid therapy. They must be eligible for standard immunotherapy, have measurable brain disease, stable thyroid issues on hormones if present, and use birth control if applicable. Excluded are those with HIV, hepatitis B/C, recent autoimmune treatments or severe drug allergies.

Inclusion Criteria

I am able to get out of my bed or chair and move around.

My thyroid condition is stable with medication.

I have been diagnosed with melanoma, lung, kidney, or genitourinary cancer.

Exclusion Criteria

I have a history of HIV, Hepatitis B, or Hepatitis C.

I have been treated for an autoimmune disease in the last 2 years.

Known prior severe hypersensitivity to study drugs or any component in its formulations

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive immunotherapy while on corticosteroid therapy to assess efficacy and safety

24 weeks

Baseline imaging, followed by assessments every 6 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 months

Regular follow-up visits as part of standard care

What Are the Treatments Tested in This Trial?

Interventions

• Accelerated Checkpoint Therapy
• Glucocorticoid therapy

Trial Overview The study tests whether immunotherapy can still work effectively in patients who also require steroids due to brain metastases from cancers like melanoma or lung cancer. It compares the effects of different steroids alongside standard immune checkpoint inhibitors.

How Is the Trial Designed?

Group I: Prednisone Active Control 1 Intervention

Dose starting at 25 mg/day (a calculation of equipotent steroid equivalencies will be used).

Group II: Dexamethasone Active Control 1 Intervention

Dose starting at 4 mg daily (for patients randomized to the Dexamethasone arm).

Accelerated Checkpoint Therapy is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Opdivo + Yervoy for:

• Melanoma
• Renal cell carcinoma
• Colorectal cancer
• Hepatocellular carcinoma
• Non-small cell lung cancer

Approved in United States as Opdivo + Yervoy for:

• Melanoma
• Renal cell carcinoma
• Colorectal cancer
• Hepatocellular carcinoma
• Non-small cell lung cancer

Approved in Canada as Opdivo + Yervoy for:

• Melanoma
• Renal cell carcinoma
• Colorectal cancer

Approved in Japan as Opdivo + Yervoy for:

• Melanoma
• Renal cell carcinoma
• Non-small cell lung cancer

Who Is Running the Clinical Trial?

AHS Cancer Control Alberta

Lead Sponsor

Trials

188

Recruited

26,900+

Published Research Related to This Trial

Nivolumab plus ipilimumab significantly improved overall survival in patients with metastatic non-small cell lung cancer (NSCLC), including those with baseline brain metastases, compared to chemotherapy, with a hazard ratio of 0.63 for those with brain metastases and 0.76 for those without.

At 5 years, patients with baseline brain metastases treated with nivolumab plus ipilimumab had higher rates of systemic (12%) and intracranial (16%) progression-free survival compared to chemotherapy (0% and 6%, respectively), and fewer developed new brain lesions (4% vs. 20%).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Systemic and Intracranial Outcomes With First-Line Nivolumab Plus Ipilimumab in Patients With Metastatic NSCLC and Baseline Brain Metastases From CheckMate 227 Part 1. Reck, M., Ciuleanu, TE., Lee, JS., et al.[2023]

In a study of 29 patients with symptomatic melanoma brain metastases receiving PD-1-directed therapy (ipilimumab plus nivolumab) alongside corticosteroids, the median overall survival was 5.45 months, with 21% of patients surviving after 3 years.

The overall response rate was 28%, and patients who responded to treatment had a significantly longer median overall survival of 56.4 months, indicating that while the benefits are modest, there is potential for long-term survival in responding patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ipilimumab plus nivolumab in patients with symptomatic melanoma brain metastasis requiring corticosteroids. Manacorda, S., Carmena, MT., Malone, C., et al.[2023]

Two cases of patients with metastatic melanoma treated with the combined checkpoint inhibitors Ipilimumab and Nivolumab showed new intracranial metastases despite positive systemic responses, suggesting a complex interaction between immunotherapy and brain metastasis.

The findings raise the possibility that the immune activation from these therapies may reveal previously undetected brain metastases rather than causing new ones, highlighting the need for further research on the effects of immunotherapy on brain-specific disease and adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Unmasking of intracranial metastatic melanoma during ipilimumab/nivolumab therapy: case report and literature review. McDonald, MA., Sanghvi, P., Bykowski, J., et al.[2018]

Nivolumab and ipilimumab show significant intracranial activity in patients with melanoma brain metastases, with response rates of 46% and 57% in two phase II studies, respectively.

Nivolumab can penetrate the cerebrospinal fluid (CSF), achieving concentrations that are effective for therapeutic action, challenging the belief that large molecules like monoclonal antibodies cannot affect the central nervous system.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intracranial antitumor responses of nivolumab and ipilimumab: a pharmacodynamic and pharmacokinetic perspective, a scoping systematic review. van Bussel, MTJ., Beijnen, JH., Brandsma, D.[2020]

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]

A patient with lung cancer brain metastases showed an exceptional and lasting response to short-term nivolumab immunotherapy, despite being on high-dose steroids and having low PDL1 expression, which are typically poor indicators for treatment success.

This case highlights the potential for immunotherapy to yield significant benefits even in challenging circumstances and emphasizes the need for ongoing follow-up after treatment, regardless of initial prognosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Exceptional response of brain metastases to short course nivolumab while on high-dose steroids. de Jong, WK., Mulders, ACM., Westendorp, W., et al.[2020]

Immunotherapy, particularly with anti-CTLA4 and anti-PD-1 antibodies, shows promising efficacy in treating brain metastases from melanoma, achieving durable responses in 15%-20% of asymptomatic patients and over 50% when combined, but effectiveness drops significantly in symptomatic patients or those on corticosteroids.

The study highlights the need for further research to enhance response rates and reduce toxicity in immunotherapy for brain metastases, suggesting that understanding resistance mechanisms and exploring novel agents could improve treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Emergent immunotherapy approaches for brain metastases. Wang, J., Tawbi, HA.[2021]

In a study of 119 patients with melanoma brain metastases, those who were asymptomatic showed a significant clinical benefit from the combination of nivolumab and ipilimumab, with a 36-month overall survival rate of 71.9%.

Symptomatic patients had much lower efficacy, with only 36.6% overall survival at 36 months, highlighting the challenges in treating symptomatic melanoma brain metastases with this combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term outcomes of patients with active melanoma brain metastases treated with combination nivolumab plus ipilimumab (CheckMate 204): final results of an open-label, multicentre, phase 2 study. Tawbi, HA., Forsyth, PA., Hodi, FS., et al.[2022]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8563325/

Safety and efficacy of the combination of nivolumab plus ... In patients with melanoma and asymptomatic brain metastases (MBM), nivolumab plus ipilimumab provided an intracranial response rate of 55%.

2. news.bms.com news.bms.com/news/details/2017/First-Presentation-of-Efficacy-Data-from-CheckMate--204-Evaluating-the-Combination-of-Opdivonivolumab-and-Yervoyipilimumab-Demonstrates-Anti-tumor-Activity-in-Advanced-Melanoma-Patients-with-Brain-Metastases/default.aspx

First Presentation of Efficacy Data from CheckMate -204 ... Over half of patients (55%) experienced an intracranial objective response with 21% achieving a complete intracranial response Bristol-Myers Squibb Company ...

3. nejm.org nejm.org/doi/full/10.1056/NEJMoa1910836

Five-Year Survival with Combined Nivolumab and ... Overall survival at 5 years was 52% in the nivolumab-plus-ipilimumab group and 44% in the nivolumab group, as compared with 26% in the ipilimumab group.

4. cancer.gov cancer.gov/news-events/cancer-currents-blog/2018/melanoma-brain-metastases-nivolumab-ipilimumab

Immunotherapy Drugs Shrink Brain Metastases from ... Results from a clinical trial show that the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) halted the growth of or shrank metastatic brain tumors.

5. onclive.com onclive.com/view/nivolumabipilimumab-combo-leads-to-durable-responses-in-metastatic-melanoma--with-asymptomatic-brain-mets

Nivolumab/Ipilimumab Combo Leads to Durable ... Previously, clinically meaningful intracranial efficacy was reported for the nivolumab/ipilimumab combination in 94 patients with asymptomatic brain metastases ...

6. nejm.org nejm.org/doi/full/10.1056/NEJMoa1805453

Combined Nivolumab and Ipilimumab in Melanoma ... Treatment-related grade 3 or 4 adverse events were reported in 55% of patients, including events involving the central nervous system in 7%. One ...

7. sciencedirect.com sciencedirect.com/science/article/abs/pii/S1470204524007356

Ipilimumab plus nivolumab versus nivolumab alone in ... Patients with asymptomatic, active brain metastases had a best intracranial response rate of 51% with ipilimumab plus nivolumab and 20% with nivolumab alone; ...

8. jto.org jto.org/article/S1556-0864(23)00525-7/fulltext

Systemic and Intracranial Outcomes With First-Line ... No new safety signals were observed in patients with or without baseline brain metastases treated with nivolumab plus ipilimumab. These data ...