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.
The study has 2 arms:
Arm A (Cohort A) is a nonsurgical arm (N=16) that will serve as the primary study cohort and
evaluated for the primary study endpoint. Subjects in this arm receive a single priming dose
of both INCMGA00012 and INCAGN01876 prior to stereotactic radiosurgery (SRS), then undergo
SRS (8 Gy x 3 fractions). Following SRS, INCMGA00012 (IV every 4 weeks) and INCAGN01876 (IV
every 2 weeks) are resumed and continued until disease progression, unacceptable toxicity, or
for 2 years, whichever occurs first.
Arm B (Cohort B) is a surgical arm (N=16) that will allow for evaluation of the effects on
the tumor immune microenvironment of INCMGA00012, INCAGN01876, and SRS. In order to be
enrolled on this arm, subjects must have a clinical indication for surgical resection of the
recurrent GBM tumor. Prior to planned surgical resection, subjects receive neoadjuvant
immunotherapy (one of two possible combinations, as outlined below). 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. Subjects in the surgical arm
with a focus of contrast-enhancing tumor that is amenable to SRS will be assigned to surgical
sub-arm #1 of Cohort B (N=8). These subjects will receive neoadjuvant INCMGA00012 +
INCAGN01876 + SRS. All other subjects enrolled on Cohort B (N=8) are treated with neoadjvuant
INCMGA00012 + INCAGN01876 (without SRS).
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).
2. Glial tumor must be recurrent and progressive following prior first-line radiation
therapy (prior dose must have been 40-75 Gy and may have been either photon or proton
radiation), defined as meeting any one of the following criteria:
- New contrast-enhancing lesion outside the 80% isodose line of the original
radiation field as determined by the treating investigator
- Surgically proven recurrence of tumor
- Per RANO criteria, an increase by >=25% of the sum of the products of
perpendicular diameters between the smallest tumor measurements previously
obtained by the subject following radiation and a scan at least 12 weeks from
completion of radiation therapy (on stable or increasing doses of
corticosteroids) AND MRI performed at the University of Pennsylvania with
advanced imaging (dynamic contrast-enhanced [DCE] and dynamic susceptibility
contrast [DSC] perfusion imaging for perfusion and permeability data) that is
favored by the University of Pennsylvania Brain Tumor Board, based on these
advanced imaging metrics, to represent true tumor progression rather than
pseudoprogression
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 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:
- 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. Patients must be maintained on a systemic corticosteroid dose of 2mg 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. Adequate hematologic parameters, including:
- Absolute neutrophil count >= 1,500/ul
- Absolute lymphocyte count >= 600/uL
- Platelets >= 100,000/ul and without a platelet transfusion within 4 weeks prior
to initiating protocol therapy
- Hemoglobin >= 9 g/dl and without a packed red blood cell transfusion within 4
weeks prior to initiating protocol therapy
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.
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. Prior immune checkpoint inhibitor therapy (targeted against PD-1, PD-L1, PD-L2,
CTLA-4, e.g.) or prior immune costimulatory agonist therapy (targeted against
GITR, OX40, CD137, e.g.)
11. Known active hepatitis B virus (HBsAg reactive) or active hepatitis C virus (HCV
RNA detectable by PCR)
12. Human immunodeficiency virus (HIV)-positive patients on antiretroviral therapy
13. 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.
14. 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.
15. 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
16. Known hypersensitivity to another monoclonal antibody that cannot be controlled
with standard measures (e.g., antihistamines and corticosteroids)
17. Prisoners or subjects who are involuntarily incarcerated
18. Subjects who are compulsorily detained for treatment of either a psychiatric or
physical (eg, infectious disease) illness
19. Pregnant women are excluded
20. 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.
21. Participant must not be simultaneously enrolled in any interventional clinical
trial