Immunotherapy + Radiosurgery for Glioblastoma

Overseen By Abranmson Cancent Center Clinical Trials Service

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University of Pennsylvania

Must not be taking: Immunosuppressants, Antiretrovirals

Disqualifiers: Immunodeficiency, Hepatitis, Cardiovascular, 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

Compensation: Varies

Number of Visits: Unknown

39 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, you must not be on immunosuppressive medications other than steroids, and certain time intervals from previous treatments are required before starting the trial.

What data supports the effectiveness of this treatment for glioblastoma?

Research shows that combining immunotherapy with stereotactic radiosurgery (SRS) can improve survival in glioblastoma, as seen in studies with mice. The combination of anti-GITR monoclonal antibody and SRS has demonstrated a survival benefit in a glioma model, suggesting potential effectiveness in humans. ^{1 2 3 4 5}

Is the combination of immunotherapy and radiosurgery generally safe for humans?

Studies suggest that combining immunotherapy with stereotactic radiosurgery (a precise form of radiation therapy) can increase both effectiveness and potential side effects, such as radiation necrosis (tissue damage due to radiation). While these treatments have been tested in various cancers, including gliomas and melanoma, safety data indicates that side effects can occur, and careful monitoring is necessary. ^{2 6 7 8 9}

How is the treatment of Immunotherapy + Radiosurgery for Glioblastoma different from other treatments?

This treatment combines immunotherapy with stereotactic radiosurgery (SRS), which is a precise form of radiation therapy, to potentially enhance the immune system's ability to fight glioblastoma. The use of anti-GITR and anti-PD-1 antibodies in this combination aims to boost immune response and improve survival, which is a novel approach compared to traditional treatments. ^{2 4 8 10 11}

What is the purpose of this trial?

This is a phase II study of the combination of the GITR agonist monoclonal antibody INCAGN01876, the anti-PD1 monoclonal antibody INCMGA00012, and stereotactic radiosurgery (SRS) for recurrent Glioblastoma (GBM). The investigators hypothesize that the proposed regimen will be safe and stimulate a robust anti-tumor immune response and result in improved tumor responses.

Research Team

Stephen Bagley, MD

Principal Investigator

University of Pennsylvania

Eligibility Criteria

Adults over 18 with recurrent glioblastoma who've completed prior treatments, have a life expectancy of more than 3 months, and adequate organ function. They must not be pregnant or breastfeeding and agree to use contraception. Excluded are those with certain brain locations of cancer, previous specific cancer treatments like VEGF inhibitors (unless for radiation necrosis), immunosuppressant use within six months, significant heart disease, other active cancers that could affect the trial's outcomes, or infectious conditions like hepatitis B/C or HIV.

Inclusion Criteria

I can care for myself but may need occasional help.

I've had treatments for relapses but never VEGF inhibitors, except for radiation necrosis.

I am scheduled for a surgery that my doctor says I need.

Exclusion Criteria

I am currently receiving or have recently received treatment for an autoimmune disease.

I do not have any serious, uncontrolled health conditions or infections.

I have had a solid organ or bone marrow transplant.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Neoadjuvant Immunotherapy

Subjects receive a single priming dose of INCMGA00012 and INCAGN01876 prior to stereotactic radiosurgery (SRS) or surgery

2 weeks

Stereotactic Radiosurgery (SRS)

Subjects undergo SRS (8 Gy x 3 fractions) following the priming dose of immunotherapy

1 week

Postoperative Immunotherapy

Post-surgery, the immunotherapy combination of INCMGA00012 and INCAGN01876 is resumed and continued until disease progression, unacceptable toxicity, or for 2 years

Up to 2 years

Follow-up

Participants are monitored for safety and effectiveness after treatment

25 months

Treatment Details

Interventions

• Brain surgery
• INCAGN01876
• INCMGA00012
• Stereotactic Radiosurgery

Trial Overview The study tests a combination therapy using INCAGN01876 (GITR agonist antibody), INCMGA00012 (anti-PD1 antibody), and stereotactic radiosurgery (SRS) in patients with recurrent glioblastoma. The goal is to evaluate safety and effectiveness in stimulating an immune response against the tumor.

Participant Groups

Group I: Cohort B sub-arm #2 Experimental Treatment 3 Interventions

Subjects in this arm (N=8) receive neoadjuvant immunotherapy INCMGA00012 + INCAGN01876 (without SRS). Subjects then undergo surgery. Postoperatively, the immunotherapy combination of INCMGA00012 (IV every 4 weeks) and INCAGN01876 (IV every 2 weeks) is resumed and continued until disease progression, unacceptable toxicity, or for 2 years, whichever occurs first.

Group II: Cohort B sub-arm #1 Experimental Treatment 4 Interventions

Subjects in this arm (N=8) receive neoadjuvant immunotherapy INCMGA00012 (500mg) + INCAGN01876 (300mg) + SRS. Subjects then undergo surgery. Postoperatively, the immunotherapy combination of INCMGA00012 (500 mg IV every 4 weeks) and INCAGN01876 (300mg IV every 2 weeks) is resumed and continued until disease progression, unacceptable toxicity, or for 2 years, whichever occurs first.

Group III: Cohort A Experimental Treatment 3 Interventions

Subjects in this arm (N=16) receive a single priming dose of both INCMGA00012 (500mg) and INCAGN01876 (300mg) prior to stereotactic radiosurgery (SRS), then undergo SRS (8 Gy x 3 fractions). Following SRS, INCMGA00012 (500mg IV every 4 weeks) and INCAGN01876 (300mg IV every 2 weeks) are resumed and continued until disease progression, unacceptable toxicity, or for 2 years, whichever occurs first.

Who Is Running the Clinical Trial?

University of Pennsylvania

Lead Sponsor

Trials

2,118

Recruited

45,270,000+

Incyte Corporation

Industry Sponsor

Trials

408

Recruited

66,800+

Steven Stein

Incyte Corporation

Chief Medical Officer since 2015

MD from University of Witwatersrand

Hervé Hoppenot

Incyte Corporation

Chief Executive Officer since 2014

MBA from ESSEC Business School

Findings from Research

In a study of 73 patients with glioblastoma multiforme, locoregional radioimmunotherapy (LR-RIT) demonstrated a safety profile with 75% of patients achieving disease stabilization and no major hematological toxicity observed.

The combination of LR-RIT with Temozolomide (TMZ) significantly improved overall survival (25 months) and progression-free survival (10 months) compared to LR-RIT alone, indicating that this combined treatment approach is both effective and safe.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combined treatment of glioblastoma patients with locoregional pre-targeted 90Y-biotin radioimmunotherapy and temozolomide. Bartolomei, M., Mazzetta, C., Handkiewicz-Junak, D., et al.[2018]

The combination of anti-GITR monoclonal antibody (mAb) and stereotactic radiosurgery (SRS) significantly improved survival rates in a mouse model of glioblastoma, with a cure rate of 24% compared to 0% for either treatment alone, indicating a strong immune-mediated effect.

The treatment with anti-GITR (1) and SRS led to increased infiltration of CD4+ effector T-cells and enhanced production of immune signaling molecules like IFNγ and IL-2, suggesting that this combination effectively shifts the immune response against the tumor.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Agonist anti-GITR monoclonal antibody and stereotactic radiation induce immune-mediated survival advantage in murine intracranial glioma. Patel, MA., Kim, JE., Theodros, D., et al.[2022]

The combination of pembrolizumab, hypofractionated stereotactic irradiation (HFSRT), and bevacizumab was found to be generally safe and well tolerated in 32 patients with recurrent high-grade gliomas, with manageable treatment-related adverse events such as proteinuria and fatigue.

In the bevacizumab-naïve group, 83% of patients showed a complete or partial response, with a median overall survival of 13.45 months, indicating promising preliminary efficacy of this treatment combination.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hypofractionated stereotactic re-irradiation with pembrolizumab and bevacizumab in patients with recurrent high-grade gliomas: results from a phase I study. Sahebjam, S., Forsyth, PA., Tran, ND., et al.[2021]

In a study of 179 patients with non-small cell lung cancer, renal cell carcinoma, or melanoma treated with immune checkpoint inhibitors (ICI) and stereotactic radiosurgery (SRS), the combination showed a low local failure rate of 5.8%, suggesting effective intracranial control when these treatments are used together.

Higher PD-L1 expression (≥50%) was linked to increased rates of grade 2+ radiation necrosis (17% vs. 3%), indicating that while the combination therapy is generally safe, patients with high PD-L1 levels may need closer monitoring for potential side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Factors associated with radiation necrosis and intracranial control in patients treated with immune checkpoint inhibitors and stereotactic radiotherapy. Hall, J., Lui, K., Tan, X., et al.[2023]

In a phase 1 study involving 16 patients with brain metastases from melanoma, ipilimumab combined with stereotactic radiosurgery (SRS) was found to be safe at a maximum dose of 10 mg/kg, with no dose-limiting toxicities reported.

The study showed that while the median progression-free survival was similar for both treatment arms (2.1 months for SRS and 2.5 months for whole brain radiation therapy), the overall survival was not reached for the SRS group, indicating potential benefits of this combination therapy that warrant further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 1 Study of Ipilimumab Combined With Whole Brain Radiation Therapy or Radiosurgery for Melanoma Patients With Brain Metastases. Williams, NL., Wuthrick, EJ., Kim, H., et al.[2022]

References

1. Italy pubmed.ncbi.nlm.nih.gov

Combined treatment of glioblastoma patients with locoregional pre-targeted 90Y-biotin radioimmunotherapy and temozolomide. [2018]

2. England pubmed.ncbi.nlm.nih.gov

Agonist anti-GITR monoclonal antibody and stereotactic radiation induce immune-mediated survival advantage in murine intracranial glioma. [2022]

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

Epidermal growth factor receptor expression modulates antitumor efficacy of vandetanib or cediranib combined with radiotherapy in human glioblastoma xenografts. [2022]

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

A Phase II study of anti-epidermal growth factor receptor radioimmunotherapy in the treatment of glioblastoma multiforme. [2018]

5. England pubmed.ncbi.nlm.nih.gov

Axitinib plus avelumab in the treatment of recurrent glioblastoma: a stratified, open-label, single-center phase 2 clinical trial (GliAvAx). [2021]

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

Characterization and Comparison of GITR Expression in Solid Tumors. [2020]

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

Hypofractionated stereotactic re-irradiation with pembrolizumab and bevacizumab in patients with recurrent high-grade gliomas: results from a phase I study. [2021]

8. Ireland pubmed.ncbi.nlm.nih.gov

Factors associated with radiation necrosis and intracranial control in patients treated with immune checkpoint inhibitors and stereotactic radiotherapy. [2023]

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

Phase 1 Study of Ipilimumab Combined With Whole Brain Radiation Therapy or Radiosurgery for Melanoma Patients With Brain Metastases. [2022]

10. Germany pubmed.ncbi.nlm.nih.gov

Reirradiation with radiosurgery or stereotactic fractionated radiotherapy in association with regorafenib in recurrent glioblastoma. [2023]

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

Anti-PD-1 blockade and stereotactic radiation produce long-term survival in mice with intracranial gliomas. [2023]