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 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
\. Reproductive Status
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
Women must agree to not breastfeed during the study or for 180 days after the last dose of study treatment
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
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
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)
Any of the following would exclude the subject from participation in the
study
Contrast-enhancing tumor in brainstem or spinal cord (subjects do not need spinal MRI for screening, but known spinal cord tumor is exclusionary)
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
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
Yes for 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 exclusion criteria 41
No for 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 exclusion criteria 41
Not sure for 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 exclusion criteria 41