Inclusion Criteria. 1. Signed and dated informed consent.
2. Male or female subjects aged ≥ 18 years on the day of signing informed consent.
3. Has histologically confirmed supratentorial World Health Organization grade 4
recurrent astrocytoma to include recurrent glioblastoma (IDH-wildtype grade 4
astrocytoma) recurrent IDH-mutant grade 4 astrocytoma, and recurrent gliosarcoma
with any prior number of recurrences, and who have received prior radiation and
temozolomide therapy. Participants will be eligible if the original histology was
lower-grade glioma grade 2 or 3 and a subsequent histological diagnosis of recurrent
glioblastoma or IDH-mutant grade 4 astrocytoma is made.
4. Karnofsky Performance Score (KPS) of >70 at trial entry.
5. Must be at least 12 weeks from receiving conformal radiation, unless RANO criteria
for early progression are met.
6. A baseline brain MRI with Advance Brain Tumor Imaging (ABTI) must be obtained no
more than 30 days prior to study registration. 7. Patients having undergone recent surgery are eligible so long as they are at least 3
weeks from resection or at least 1 week from stereotactic biopsy and recovered from
any operative or perioperative complications. Patients with non-measurable tumor
after resection will NOT be excluded; if they do not experience tumor progression
while on trial, response will be labeled as "stable disease" (and not as "complete
response").
8. Adequate hematological function defined by white blood cell (WBC) count ≥ 3 × 109 /L
with absolute neutrophil count (ANC) ≥ 1.5 × 109 /L, lymphocyte count ≥ 0.5 × 109
/L, platelet count ≥ 100 × 109 /L, and Hgb ≥ 9 g/ dL (in absence of blood
transfusion).
9. Adequate hepatic function defined by a total bilirubin level ≤ 1.5 × ULN, an AST
level ≤ 2.5 × ULN, and an ALT level ≤ 2.5 × ULN, and INR ≤ 1.5. 10. Adequate renal function defined creatinine ≤1.5 X upper limit of normal (ULN) OR
creatinine clearance ≥60 mL/min for subject with creatinine levels > 1.5 X
institutional ULN. 11. Female subject of childbearing potential should have a negative serum pregnancy test
within 14 days (+/-2 working days) of study registration.
12. Female subjects of childbearing potential should be willing to use 2 methods of
birth control or be surgically sterile, or abstain from heterosexual activity for
the course of the study and for 3 months after the last dose of study therapy.
Subjects of childbearing potential are those who have not been surgically sterilized
or have not been free from menses for > 1 year.
13. Male subjects should agree to use 2 methods of highly effective contraception
starting with the first dose of study therapy and for 3 months after the last dose
of study therapy.
14. Have evaluable or measurable disease of at least 1cm2 of contrast-enhancing disease
that is considered resectable by the neurosurgeon.
15. Have a tumor that is judged to be surgically resectable by the treating
neurosurgeon.
Exclusion Criteria.The subject must be excluded from participating in the trial if the subject:
1. Has been treated previously with bevacizumab or Gliadel® wafers.
2. Has received prior interstitial brachytherapy, implanted chemotherapy, or
therapeutics delivered by local injection or convection enhanced delivery.
3. Is currently participating in or has participated in a study of an investigational
agent or using an investigational device 4 weeks since last dose of agent
administration, or is planning to continue or start treatment with Optune® during
participation in this trial.
4. Has known severe hypersensitivity reactions to monoclonal antibodies (Grade ≥ 3
NCI-CTCAE v5.0), any history of anaphylaxis, or recent, within 5 months, history of
uncontrolled asthma.
5. Has a known history of Human Immunodeficiency Virus (HIV) (positive HIV 1/2
antibodies); HTLV1 and/or HTLV2; active Hepatitis B (e.g., HBsAg reactive) or
Hepatitis C (e.g., HCV RNA [qualitative] is detected). Patients with prior HBV
vaccination (anti-HBs positive, HBsAg negative, anti-HBc negative) will NOT be
excluded.
6. Has a diagnosis of immunodeficiency or is receiving any immunosuppressive therapy
within 7 days prior to study registration.
7. Has had prior chemotherapy or targeted small molecule therapy within 2 weeks prior
to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from
adverse events due to a previously administered agent.
1. Note: Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and
may qualify for the study.
2. Note: If subject received major surgery (other than craniotomy), they must have
recovered adequately from the toxicity and/or complications from the
intervention prior to starting therapy.
8. Has had prior radiation therapy less than 12 weeks prior to enrollment; unless RANO
criteria for early progression are met.
9. Has had prior therapy with any antibody/drug targeting T cell co-regulatory proteins
(immune checkpoints) such as anti-PD-1, anti-PD-L1, or anti-CTLA-4 antibody. 10. Has a known additional malignancy that is progressing or requires active treatment.
Exceptions include superficial tumors considered adequately treated locally with
curative intent, including but not limited to basal cell carcinoma of the skin,
squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone
potentially curative therapy. Any exceptions must be discussed with the protocol PI.
11. Has known gliomatous meningitis or extracranial disease, or tumor localized
primarily to the brainstem or spinal cord. 12. Midline shift greater than 0.5 cm or pending herniation.
13. Tumors larger than 5 cm in its greatest diameter.
14. Has an active autoimmune disease requiring systemic treatment within the past 3
months or a documented history of clinically severe autoimmune disease, or a
syndrome that requires systemic steroids or immunosuppressive agents. Subjects with
vitiligo or resolved childhood asthma/atopy would be an exception to this rule.
Subjects that require intermittent use of bronchodilators or local steroid
injections would not be excluded from the study. Subjects with hypothyroidism stable
on hormone replacement or Sjogren's syndrome will not be excluded from the study.
15. Has evidence of interstitial lung disease or active, non-infectious pneumonitis.
16. Has an active infection requiring systemic therapy or that in the opinion of the PI
may interfere with the subject's participation, assessment of experimental treatment
toxicity or increase the subject's risk of side effects.
17. Has a history or current evidence of any condition, therapy, or laboratory
abnormality that might confound the results of the trial, interfere with the
subject's participation for the full duration of the trial, or is not in the best
interest of the subject to participate in the opinion of the treating investigator.
18. Has known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial.
19. Is pregnant or breastfeeding, or expecting to conceive or father children within the
projected duration of the trial, starting with the screening visit and through 3
months after last dose of the study treatment.
20. Has received a live vaccine within 30 days prior to the first dose of trial
treatment.
21. Has a contraindication for undergoing MRIs.
22. Has evidence of bleeding diathesis or coagulopathy.
23. Is on full dose anticoagulation or antiplatelet therapy.
24. Has significant hemorrhage on baseline MRI ABTI defined as >1 cm diameter of acute
blood.
25. Has received any organ transplantation, including allogeneic stem-cell
transplantation, but with the exception of transplants that do not require
immunosuppression (e.g., corneal transplant, hair transplant).
26. Has multifocal disease. Subject has multifocal GBM, defined as discrete sites of
contrast enhancing disease without contiguous T2/FLAIR abnormality that require
distinct radiotherapy ports. Satellite lesions that are associated with a contiguous
area of T2/FLAIR abnormality as the main lesion(s) and that are encompassed within
the same radiotherapy port as the main lesion(s) are permitted.
