Nivolumab + Ipilimumab with Surgery for Glioblastoma

Recruiting at 3 trial locations

Overseen By Patrick Wen, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Patrick Wen, MD

Must not be taking: Immunosuppressants, Bevacizumab

Disqualifiers: Immunodeficiency, Active TB, Autoimmune, 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: Unknown

63 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications. However, there are specific time periods required between certain prior treatments and registration, such as 4 weeks from cytotoxic therapy and 5 half-lives from any investigational agent. It's best to discuss your current medications with the trial team to ensure they don't interfere with the study.

What data supports the effectiveness of the drug combination of Nivolumab and Ipilimumab with surgery for glioblastoma?

Research shows that Nivolumab, when given before and after surgery, can change the immune environment in glioblastoma tumors, potentially helping the body's immune system fight the cancer. Additionally, Ipilimumab has shown promise in treating other cancers like melanoma, suggesting it might also help in glioblastoma. ^{1 2 3 4 5}

Is the combination of Nivolumab and Ipilimumab safe for humans?

Nivolumab and Ipilimumab have been studied for safety in patients with glioblastoma, showing some immune-related side effects like liver injury, which can be serious but are rare. These treatments have been used in various cancers, and while they can cause inflammatory side effects, they are generally considered safe when monitored properly. ^{3 6 7 8 9}

How does the treatment of Nivolumab + Ipilimumab with Surgery for Glioblastoma differ from other treatments?

This treatment is unique because it combines surgery with two immune checkpoint inhibitors, Nivolumab and Ipilimumab, which work by enhancing the body's immune response against cancer cells. Unlike standard treatments that primarily involve surgery followed by chemotherapy and radiation, this approach aims to modify the tumor's immune environment, potentially offering a novel way to improve outcomes in glioblastoma. ^{1 2 3 4 6}

What is the purpose of this trial?

This research trial is studying the safety and effectiveness of nivolumab in combination with ipilimumab and surgery when used in the treatment of recurrent glioblastoma. The names of the study drugs involved in this study are: * Nivolumab * Ipilimumab * Placebo (IV solution with no medicine) * Zr-89 Crefmirlimab berdoxam (optional sub-study)

Research Team

Patrick Y Wen, MD

Principal Investigator

Dana-Farber Cancer Institute

Eligibility Criteria

Adults (18+) with Grade IV IDH wildtype glioblastoma at first or second relapse, who are undergoing clinically indicated surgery. Participants must have a Karnofsky performance status ≥ 70, sufficient tissue from prior surgery for analysis, and no active infections or additional malignancies. They should not have received certain treatments like bevacizumab or systemic immunosuppressives recently and must agree to use effective contraception.

Inclusion Criteria

Women of child-bearing potential using highly effective contraception during study treatment and for 5 months after study discontinuation

My MRI shows my tumor is growing.

MRI within 14 days prior of registration

Exclusion Criteria

Known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected)

You have mental health or addiction issues that could prevent you from following the trial requirements.

You are currently or planning to participate in a study involving an experimental drug or device.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Pre-Surgery Treatment

Participants receive one dose of study drugs (nivolumab plus ipilimumab or placebo) 14(±5) days before surgery

2-3 weeks

Surgery

Participants undergo surgery for tumor removal

Post-Surgery Treatment

Participants receive nivolumab in combination with ipilimumab every 3 weeks for 9 weeks, followed by nivolumab alone every 4 weeks

13 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

24 months

Treatment Details

Interventions

• Ipilimumab
• Nivolumab
• Surgery

Trial Overview The trial is testing the safety and effectiveness of nivolumab combined with ipilimumab alongside surgery in treating recurrent glioblastoma. A placebo group is included for comparison. An optional sub-study involves Zr-89 Crefmirlimab berdoxam.

Participant Groups

Group I: Placebo-Nivolumab and Placebo-Ipilimumab Before Surgery, Nivolumab and Ipilimumab After Surgery Experimental Treatment 5 Interventions

One dose of placebo-nivolumab plus placebo-ipilimumab will be administered 14(±5) days before surgery. After surgery, participants receive nivolumab in combination with ipilimumab every 3 weeks for 9 weeks and then nivolumab alone every 4 weeks

Group II: Nivolumab and Placebo-Ipilimumab Before Surgery, Nivolumab After Surgery Experimental Treatment 3 Interventions

One dose of nivolumab plus placebo-ipilimumab will be administered 14(±5) days before surgery. After surgery, participants receive nivolumab in combination with ipilimumab every 3 weeks for 9 weeks and then nivolumab alone every 4 weeks.

Group III: Nivolumab and Ipilimumab Before and After Surgery Experimental Treatment 3 Interventions

One dose of nivolumab plus ipilimumab will be administered 14(±5) days before surgery. After surgery, participants receive nivolumab in combination with ipilimumab every 3 weeks for 9 weeks and then nivolumab alone every 4 weeks.

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?

Patrick Wen, MD

Lead Sponsor

Trials

3

Recruited

600+

Patrick Y. Wen, MD

Lead Sponsor

Trials

10

Recruited

990+

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

Findings from Research

Intracerebral administration of ipilimumab (IPI) and nivolumab (NIVO) after maximal safe resection of recurrent glioblastoma (rGB) was found to be feasible and safe, with mild immune-related adverse events and no significant central nervous system toxicity observed.

The treatment resulted in a median overall survival of 38 weeks, which is favorable compared to historical data, suggesting that this approach may improve outcomes for patients with rGB.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intracerebral administration of CTLA-4 and PD-1 immune checkpoint blocking monoclonal antibodies in patients with recurrent glioblastoma: a phase I clinical trial. Duerinck, J., Schwarze, JK., Awada, G., et al.[2022]

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]

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]

Nivolumab alone was better tolerated than when combined with ipilimumab, with treatment-related adverse events like fatigue and diarrhea being more common in the combination therapy group.

Despite the safety concerns, some patients showed promising responses, with three achieving partial responses and eight maintaining stable disease for at least 12 weeks, indicating potential efficacy of nivolumab in treating recurrent glioblastoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab with or without ipilimumab in patients with recurrent glioblastoma: results from exploratory phase I cohorts of CheckMate 143. Omuro, A., Vlahovic, G., Lim, M., et al.[2023]

Immune checkpoint inhibitors like nivolumab have revolutionized cancer treatment but can lead to serious autoimmune-like side effects known as immune-related adverse events (irAEs).

This study highlights a specific case of severe liver injury linked to nivolumab in a glioblastoma patient, emphasizing the need for better understanding and management of these potential toxicities to ensure patient safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pathological characterization of nivolumab-related liver injury in a patient with glioblastoma. Simonelli, M., Di Tommaso, L., Baretti, M., et al.[2018]

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]

References

1. England pubmed.ncbi.nlm.nih.gov

Intracerebral administration of CTLA-4 and PD-1 immune checkpoint blocking monoclonal antibodies in patients with recurrent glioblastoma: a phase I clinical trial. [2022]

2. 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]

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

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

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

Ipilimumab and Bevacizumab in Glioblastoma. [2023]

5. Germany pubmed.ncbi.nlm.nih.gov

Identification of cytokine-predominant immunosuppressive class and prognostic risk signatures in glioma. [2023]

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

Nivolumab with or without ipilimumab in patients with recurrent glioblastoma: results from exploratory phase I cohorts of CheckMate 143. [2023]

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

Pathological characterization of nivolumab-related liver injury in a patient with glioblastoma. [2018]

8. Japan pubmed.ncbi.nlm.nih.gov

Efficacy and safety of nivolumab in Japanese patients with first recurrence of glioblastoma: an open-label, non-comparative study. [2022]

9. 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]