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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new method to treat glioblastoma, a type of brain cancer that has recurred after treatment. The study combines two immunotherapy drugs, INCAGN01876 and INCMGA00012, with stereotactic radiosurgery (SRS), a precise form of radiation, to enhance the body's immune response against tumors. Participants may receive different combinations of these treatments, with some also undergoing surgery. The trial seeks individuals with a confirmed diagnosis of glioblastoma that has returned after initial treatment and shows tumor growth on an MRI. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that the combination of treatments INCMGA00012 and INCAGN01876 is generally well-tolerated by patients with recurring glioblastoma. Although some side effects may occur, studies suggest that most patients manage the treatments without serious issues.

Stereotactic radiosurgery (SRS) is also considered safe. It uses targeted radiation to treat tumors like glioblastoma while aiming to protect nearby healthy tissue.

Overall, previous studies have tested the treatments in this trial and found them manageable for most patients. However, individual reactions can vary with any medical treatment. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for glioblastoma because they combine immunotherapy with stereotactic radiosurgery (SRS) in a novel way. Unlike standard treatments like temozolomide chemotherapy and conventional radiation, this approach uses the immune system's power to target cancer cells more precisely. The combination of INCMGA00012 and INCAGN01876, both immunotherapy agents, is designed to enhance the body's immune response against glioblastoma cells, potentially offering a new way to control tumor growth. Additionally, the integration of SRS allows for targeted high-dose radiation, which may improve outcomes by minimizing damage to surrounding healthy tissue. This innovative approach could lead to more effective and less toxic treatment options for patients with this aggressive brain cancer.

What evidence suggests that this trial's treatments could be effective for glioblastoma?

Research shows that combining the drugs INCAGN01876 and INCMGA00012 with stereotactic radiosurgery, a precise type of radiation therapy, may help treat glioblastoma, an aggressive brain cancer. In this trial, participants in Cohort A will receive this combination of treatments. These treatments might boost the immune system to attack the tumor more effectively. Together, they aim to improve the tumor's response and possibly extend the patient's life. However, studies found that this drug combination was not very effective without radiosurgery. Therefore, using these drugs with stereotactic radiosurgery appears to be a more promising approach for treating glioblastoma. ^{1 6 7 8 9}

Who Is on the Research Team?

Stephen Bagley, MD

Principal Investigator

University of Pennsylvania

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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

Published Research Related to This Trial

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]

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]

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]

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]

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]

Citations

1. cdn.clinicaltrials.gov cdn.clinicaltrials.gov/large-docs/39/NCT04225039/Prot_SAP_000.pdf

a phase ii study of the anti-gitr agonist incagn01876 and ... This is an open-label, single-institution, phase II study of the anti-GITR agonist INCAGN01876 and the PD-1 inhibitor INCMGA00012 in combination with ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12238593/

Glioblastoma at the crossroads: current understanding and ... Studies indicate that higher 11C-MET uptake correlates with poorer survival, whereas 18F-FET and 18F-FDOPA effectively differentiate glioma ...

3. youtube.com youtube.com/watch?v=VRyh8RGwL3M

Phase II trial of retifanlimab and INCAGN01876 with FSRT in ... Phase II trial of retifanlimab and INCAGN01876 with FSRT in glioblastoma.

4. withpower.com withpower.com/trial/phase-3-glioblastoma-5-2020-4679a

Immunotherapy + Radiosurgery for Glioblastoma This Phase 2 medical study run by University of Pennsylvania needs participants to evaluate whether INCAGN01876, INCMGA00012 and Stereotactic Radiosurgery ...

5. go.drugbank.com go.drugbank.com/conditions/DBCOND0043840

Glioblastomas (DBCOND0043840) ... Efficacy in Glioblastoma. Daratumumab ... Early Stereotactic Gamma Knife Radiosurgery to Residual Tumor After Surgery of Newly Diagnosed Glioblastoma ...

6. jitc.bmj.com jitc.bmj.com/content/10/suppl_2/a707

Main menu The primary endpoints are the safety and tolerability of INCAGN01876 in combination with retifanlimab (part 1) and the objective response rate determined by ...

7. researchgate.net researchgate.net/publication/365390346_CTIM-35_A_PHASE_II_STUDY_OF_GITR_AGONIST_INCAGN01876_AND_PD-1_INHIBITOR_RETIFANLIMAB_IN_COMBINATION_WITH_STEREOTACTIC_RADIOTHERAPY_IN_PATIENTS_WITH_RECURRENT_GLIOBLASTOMA

CTIM-35. A PHASE II STUDY OF GITR AGONIST ... CONCLUSIONS The combination of retifanlimab, INCAGN01876, and FSRT is generally well-tolerated in patients with recurrent GBM when administered with or without ...

8. delta.larvol.com delta.larvol.com/Products/?ProductId=fb2b8497-1fd7-4a94-87fa-d9699d5d6ba3

ragifilimab (INCAGN1876) / Agenus, Incyte - Oncology ... retifanlimab in combination with stereotactic radiotherapy in patients with recurrent glioblastoma (SNO 2022) - "The combination of retifanlimab, INCAGN01876 ...

9. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9363531/

Inspecting the Barriers in Glioblastoma Immunotherapies INCMGA00012 + INCAGN01876 + SRS, PD1, Antagonist, 2, Ongoing. NCT04977375 ... safety of patients was not improved compared to placebos. In the ...