| Eligibility |
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
|
