Anti-GITR/Anti-PD1/Stereotactic Radiosurgery, in Recurrent Glioblastoma
Condition: Glioblastoma
MeSH terms: Glioblastoma
Intervention: INCMGA00012; INCAGN01876; SRS; Brain surgery
Intervention description: 500mg IV neoadjuvant treatment; 500 mg adjuvant treatment; 300mg IV neoadjuvant treatment; 300 mg adjuvant treatment; administered over the course of 3 consecutive business days (8 Gy x 3 fractions, one fraction per day, total dose 24 Gy).; maximal safe surgical resection of the tumor.
Intervention MeSH terms: Immune Checkpoint Inhibitors
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Intervention model description: 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).
Masking: None (Open Label)
Enrollment: 39.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

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.
    

Eligibility criteria:

        Inclusion Criteria:

          1. 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).

          2. 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

          3. 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

          4. Cohort B (surgical) patients only: patients must be undergoing surgery that is
             clinically indicated as determined by their care providers

          5. 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)

          6. 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.

          7. Patients must have recovered from severe toxicity of prior therapy; the following
             intervals from previous treatments are required to be eligible:

               -  12 weeks from completion of radiation

               -  6 weeks from a nitrosourea cytotoxic chemotherapy

               -  3 weeks from a non-nitrosourea cytotoxic chemotherapy

               -  4 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

               -  3 weeks from any major surgery, including brain surgery for recurrent tumor
                  resection

          8. 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.

          9. Patients must be able to swallow oral medications

         10. Age 18 or older

         11. Karnofsky performance status >= 60

         12. Life expectancy >3 months

         13. Absolute lymphocyte count >= 500/uL

         14. Adequate hepatic function within 7 days prior to start of study treatment, defined as
             follows

               -  Total bilirubin (except patients with Gilbert's Syndrome, who are eligible for
                  the study but exempt from the total bilirubin eligibility criterion) ≤ 2.0 mg/dl

               -  ALT and AST ≤ 2.5x upper limit of normal (ULN)

         15. Adequate renal function within 7 days prior to start of study treatment, defined as
             follows:

             • Serum creatinine <=1.5 x institutional ULN OR calculated creatinine clearance
             (glomerular filtration rate can also be used in place of creatinine or CrCl) >=50
             mL/min for subjects with creatinine levels >1.5x institutional ULN

         16. Reproductive Status

               1. Women of childbearing potential (WOCBP) must have a negative serum or urine
                  pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 7
                  days prior to the start of study drug.

               2. Women must agree to not breastfeed during the study or for 180 days after the
                  last dose of study treatment

               3. WOCBP must agree to use an adequate method to avoid pregnancy (as defined below)
                  from the time of study screening through 180 days from last dose of study drug

               4. Males who are sexually active with WOCBP must agree to follow instructions for
                  method(s) of contraception (as defined below) starting with the first dose of
                  study drug through 180 days after the last dose of study

               5. Azoospermic males and WOCBP who are continuously not heterosexually active are
                  exempt from contraceptive requirements. However, these WOCBP must still undergo
                  pregnancy testing as described in this section.

             At a minimum, participants of childbearing potential who are sexually active and their
             partners must agree to the use of a highly effective form of contraception (as defined
             below) throughout their participation beginning with the time of consent, during the
             study treatment, and for 180 days after last dose of study treatment(s).

             HIGHLY EFFECTIVE METHODS OF CONTRACEPTION:

               -  Hormonal methods of contraception including combined oral contraceptive pills,
                  vaginal ring, injectables, implants and intrauterine devices (IUDs) by WOCBP
                  subject or male subject's WOCBP partner. Female partners of male subjects
                  participating in the study may use hormone-based contraceptives as one of the
                  acceptable methods of contraception since they will not be receiving study drug

               -  Nonhormonal IUDs

               -  Bilateral Tubal ligation

               -  Vasectomy

               -  Sexual Abstinence

                    -  It is not necessary to use any other method of contraception when complete
                       abstinence is elected.

                    -  WOCBP participants who choose complete abstinence must continue to have
                       pregnancy tests.

                    -  Acceptable alternate methods of highly effective contraception must be
                       discussed in the event that the WOCBP participants chooses to forego
                       complete abstinence.

         17. Participant must, in the opinion of the Investigator, be able to comply with study
             procedures

         18. Patients must be able to understand the study procedures and agree to participate in
             the study by providing written informed consent (or have legally authorized
             representative sign on patient's behalf if patient physically unable to sign consent
             due to neurologic deficit)

        Exclusion Criteria

        Any of the following would exclude the subject from participation in the study:

          1. Contrast-enhancing tumor in brainstem or spinal cord (subjects do not need spinal MRI
             for screening, but known spinal cord tumor is exclusionary)

          2. Diffuse leptomeningeal disease

          3. 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).

          4. Patients with clinically significant mass effect or midline shift (e.g., 1-2 cm of
             midline shift)

          5. 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

          6. Prior diagnosis of immunodeficiency

          7. Prior solid organ or bone marrow transplantation

          8. 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.

          9. History of non-infectious pneumonitis that required steroid treatment

         10. Known active hepatitis B virus (HBsAg reactive) or active hepatitis C virus (HCV RNA
             detectable by PCR)

         11. Human immunodeficiency virus (HIV)-positive patients on antiretroviral therapy

         12. 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.

         13. 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.

         14. Patients with uncontrolled or significant cardiovascular disease including, but not
             limited to, any of the following are ineligible:

               -  Myocardial infarction or uncontrolled angina within 90 days prior to consent

               -  History of clinically significant arrhythmia (such as ventricular tachycardia,
                  ventricular fibrillation, or torsades pointes)

               -  History of cardiomyopathy, pericarditis, significant pericardial effusion,
                  myocarditis, or New York Heart Association (NYHA) functional class III-IV
                  congestive heart failure

         15. Known hypersensitivity to another monoclonal antibody that cannot be controlled with
             standard measures (e.g., antihistamines and corticosteroids)

         16. Prisoners or subjects who are involuntarily incarcerated

         17. Subjects who are compulsorily detained for treatment of either a psychiatric or
             physical (eg, infectious disease) illness

         18. Pregnant women are excluded

         19. Received a live vaccine within 30 days prior to first dose of study drug. Examples
             include but are not limited to measles, mumps, rubella, varicella/zoster, yellow
             fever, rabies, Bacillus Celmette-Guerin (BCG), and typhoid. Intranasal influenza
             vaccines are not allowed.

         20. Participant must not be simultaneously enrolled in any interventional clinical trial