Anti-GITR/Anti-PD1/Stereotactic Radiosurgery, in Recurrent Glioblastoma

NCT04225039 | Active Not Recruiting Phase 2 Results FDA Drug

• 1 other identifier: 834197
• Study Type: interventional
• Target: 39
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Glioblastoma

Outcome Measures

Primary Outcomes (1)

• Objective Radiographic Response (ORR)

  Per modified response assessment in neuro-oncology (RANO) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=50% decrease in the sum of the products of the perpendicular diameters of target lesions; Overall Response (OR) = CR + PR.

  26 months

Secondary Outcomes (3)

• Incidence of Treatment-Emergent Adverse Events as Assessed by NCI CTCAE v 5.0

  25 months

• Overall Survival

  84 months

• Progression Free Survival

  84 months

Study Arms (3)

Cohort A

EXPERIMENTAL

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.

Drug: INCMGA00012; Drug: INCAGN01876; Drug: SRS

Cohort B sub-arm #1

EXPERIMENTAL

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.

Drug: INCMGA00012; Drug: INCAGN01876; Drug: SRS; Procedure: Brain surgery

Cohort B sub-arm #2

EXPERIMENTAL

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.

Drug: INCMGA00012; Drug: INCAGN01876; Procedure: Brain surgery

Interventions

INCMGA00012 DRUG

500mg IV neoadjuvant treatment; 500 mg adjuvant treatment

Also known as: PD-1 inhibitor, PD1

Cohort A; Cohort B sub-arm #1; Cohort B sub-arm #2

INCAGN01876 DRUG

300mg IV neoadjuvant treatment; 300 mg adjuvant treatment

Also known as: Anti-GITR agonist, GITR

Cohort A; Cohort B sub-arm #1; Cohort B sub-arm #2

SRS DRUG

administered over the course of 3 consecutive business days (8 Gy x 3 fractions, one fraction per day, total dose 24 Gy).

Also known as: stereotactic radiosurgery

Cohort A; Cohort B sub-arm #1

Brain surgery PROCEDURE

maximal safe surgical resection of the tumor.

Cohort B sub-arm #1; Cohort B sub-arm #2

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Prior histopathologically proven diagnosis of World Health Organization (WHO) grade IV glioblastoma, OR histopathologically proven diagnosis of gliosarcoma, OR molecular diagnosis of glioblastoma per c-IMPACT-NOW criteria ("diffuse astrocytic glioma, IDH-wildtype, with molecular features of glioblastoma, WHO grade IV"; this requires presence of either amplification of EGFR, whole chromosome 7 gain AND whole chromosome 10 loss, or TERT promoter mutation). Participants are eligible if the prior diagnosis was low-grade glioma and a subsequent histological diagnosis of glioblastoma was made (e.g. secondary GBM).
• Participants must have glial tumor that is recurrent following prior first-line radiation therapy (prior dose must have been 40-75 Gy and may have been either photon or proton radiation), and must have unequivocal evidence of tumor progression by MRI scan
• Cohort A and Sub-Arm 1 of Cohort B only: Patient must have at least one measurable (\>=1cm x 1cm) contrast-enhancing tumor focus for which stereotactic radiosurgery (SRS) is clinically indicated, as determined by the Investigator, and must be able to achieve radiation target coverage without exceeding dose constraints. The contrast-enhancing target must not be larger than 4 cm in maximal diameter. Multifocal disease is allowed as long as this criterion is met
• Sub-Arms 2 of Cohort B can have any size tumor, and the tumor does not need to be amenable to SRS
• Cohort B (surgical) patients only: patients must be undergoing surgery that is clinically indicated as determined by their care providers
• Tumor O-6-methylguanine-deoxyribonucleic acid (DNA) methyltransferase (MGMT) methylation status must be available from any prior GBM tumor specimen; results of routinely used methods for MGMT methylation testing (e.g. mutagenically separated polymerase chain reaction \[MSPCR\] or quantitative polymerase chain reaction \[PCR\]) are acceptable)
• Patients may have had treatment for an unlimited number of prior relapses but must not have had prior bevacizumab or other vascular endothelial growth factor (VEGF/VEGFR) inhibitors (exception: prior bevacizumab is allowed if it was administered for the treatment of radiation necrosis rather than progressive tumor and was stopped at least 4 weeks prior to MRI showing demonstrating tumor progression). Prior gliadel wafers are only allowed if placed during the first surgery for GBM at initial diagnosis.
• Patients must have recovered from severe toxicity of prior therapy; the following intervals from previous treatments are required to be eligible:
• weeks from completion of radiation
• weeks from a nitrosourea cytotoxic chemotherapy
• weeks from a non-nitrosourea cytotoxic chemotherapy
• weeks from any investigational (not Food and Drug Administration \[FDA\]-approved for glioblastoma) agents, or within a time interval less than at least 5 half-lives of the investigational agent whichever is shorter
• weeks from any major surgery, including brain surgery for recurrent tumor resection
• If patient is on systemic corticosteroids to treat brain edema and/or brain edema-related symptoms, the dose must be 2mg of dexamethasone (or equivalent) daily or less for a minimum of 5 days prior to first dose of study drug.
• Patients must be able to swallow oral medications

You may not qualify if:

• Any of the following would exclude the subject from participation in the study:
• Diffuse leptomeningeal disease
• Prior bevacizumab or other vascular endothelial growth factor (VEGF/VEGFR) inhibitors (exception: prior bevacizumab is allowed if it was administered for the treatment of radiation necrosis rather than progressive tumor and was stopped at least 4 weeks prior to MRI showing demonstrating tumor progression).
• Patients with clinically significant mass effect or midline shift (e.g., 1-2 cm of midline shift)
• Use of any immunosuppressive medication other than steroids, including but not limited to antimetabolites, calcineurin inhibitors, and/or anti-TNF agents within six months of start of study drug
• Prior diagnosis of immunodeficiency
• Prior solid organ or bone marrow transplantation
• Autoimmune or connective tissue disease that is EITHER (a) actively flaring OR (b) has required systemic treatment in the past 2 years (i.e., with use of disease modifying agents, corticosteroids, or immunosuppressive drugs).
• EXCEPTIONS: Subjects with type I diabetes mellitus, hypothyroidism only requiring hormone replacement, adrenal insufficiency requiring only replacement dose corticosteroids, skin disorders (such as vitiligo, psoriasis, pemphigus, or alopecia) controlled with topical medications, or conditions not expected to recur in the absence of an external trigger are permitted to enroll. Patients with asthma that is not actively flaring are allowed. Patients with history of Grave's disease that is previously treated with thyroidectomy or radioiodine are allowed. Patients with celiac disease whose symptoms are controlled with a gluten-free diet are allowed. Patients with rheumatoid arthritis and other arthropathies such as ankylosing spondylitis, Sjogren's syndrome, Raynaud syndrome, and patients with positive serologies, such as antinuclear antibodies (ANA) or anti-thyroid antibodies, should be evaluated for the presence of target organ involvement and potential need for systemic treatment but should otherwise be eligible.
• History of non-infectious pneumonitis that required steroid treatment
• Known active hepatitis B virus (HBsAg reactive) or active hepatitis C virus (HCV RNA detectable by PCR)
• Human immunodeficiency virus (HIV)-positive patients on antiretroviral therapy
• Patients with a prior or concurrent malignancy whose natural history or treatment has the potential to interfere with the safety or efficacy assessment of the investigational regimen are excluded from this trial. Otherwise, patients with prior or concurrent malignancy are eligible.
• Any serious, uncontrolled medical disorder, nonmalignant systemic disease, or active, uncontrolled infection that, in the opinion of the investigator, would put the subject at undue risk from the study treatment.
• Patients with uncontrolled or significant cardiovascular disease including, but not limited to, any of the following are ineligible:

Sponsors & Collaborators

• University of Pennsylvania: lead
• Incyte Corporation: collaborator

Study Sites (1)

Hospital of the University of Pennsylvania

Philadelphia, Pennsylvania, 19104, United States

Location

MeSH Terms

Conditions

Glioblastoma

Interventions

Immune Checkpoint Inhibitors; Radiosurgery

Condition Hierarchy (Ancestors)

Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue

Intervention Hierarchy (Ancestors)

Molecular Mechanisms of Pharmacological Action; Pharmacologic Actions; Chemical Actions and Uses; Antineoplastic Agents, Immunological; Antineoplastic Agents; Therapeutic Uses; Radiotherapy; Therapeutics; Stereotaxic Techniques; Neurosurgical Procedures; Surgical Procedures, Operative; Investigative Techniques

Results Point of Contact

• Title: Regulatory Lead
• Organization: University of Pennsylvania

psom-ind-ide@pobox.upenn.edu

215-662-4484

Study Officials

• Stephen Bagley, MD, MSCE

  University of Pennsylvania

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: The overall study population will be broken down into two cohorts: Cohort A (N=16) and Cohort B (N=16). Subjects for whom surgical resection is not clinically indicated at the time of study screening will be enrolled into Cohort A (non-surgical cohort). Subjects for whom surgical resection is clinically indicated at the time of study screening will be enrolled into Cohort B (surgical cohort).

Study Record Dates

• First Submitted: December 23, 2019
• First Posted: January 13, 2020
• Study Start: June 23, 2020
• Primary Completion: September 8, 2022
• Study Completion (Estimated): April 30, 2029
• Last Updated: August 15, 2025
• Results First Posted: September 15, 2023

Record last verified: 2025-08

Locations

US (1)