Immunotherapy with Steroids for Brain Metastases

(ACT-FAST Trial)

Recruiting in Palo Alto (17 mi)

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

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

Prior Safety Data

Approved in 4 Jurisdictions

Trial Summary

What is the purpose of this trial?

Immunotherapy treatments are intended to boost a person's immune system to fight their cancer. Treatment with immunotherapy has been shown to be effective in a wide range of cancers, including melanoma skin cancer, lung cancer and kidney cancer, among others. Steroids are anti-inflammatory medications which may suppress the immune system. For this reason, persons requiring treatment with steroids have not previously been allowed to participate in immunotherapy clinical trials. Therefore, we do not know whether or not immunotherapy treatments are effective in patients who are also receiving treatment with steroids. When cancer has spread to the brain swelling may occur around the tumors, and headache, nausea, seizures or stroke-like symptoms may occur. In this instance, steroids are important to reduce swelling within the brain, thus alleviating these symptoms. Because patients requiring treatment with steroids have not previously been allowed to participate in immunotherapy clinical trials, we do not know whether treatment with immunotherapy is effective when steroid treatments are also used. This study will investigate this question, and also attempt to determine whether treatment with one steroid versus another results in a better response to immunotherapy.

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.

What data supports the effectiveness of the drug combination Nivolumab and Ipilimumab for treating brain metastases?

Research shows that the combination of Nivolumab and Ipilimumab can lead to significant responses in brain metastases, particularly in patients with melanoma, with over 50% of asymptomatic patients showing an intracranial response. Additionally, a case study reported an exceptional response in a patient with brain metastases from lung cancer using Nivolumab while on high-dose steroids.

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Is the combination of Nivolumab and Ipilimumab safe for humans?

The combination of Nivolumab and Ipilimumab has been used in patients with advanced melanoma and non-small-cell lung cancer, but it can cause serious side effects. In a study, about half of the patients experienced severe side effects, and many needed hospital care. While it can help some patients live longer, the treatment comes with significant risks.

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How is the drug combination of Nivolumab and Ipilimumab unique for treating brain metastases?

The combination of Nivolumab and Ipilimumab is unique because it can induce significant responses in brain metastases, even in patients who are symptomatic or on steroids, which is challenging for other treatments. This drug combination works by enhancing the immune system's ability to fight cancer cells in the brain, offering a novel approach compared to traditional therapies.

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Eligibility Criteria

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.

I am taking medication that suppresses my immune system, but it's not a steroid.

Trial Timeline

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

Participant Groups

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.

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

Find a Clinic Near You

Research Locations Nearby Select from list below to view details:

Cross Cancer Institute Edmonton, Canada

Who Is Running the Clinical Trial?

AHS Cancer Control Alberta Lead Sponsor

References

1. United States 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. [2023] In CheckMate 227 Part 1, nivolumab plus ipilimumab prolonged overall survival (OS) versus chemotherapy in patients with metastatic NSCLC, regardless of tumor programmed death-ligand 1 (PD-L1) expression. Here, we report post hoc exploratory systemic and intracranial efficacy outcomes and safety by baseline brain metastasis status at 5 years' minimum follow-up.

2. Netherlands pubmed.ncbi.nlm.nih.gov

Exceptional response of brain metastases to short course nivolumab while on high-dose steroids. [2020] In this manuscript, we describe a patient with an exceptional response of brain metastases from lung cancer to short course nivolumab while on high-dose steroids. This case shows that immunotherapy can cause delayed and enduring responses even in patients with poor predictive parameters for treatment success, such as low programmed death ligand-1 (PDL1) expression and long-term treatment with high-dose corticosteroids. Secondly, it underscores the importance of follow up after the administration of immunotherapy, even in cases with a deemed poor prognosis and few received cycles of immunotherapy.

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

Emergent immunotherapy approaches for brain metastases. [2021] Brain metastases from solid tumors are increasing in incidence, especially as outcomes of systemic therapies continue to extend patients' overall survival. The long-held notion that the brain is an immune sanctuary has now been largely refuted with increasing evidence that immunotherapy can induce durable responses in brain metastases. Single agent immune checkpoint inhibition with anti-CTLA4 and anti-PD1 antibodies induces durable responses in 15%-20% in melanoma brain metastases as long as patients are asymptomatic and do not require corticosteroids. The combination of anti-CTLA4 with anti-PD-1 antibodies induces an intracranial response in over 50% of asymptomatic melanoma patients, and much lower rate of otherwise durable responses (20%) in symptomatic patients or those on steroids. Data in other cancers, such as renal cell carcinoma, are accumulating indicating a role for immunotherapy. Emerging immunotherapy approaches will have to focus on increasing response rates, decreasing toxicity, and decreasing steroid dependency. The path to those advances will have to include a better understanding of the mechanisms of response and resistance to immunotherapy in brain metastases, the use of novel agents such as anti-LAG3 checkpoint inhibitors, targeted therapy (oncogene directed or TKIs), and possibly surgery and SRS to improve the outcomes of patients with brain metastases.

4. England pubmed.ncbi.nlm.nih.gov

Intracranial antitumor responses of nivolumab and ipilimumab: a pharmacodynamic and pharmacokinetic perspective, a scoping systematic review. [2020] Recently, two phase II trials showed intracranial activity of the immune checkpoint inhibitors nivolumab and ipilimumab in patients with melanoma brain metastases. However, it is generally assumed that large molecules like monoclonal antibodies nivolumab and ipilimumab cannot penetrate and pass an intact blood brain barrier (BBB). In this systematic review we provide a pharmacodynamic and pharmacokinetic consideration of the clinical activity of the immune checkpoint inhibitors nivolumab and ipilimumab in melanoma brain metastases.

5. England 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. [2022] Combination nivolumab plus ipilimumab was efficacious in patients with asymptomatic melanoma brain metastases (MBM) in CheckMate 204, but showed low efficacy in patients with symptomatic MBM. Here, we provide final 3-year follow-up data from the trial.

6. England 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. [2022] Immunotherapy targeting the PD-1 axis has activity in several tumour types. We aimed to establish the activity and safety of the PD-1 inhibitor pembrolizumab in patients with untreated brain metastases from melanoma or non-small-cell lung cancer (NSCLC).

7. 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] In phase III trials, ipilimumab plus nivolumab combination therapy is highly efficacious for advanced melanoma, despite many treatment-related grades 3-4 adverse events. Here, we report real-world safety and survival outcomes of ipilimumab plus nivolumab for advanced melanoma. Patients with advanced melanoma who received first-line ipilimumab plus nivolumab between January 1, 2015 and June 30, 2021 were selected from the Dutch Melanoma Treatment Registry. We evaluated response status at 3, 6, 12, 18, and 24 months. OS and PFS were estimated with the Kaplan-Meier method. Separate analyses were performed for patients with or without brain metastases and for patients who met the inclusion criteria of the Checkmate-067 trial. In total, 709 patients received first-line ipilimumab plus nivolumab. Three hundred sixty (50.7%) patients experienced grade 3-4 adverse events, with 211 of the (58.6%) patients requiring hospital admission. The median treatment duration was 42 days (IQR = 31-139). At 24 months, disease control was achieved in 37% of patients. Median PFS since the start of treatment was 6.6 months (95% CI: 5.3-8.7), and median OS was 28.7 months (95% CI: 20.7-42.2). CheckMate-067 trial-like patients had a 4-year OS of 50% (95% CI: 43-59). Among patients with no asymptomatic or symptomatic brain metastases, the 4-year OS probabilities were 48% (95% CI: 41-55), 45% (95% CI: 35-57), and 32% (95% CI: 23-46). Ipilimumab plus nivolumab can achieve long-term survival in advanced melanoma patients in a real-world setting, including patients not represented in the CheckMate-067 trial. However, the proportion of patients with disease control in the real world is lower compared with clinical trials.

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

Unmasking of intracranial metastatic melanoma during ipilimumab/nivolumab therapy: case report and literature review. [2018] While data from several studies over the last decade has demonstrated that introduction of immunologic checkpoint blockage therapy with anti-CTLA-4/PD-1 drugs leads to improved survival in metastatic melanoma patients, relatively little is known about brain-specific therapeutic response and adverse events in the context of immunotherapeutic treatment of intracranial disease. Here we report two independent cases of new intracranial metastases presenting after initiation of combined checkpoint blockade Ipilimumab and Nivolumab for recurrent metastatic melanoma in the context of positive systemic disease response.

9. England pubmed.ncbi.nlm.nih.gov

Ipilimumab plus nivolumab in patients with symptomatic melanoma brain metastasis requiring corticosteroids. [2023] To investigate the efficacy of PD-1-directed antibody-based therapy in patients with symptomatic melanoma brain metastases (MBM) and concurrent treatment with corticosteroids.