INCLUSION CRITERIA:
1.1 Histologically confirmed World Health Organization (WHO) Grade IV glioblastoma.
Patients with original histology of low-grade glioma and subsequent histological
diagnosis of GBM are eligible. Other WHO grade IV glial neoplasms such as gliosarcoma are
NOT eligible 1.2 Willing and able to provide written informed consent/assent for the
trial 1.3 ≥ 18 years of age on day of signing informed consent 1.4 Karnofsky performance
status (KPS) ≥ 70 (Appendix A) 1.5 Unequivocal evidence for tumor progression by MRI scan
1.6 MRI within 14 days prior to start of study therapy (with vascular imaging when
possible). Corticosteroid dose must be stable or decreasing for at least 5 days prior to
the scan. If steroids are added or the steroid dose is increased between the date of the
screening MRI scan and Day 1 dose, a new baseline scan is required 1.7 Measurable disease
as per Response Assessment in Neuro-Oncology (RANO) criteria 1.8 Cohort A patients must
be at their first or second relapse; Cohort B patients must have progressed on no more
than one prior bevacizumab-containing regimen (may have received any # of
non-bevacizumab-containing regimens). Patients who were treated with prior bevacizumab
but did not progress or experienced significant toxicity, are not eligible 1.9 Previous
first line therapy with at least radiotherapy utilizing standard dosing of CNS radiation
- - for either high-grade or low-grade glial neoplasm 1.10 The following time periods must
have elapsed from projected Day 1 dose:
1.
At least 3 weeks from prior surgical resection. 2. At least 1 week from stereotactic biopsy. 3. At least 6 months from completion of prior radiotherapy (patient may still be
eligible if s/he has a new area of enhancement outside the 80% isodose line of the
original radiation field)
4. At least 4 weeks from cytotoxic therapy (at least 23 days for temozolomide, and at
least 6 weeks from nitrosoureas)
5. At least 1 week from cancer vaccines. 6. At least 6 weeks from antibodies. 7. At least 4 weeks (or 5 half-lives, whichever is shorter) from other anti-tumor
therapies (not including tumor treating fields or cancer vaccines); at least 1 week
from NovoTTF (Optune) or other tumor treating fields and cancer vaccines. 8. Cohort B patients only: Day 1 of bevacizumab on-study must be at least 3 weeks from
last dose of prior course of Avastin/bevacizumab.
1.11 All clinically significant toxic effects of prior therapy must have recovered to
grade 0 or 1 or pre-treatment baseline (excluding alopecia, laboratory values listed per
inclusion criteria, and lymphopenia) 1.12 Adequate organ function as defined below
(screening labs performed within 14 days of treatment initiation): 1.12.1 Hematologic:
Absolute neutrophil count (ANC) ≥1,500 /uL; Platelets ≥100,000 / uL; Hemoglobin ≥9 g/dL
or ≥5.6 mmol/L 1.12.2 Renal: Serum creatinine ≤1.5 X institutional upper limit of normal
(ULN) OR Measured or calculated creatinine clearance (GFR can also be used in place of
creatinine or CrCl) ≥60 mL/min for participant with creatinine levels > 1.5 X
institutional ULN 1.12.3 Hepatic Serum total bilirubin ≤ 1.5 X institutional ULN OR
Direct bilirubin ≤ institutional ULN for participants with total bilirubin levels > 1.5 X
institutional ULN; aspartate aminotransferase (AST; SGOT) and alanine aminotransferase
(ALT; SGPT) ≤ 2.5 X institutional ULN (OR ≤ 5 X institutional ULN for participants with
Gilberts syndrome) 1.12.4 Coagulation: International Normalized Ratio (INR) or
Prothrombin Time (PT) Activated Partial Thromboplastin Time (aPTT) ≤1.5 X institutional
ULN unless participant is receiving anticoagulant therapy as long as PT or aPTT is within
therapeutic range of intended use of anticoagulants 1.12.5 Pulmonary: Resting baseline
oxygen saturation by pulse oximetry ≥92% at rest.1.13 Negative urine or serum pregnancy within 72 hours prior to registration from any
woman of child-bearing potential (WOCBP), defined as any woman physiologically capable of
becoming pregnant. If the urine test is positive or cannot be confirmed as negative, a
serum pregnancy test will be required.
1.14 WOCBP (defined above) must agree to use a highly effective method of contraception
(detailed in protocol eligibility) consistently and correctly as described below during
study treatment and for 120 days after study discontinuation.
1.15 Male participants must agree to use at least one of the methods of contraception
detailed in protocol eligibility starting with the first dose of study therapy through
120 days after the last dose of therapy.
EXCLUSION CRITERIA:
2.1 Recurrent tumor greater than 6 cm in maximum diameter 2.2 Currently participating or
plans to participate in another study of an investigational agent or using an
investigational device.
2.3 Tumor primarily localized to the brainstem or spinal cord. 2.4 Presence of multifocal
tumor, diffuse leptomeningeal or extracranial disease.
NOTE: Not all instances of multifocal disease will exclude a potential patient; only
patients with multifocal sites of active disease will be excluded. (e.g. A patient with a
previously treated lesion that remains stable would not be excluded.)
Medical History/Conditions/Concomitant Medical Illnesses:
2.5 Diagnosis of immunodeficiency. 2.6 History or current evidence of any condition,
therapy, or laboratory abnormality that might confound the results of the trial,
interfere with the participant's participation for the full duration of the trial, or is
not in the best interest of the participant to participate, in the opinion of the
treating investigator. e.g. unstable angina pectoris, cardiac arrhythmia or psychiatric
illness/social situations that would limit compliance with study requirements.
2.7 History of known coagulopathy that increases risk of bleeding or a history of
clinically significant hemorrhage within 12 months of start of study drug.
2.8 Evidence of intratumoral or peritumoral hemorrhage on baseline MRI scan other than
those that are grade ≤ 1 and either post-operative or stable on at least 2 consecutive
MRI scans.
2.9 Gastrointestinal bleeding or any other hemorrhage/bleeding event CTCAE Grade > 3
within 6 months of start of study drug.
2.10 Known additional malignancy that is progressing or requires active treatment within
1 year of start of study drug, except for those treated with surgical therapy only (e.g.
basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ
cervical cancer that has undergone potentially curative therapy).
2.11 Active autoimmune disease requiring systemic treatment in the past 2 years (e.g.
with use of disease modifying agents, corticosteroids or immunosuppressive drugs).
Replacement therapy (eg thyroxine, insulin, or physiologic corticosteroid replacement for
adrenal insufficiency or pituitary/hypothalamic dysfunction, etc.) is not considered a
form of systemic treatment.
2.12 History of (non-infectious) pneumonitis that required steroids or has current
pneumonitis.
2.13 Active infection requiring systemic therapy. 2.14 Known psychiatric or substance
abuse disorders that would interfere with cooperation with the requirements of the trial.
2.15 Known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies) and is
receiving antiretroviral therapy.
2.16 Known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C [e.g., hepatitis C
virus (HCV) RNA (qualitative) is detected].
2.17 History of non-healing wounds or ulcers, or bone refractures within 3 months of
fracture.
2.18 History of arterial thromboembolism within 12 months of start of study drug.
2.19 Clinically significant cardiovascular disease within 12 months of start of study
drug, including myocardial infarction, unstable angina, grade 2 or greater peripheral
vascular disease, cerebrovascular accident, transient ischemic attack, congestive heart
failure, or arrhythmias not controlled by outpatient medication, percutaneous
transluminal coronary angioplasty/stent.
2.20 Known history of active Bacillus Tuberculosis (TB) 2.21 Known hypersensitivity to
any of the study therapy products and/or any of their excipients.
2.22 Is pregnant or breastfeeding, or expecting to conceive within the projected duration
of the trial, starting with the screening visit through 120 days after the last dose of
trial treatment.
Prior Therapy:
2.23 Has received prior interstitial brachytherapy, implanted chemotherapy, stereotactic
radiosurgery or therapeutics delivered by local injection or convection enhanced delivery
(this exclusion applies to any locally administered therapy, including intratumoral
vaccines).
2.24 Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 or with an
agent directed to another stimulatory or co-stimulatory T-cell receptor (eg CTLA-4,
OX-40, CD137). (These therapies target checkpoint proteins on immune cells called
T-Cells.PD-1 = Programmed cell death protein 1. CTLA-4 = cytotoxic
T-lymphocyte-associated protein 4. OX-40
- - AKA CD134 & TNFRSF4 = Tumor necrosis factor
receptor superfamily, member 4) 2.25 Has received prior Vascular endothelial growth
factor (VEGF) or VEGFR inhibitor therapy such as bevacizumab, cediranib, aflibercept,
vandetanib, XL-184 (Cabozantinib), sunitinib, etc. (Cohort A only)
Other Meds:
2.26 Is receiving any form of immunosuppressive therapy (e.g. chronic systemic steroid
therapy exceeding dosage of 10 mg daily of prednisone equivalent) within 7 days prior to
the first dose of study drug.
2.27 Has received systemic immunosuppressive treatments (aside from systemic
corticosteroids as described in protocol) within six months of start of study drug (such
as methotrexate, chloroquine, azathioprine, etc).
2.28 Requires treatment with high dose systemic corticosteroids defined as dexamethasone
> 2 mg/day or bioequivalent for at least 3 consecutive days within 2 weeks of start of
study drug.
- - Inhaled or topical steroids and adrenal replacement doses > 10 mg daily prednisone
equivalents are permitted in the absence of active autoimmune disease.
- - Participants are permitted to use topical, ocular, intra-articular, intranasal, and
inhalational corticosteroids (with minimal systemic absorption).
- - Physiologic replacement doses of systemic corticosteroids are permitted, even if >
10 mg/day prednisone equivalents.
- - A brief course of corticosteroids for prophylaxis or for treatment of non-autoimmune
conditions is permitted.
2.29 Requires therapeutic anticoagulation with warfarin at baseline; patients must be off
warfarin or warfarin-derivative anti-coagulants for at least 7 days prior to starting
study drug. (Therapeutic or prophylactic therapy with low-molecular weight heparin is
allowed.) 2.30 Has received a live vaccine within 30 days prior to the first dose of
study drug.
