Immunotherapy Before and After Surgery for Brain Tumor
Recruiting in Palo Alto (17 mi)
+22 other locations
Age: < 65
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: Sabine Mueller, MD, PhD
Must not be taking: Immunosuppressants, Corticosteroids
Disqualifiers: Immunodeficiency, Brainstem tumor, Active infection, others
No Placebo Group
Breakthrough Therapy
Trial Summary
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.
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.
12345Is 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.
14678How 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.
1291011Eligibility 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.
+10 more
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.
+13 more
Trial 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
Participant Groups
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.
1Treatment groups
Experimental Treatment
Group I: Neoadjuvant nivolumab and adjuvant nivolumabExperimental Treatment3 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
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Children's National HospitalWashington, United States
University of UtahSalt Lake City, UT
Johns Hopkins UniversityBaltimore, MD
Washington University St. LouisSaint Louis, MO
More Trial Locations
Loading ...
Who Is Running the Clinical Trial?
Sabine Mueller, MD, PhDLead Sponsor
Bristol-Myers SquibbIndustry Sponsor
Pediatric Neuro-Oncology ConsortiumCollaborator
Pacific Pediatric Neuro-Oncology ConsortiumCollaborator
References
Neoadjuvant nivolumab modifies the tumor immune microenvironment in resectable glioblastoma. [2019]Glioblastoma is the most common primary central nervous system malignancy and has a poor prognosis. Standard first-line treatment, which includes surgery followed by adjuvant radio-chemotherapy, produces only modest benefits to survival1,2. Here, to explore the feasibility, safety and immunobiological effects of PD-1 blockade in patients undergoing surgery for glioblastoma, we conducted a single-arm phase II clinical trial (NCT02550249) in which we tested a presurgical dose of nivolumab followed by postsurgical nivolumab until disease progression or unacceptable toxicity in 30 patients (27 salvage surgeries for recurrent cases and 3 cases of primary surgery for newly diagnosed patients). Availability of tumor tissue pre- and post-nivolumab dosing and from additional patients who did not receive nivolumab allowed the evaluation of changes in the tumor immune microenvironment using multiple molecular and cellular analyses. Neoadjuvant nivolumab resulted in enhanced expression of chemokine transcripts, higher immune cell infiltration and augmented TCR clonal diversity among tumor-infiltrating T lymphocytes, supporting a local immunomodulatory effect of treatment. Although no obvious clinical benefit was substantiated following salvage surgery, two of the three patients treated with nivolumab before and after primary surgery remain alive 33 and 28 months later.
Lung brain metastasis pseudoprogression after nivolumab and ipilimumab combination treatment. [2023]Immunotherapy has revolutionized the treatment of non-small cell lung cancer; however, its role in the treatment response of lung brain metastasis is unknown. Understanding immunotherapy activity in the central nervous system is important in order to avoid additional toxicity, such as that associated with the use of cerebral radiotherapy. We present two cases with clinical and radiological progression with increases in size and perilesional edema of brain lesions after treatment with a combination of ipilimumab and nivolumab. The increasing use of immunotherapy in lung cancer requires increased knowledge of new patterns of radiological response, such as pseudoprogression.
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]Median survival for patients with glioblastoma is less than a year. Standard treatment consists of surgical debulking if feasible followed by temozolomide chemo-radiotherapy. The immune checkpoint inhibitor ipilimumab targets cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and has shown clinical efficacy in preclinical models of glioblastoma. The aim of this study is to explore the addition of ipilimumab to standard therapy in patients with glioblastoma.
Circulating Immune Cell and Outcome Analysis from the Phase II Study of PD-L1 Blockade with Durvalumab for Newly Diagnosed and Recurrent Glioblastoma. [2023]PD-L1 is upregulated in glioblastoma and supports immunosuppression. We evaluated PD-L1 blockade with durvalumab among glioblastoma cohorts and investigated potential biomarkers.
Neoadjuvant anti-PD-1 immunotherapy promotes a survival benefit with intratumoral and systemic immune responses in recurrent glioblastoma. [2023]Glioblastoma is the most common primary malignant brain tumor in adults and is associated with poor survival. The Ivy Foundation Early Phase Clinical Trials Consortium conducted a randomized, multi-institution clinical trial to evaluate immune responses and survival following neoadjuvant and/or adjuvant therapy with pembrolizumab in 35 patients with recurrent, surgically resectable glioblastoma. Patients who were randomized to receive neoadjuvant pembrolizumab, with continued adjuvant therapy following surgery, had significantly extended overall survival compared to patients that were randomized to receive adjuvant, post-surgical programmed cell death protein 1 (PD-1) blockade alone. Neoadjuvant PD-1 blockade was associated with upregulation of T cell- and interferon-γ-related gene expression, but downregulation of cell-cycle-related gene expression within the tumor, which was not seen in patients that received adjuvant therapy alone. Focal induction of programmed death-ligand 1 in the tumor microenvironment, enhanced clonal expansion of T cells, decreased PD-1 expression on peripheral blood T cells and a decreasing monocytic population was observed more frequently in the neoadjuvant group than in patients treated only in the adjuvant setting. These findings suggest that the neoadjuvant administration of PD-1 blockade enhances both the local and systemic antitumor immune response and may represent a more efficacious approach to the treatment of this uniformly lethal brain tumor.
Primary and metastatic brain cancer genomics and emerging biomarkers for immunomodulatory cancer treatment. [2018]Recent studies with immunomodulatory agents targeting both cytotoxic T-lymphocyte protein 4 (CTLA4) and programmed cell death 1 (PD1)/programmed cell death ligand 1 (PDL1) have shown to be very effective in several cancers revealing an unexpected great activity in patients with both primary and metastatic brain tumors. Combining anti-CTLA4 and anti-PD1 agents as upfront systemic therapy has revealed to further increase the clinical benefit observed with single agent, even at cost of higher toxicity. Since the brain is an immunological specialized area it's crucial to establish the specific composition of the brain tumors' microenvironment in order to predict the potential activity of immunomodulatory agents. This review briefly summarizes the basis of the brain immunogenicity, providing the most updated clinical evidences in terms of immune-checkpoint inhibitors efficacy and toxicity in both primary and metastatic brain tumors with the final aim of defining potential biomarkers for immunomodulatory cancer treatment.
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.
Emerging options for the treatment of melanoma - focus on ipilimumab. [2020]Ipilimumab is a fully human immunoglobulin subclass G1 anticytotoxic-T-lymphocyte-antigen-4 monoclonal antibody. It has been approved by the US Food and Drug Administration (FDA) and the European Medicines Agency for use in advanced melanoma following clear evidence of survival benefit in randomized Phase III studies. It is also under investigation as a treatment for other solid tumors such as renal cell, lung, and prostate cancers. The purported mechanism of antitumor activity of ipilimumab is through T-cell activation, and the side effect profile reflects this. Immune-related adverse events (irAEs) affect 60% of treated patients and 15% are defined as severe. Fortunately, most irAEs are reversible with early diagnosis and correct management. FDA approval of ipilimumab is dependent on the careful execution of a risk evaluation and mitigation strategy, with the aim of increasing awareness amongst patients and clinicians of the immunological risks of treatment, and providing algorithms for management of irAEs as they develop. Ipilimumab is one of the first immunotherapies to become widely available in the setting of solid tumors, and ongoing research aims to elucidate optimal dosing, optimal scheduling, and expanded access to ipilimumab as an adjuvant or maintenance therapy where appropriate. The identification of clinical correlates or biomarkers to identify those likely to benefit from this high-cost therapy is a top priority.
Successful Treatment of Unresectable Advanced Melanoma by Administration of Nivolumab With Ipilimumab Before Primary Tumor Resection. [2020]Ipilimumab, in combination with nivolumab, is one of the promising drugs that enhance the anti-tumor immune response of patients with advanced melanoma. Since the co-administration of nivolumab with ipilimumab in the neoadjuvant setting expands melanoma-reactive T cells at the primary site of melanoma and has a high rate of histological complete response, the pre-surgical administration of this combination could be the optimal therapy for unresectable advanced melanoma. In this report, a case of unresectable advanced melanoma treated successfully with administration of nivolumab with ipilimumab before primary tumor resection is presented. In addition, CD8+ T cells increased among the tumor-infiltrating lymphocytes that were surrounding melanoma cells and caspase 3+ cells. The present case suggests that pre-surgical administration of nivolumab with ipilimumab could be the optimal therapy for the treatment of unresectable advanced melanoma.
Ipilimumab and craniotomy in patients with melanoma and brain metastases: a case series. [2022]OBJECT In patients with large or symptomatic brain lesions from metastatic melanoma, the value of resection of metastases to facilitate administration of systemic ipilimumab therapy has not yet been described. The authors undertook this study to investigate whether craniotomy creates the opportunity for patients to receive and benefit from ipilimumab who would otherwise succumb to brain metastasis prior to the onset of regression. METHODS All patients with metastatic melanoma who received ipilimumab and underwent craniotomy for metastasis resection between 2008 and 2014 at the Massachusetts General Hospital were identified through retrospective chart review. The final analysis included cases involving patients who underwent craniotomy within 3 months prior to initiation of therapy or up to 6 months after cessation of ipilimumab administration. RESULTS Twelve patients met the inclusion criteria based on timing of therapy (median age 59.2). The median number of metastases at the time of craniotomy was 2. The median number of ipilimumab doses received was 4. Eleven of 12 courses of ipilimumab were stopped for disease progression, and 1 was stopped for treatment-induced colitis. Eight of 12 patients had improvement in their performance status following craniotomy. Of the 6 patients requiring corticosteroids prior to craniotomy, 3 tolerated corticosteroid dose reduction after surgery. Ten of 12 patients had died by the time of data collection, with 1 patient lost to follow-up. The median survival after the start of ipilimumab treatment was 7 months. CONCLUSIONS In this series, patients who underwent resection of brain metastases in temporal proximity to receiving ipilimumab had qualitatively improved performance status following surgery in most cases. Surgery facilitated corticosteroid reduction in select patients. Larger analyses are required to better understand possible synergies between craniotomy for melanoma metastases and ipilimumab treatment.
Ipilimumab-induced hypophysitis in melanoma patients: an Australian case series. [2022]Ipilimumab (Yervoy; Bristol-Myers Squibb) is a novel fully humanised monoclonal antibody that blocks cytotoxic T-lymphocyte antigen 4, an immune checkpoint molecule, to augment anti-tumour T-cell responses. It is associated with significant immune-related side-effects including hypophysitis.