Immunotherapy Before and After Surgery for Brain Tumor

Recruiting at 23 trial locations

Overseen By Jannerfer An

Age: < 65

Sex: Any

Trial Phase: Phase 1

Sponsor: Sabine Mueller, MD, PhD

Must not be taking: Immunosuppressants, Corticosteroids

Disqualifiers: Immunodeficiency, Brainstem tumor, Active infection, 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: 6

20 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial requires participants to stop taking certain medications, especially those that are immunosuppressive or related to cancer treatment, before joining. You may need to stop these medications for a specific period, like 21 days for some treatments, before starting the trial. It's best to discuss your current medications with the study team to understand what changes might be needed.

What data supports the effectiveness of the drug combination of Ipilimumab, Yervoy, Nivolumab, and Opdivo for brain tumors?

Research shows that using nivolumab before and after surgery can change the immune environment in brain tumors, potentially helping the body's immune system fight the cancer. Additionally, combining immunotherapy drugs like pembrolizumab before surgery has been linked to longer survival in brain tumor patients, suggesting a similar approach with nivolumab and ipilimumab might be beneficial. ^{1 2 3 4 5}

Is immunotherapy with drugs like Ipilimumab and Nivolumab generally safe for humans?

Immunotherapy drugs like Ipilimumab and Nivolumab have been used in various cancers and are generally considered safe, but they can cause immune-related side effects in about 60% of patients, with 15% experiencing severe effects. Most side effects are reversible with early diagnosis and proper management. ^{1 4 6 7 8}

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

The combination of Ipilimumab and Nivolumab is unique for treating brain tumors because it uses the body's immune system to target the tumor, potentially enhancing immune cell activity and diversity in the tumor environment, which is different from traditional surgery and chemotherapy approaches. ^{1 2 9 10 11}

What is the purpose of this trial?

This trial studies the effects of nivolumab, an immunotherapy drug, in children and young adults with severe brain cancer that has returned or worsened. The drug helps the immune system fight the cancer and may prevent it from growing.

Research Team

Tom Davidson ([e-mail]), MD

Principal Investigator

Children's Hospital Los Angeles

Eligibility Criteria

This trial is for children and young adults aged 6 months to less than 22 years with high-grade gliomas (brain tumors) that have recurred or progressed. They must have recovered from previous cancer treatments, meet specific blood count and organ function criteria, be candidates for surgical tumor removal, and not be on certain medications or have conditions like active TB or autoimmune diseases.

Inclusion Criteria

My MRI shows my disease is getting worse.

Organ Function Requirements: Peripheral absolute neutrophil count (ANC) >= 1000/mm^3, Platelet count >= 100,000/mm^3, Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 mL/min/1.73 m^2 OR a serum creatinine based on age/gender as specified, Bilirubin =< 1.5 x upper limit of normal (ULN) for age, Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 3.0 x ULN, Serum albumin >= 2, Pregnancy criteria must be met, MRI within 28 days prior to registration

My neurological condition has been stable for at least a week.

Exclusion Criteria

I am currently being treated for an infection with medication.

I have or had lung inflammation not caused by an infection.

I have another cancer that is getting worse or needs treatment.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Neoadjuvant Treatment

Participants receive a single infusion of nivolumab 14 days before surgery

2 weeks

1 visit (in-person)

Surgery

Participants undergo standard of care surgical resection

1 day

1 visit (in-person)

Adjuvant Treatment

Participants receive nivolumab IV on days 1 and 15 of each 28-day cycle

Until progression or unacceptable toxicity

2 visits per cycle (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 5 years

Every 2 months

Treatment Details

Interventions

• Ipilimumab
• Nivolumab
• Placebo Administration

Trial Overview The trial tests the safety of nivolumab and ipilimumab immunotherapies before and after surgery in patients with aggressive brain tumors. These drugs are designed to help the immune system fight cancer by blocking pathways that allow tumor cells to evade an immune response.

Participant Groups

Group I: Neoadjuvant nivolumab and adjuvant nivolumab Experimental Treatment 3 Interventions

NEOADJUVANT: Patients receive nivolumab IV over 30 minutes 14 days before undergoing standard of care surgical resection. ADJUVANT MAINTENANCE: After completion of neoadjuvant infusion, patients receive nivolumab IV over 30 minutes on days 1 and 15. Cycles repeat every 28 days 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?

Sabine Mueller, MD, PhD

Lead Sponsor

Trials

9

Recruited

440+

Bristol-Myers Squibb

Industry Sponsor

Trials

2,731

Recruited

4,127,000+

Headquarters

New York City, USA

Known For

Oncology & Cardiovascular

Top Products

Eliquis, Opdivo, Revlimid, Orencia

Christopher Boerner

Bristol-Myers Squibb

Chief Executive Officer since 2023

PhD in Business Administration from the Haas School of Business, University of California, Berkeley; BA in Economics and History from Washington University in St. Louis

Deepak L. Bhatt

Bristol-Myers Squibb

Chief Medical Officer since 2024

MD from Yale University; MSc in Clinical Epidemiology from the University of Pennsylvania

Pediatric Neuro-Oncology Consortium

Collaborator

Trials

4

Recruited

130+

Pediatric Neuro-Oncology Consortium

Collaborator

Pacific Pediatric Neuro-Oncology Consortium

Collaborator

Trials

16

Recruited

840+

Findings from Research

A phase II clinical trial involving 30 patients with glioblastoma tested the safety and immunological effects of the PD-1 inhibitor nivolumab, showing enhanced immune responses in the tumor microenvironment after treatment.

While the study did not demonstrate clear clinical benefits for most patients, two out of three patients who received nivolumab before and after primary surgery had prolonged survival, living 33 and 28 months post-treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neoadjuvant nivolumab modifies the tumor immune microenvironment in resectable glioblastoma. Schalper, KA., Rodriguez-Ruiz, ME., Diez-Valle, R., et al.[2019]

Immunotherapy, specifically the combination of ipilimumab and nivolumab, may lead to clinical and radiological progression in lung cancer patients with brain metastasis, as seen in two reported cases.

There is a need for greater understanding of how immunotherapy affects brain lesions, including the potential for pseudoprogression, to prevent unnecessary additional treatments like cerebral radiotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lung brain metastasis pseudoprogression after nivolumab and ipilimumab combination treatment. Melian, M., Lorente, D., Aparici, F., et al.[2023]

The Ipi-Glio study is a phase II clinical trial investigating the addition of the immune checkpoint inhibitor ipilimumab to standard temozolomide treatment in patients with glioblastoma, aiming to enroll 120 participants.

The trial will assess key outcomes such as overall survival and adverse events, providing valuable insights into the efficacy and safety of combining ipilimumab with standard therapy for this aggressive brain cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase II open label, randomised study of ipilimumab with temozolomide versus temozolomide alone after surgery and chemoradiotherapy in patients with recently diagnosed glioblastoma: the Ipi-Glio trial protocol. Brown, NF., Ng, SM., Brooks, C., et al.[2020]

In a study involving 40 newly diagnosed and 86 recurrent glioblastoma patients, PD-L1 blockade with durvalumab did not meet primary efficacy endpoints, indicating it was ineffective in improving outcomes compared to standard treatments.

Recurrent glioblastoma patients exhibited significantly lower levels of circulating immune cell subsets, and the use of dexamethasone was associated with a reduction in these immune cells, suggesting that immune suppression may hinder treatment effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Circulating Immune Cell and Outcome Analysis from the Phase II Study of PD-L1 Blockade with Durvalumab for Newly Diagnosed and Recurrent Glioblastoma. Nayak, L., Standifer, N., Dietrich, J., et al.[2023]

In a clinical trial involving 35 patients with recurrent glioblastoma, those who received neoadjuvant therapy with pembrolizumab before surgery showed significantly longer overall survival compared to those who only received adjuvant therapy after surgery.

Neoadjuvant treatment was linked to beneficial changes in the tumor's immune environment, including increased T cell activity and reduced cell-cycle-related gene expression, suggesting that this approach may enhance the body's immune response against glioblastoma more effectively than post-surgical treatment alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neoadjuvant anti-PD-1 immunotherapy promotes a survival benefit with intratumoral and systemic immune responses in recurrent glioblastoma. Cloughesy, TF., Mochizuki, AY., Orpilla, JR., et al.[2023]

Immunomodulatory agents targeting CTLA4 and PD1/PDL1 have shown significant effectiveness in treating both primary and metastatic brain tumors, suggesting a promising avenue for cancer therapy.

Combining anti-CTLA4 and anti-PD1 therapies enhances clinical benefits compared to using them individually, although this combination may lead to increased toxicity, highlighting the need to understand the brain tumor microenvironment for better treatment predictions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Primary and metastatic brain cancer genomics and emerging biomarkers for immunomodulatory cancer treatment. Passiglia, F., Caglevic, C., Giovannetti, E., et al.[2018]

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]

Ipilimumab is an FDA-approved monoclonal antibody that activates T-cells to treat advanced melanoma, showing a clear survival benefit in Phase III studies with ongoing investigations for other solid tumors.

While ipilimumab can cause immune-related adverse events (irAEs) in 60% of patients, most of these side effects are reversible with proper management, highlighting the importance of monitoring and early intervention.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Emerging options for the treatment of melanoma - focus on ipilimumab. Roddie, C., Peggs, KS.[2020]

The combination of ipilimumab and nivolumab, when given before surgery, significantly enhances the immune response against advanced melanoma, leading to a high rate of complete tumor response.

In a reported case, this pre-surgical treatment increased the presence of CD8+ T cells in the tumor area, suggesting a stronger anti-tumor immune activity, making it a promising approach for patients with unresectable advanced melanoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Successful Treatment of Unresectable Advanced Melanoma by Administration of Nivolumab With Ipilimumab Before Primary Tumor Resection. Fujimura, T., Kambayashi, Y., Sato, Y., et al.[2020]

In a study of 12 patients with metastatic melanoma who underwent craniotomy before or after starting ipilimumab, most patients showed improved performance status after surgery, suggesting that resection may enhance the effectiveness of subsequent ipilimumab therapy.

The median survival after starting ipilimumab was 7 months, and surgery allowed for corticosteroid dose reductions in some patients, indicating potential benefits in managing treatment side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ipilimumab and craniotomy in patients with melanoma and brain metastases: a case series. Jones, PS., Cahill, DP., Brastianos, PK., et al.[2022]

Ipilimumab, a monoclonal antibody used to enhance anti-tumor T-cell responses, can cause significant side effects, including ipilimumab-induced hypophysitis (IH), which affects hormone levels and requires hormone replacement therapy in most cases.

In a review of 10 patients with IH, early detection and management guidelines were developed, highlighting the importance of monitoring hormone levels and recognizing imaging abnormalities, which often resolve without high-dose glucocorticoid therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ipilimumab-induced hypophysitis in melanoma patients: an Australian case series. Lam, T., Chan, MM., Sweeting, AN., et al.[2022]

References

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

Neoadjuvant nivolumab modifies the tumor immune microenvironment in resectable glioblastoma. [2019]

2. Singapore pubmed.ncbi.nlm.nih.gov

Lung brain metastasis pseudoprogression after nivolumab and ipilimumab combination treatment. [2023]

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

A phase II open label, randomised study of ipilimumab with temozolomide versus temozolomide alone after surgery and chemoradiotherapy in patients with recently diagnosed glioblastoma: the Ipi-Glio trial protocol. [2020]

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

Circulating Immune Cell and Outcome Analysis from the Phase II Study of PD-L1 Blockade with Durvalumab for Newly Diagnosed and Recurrent Glioblastoma. [2023]

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

Neoadjuvant anti-PD-1 immunotherapy promotes a survival benefit with intratumoral and systemic immune responses in recurrent glioblastoma. [2023]

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

Primary and metastatic brain cancer genomics and emerging biomarkers for immunomodulatory cancer treatment. [2018]

7. England pubmed.ncbi.nlm.nih.gov

Unmasking of intracranial metastatic melanoma during ipilimumab/nivolumab therapy: case report and literature review. [2018]

8. New Zealand pubmed.ncbi.nlm.nih.gov

Emerging options for the treatment of melanoma - focus on ipilimumab. [2020]

9. Switzerland pubmed.ncbi.nlm.nih.gov

Successful Treatment of Unresectable Advanced Melanoma by Administration of Nivolumab With Ipilimumab Before Primary Tumor Resection. [2020]

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

Ipilimumab and craniotomy in patients with melanoma and brain metastases: a case series. [2022]

11. Australia pubmed.ncbi.nlm.nih.gov

Ipilimumab-induced hypophysitis in melanoma patients: an Australian case series. [2022]