Inclusion Criteria. 1. Signed and dated informed consent.
2. Male or female participants aged ≥ 12 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. Lansky >70 at trial entry
for patients less than 16.
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 x 10°9/L
with absolute neutrophil count (ANC) ≥ 1.5 x 10°9/L, lymphocyte count ≥ 0.5 x
10°9/L, platelet count. ≥ 100 x 10°/L, and Hgb ≥ 9 g/ dL (in absence of blood transfusion).
9. Adequate hepatic function defined by a total bilirubin level ≤ 1.5 x ULN, an AST
level ≤ 2.5 x ULN, and an ALT level ≤ 2.5 x 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 participant with creatinine levels > 1.5 X
institutional ULN. 11. Female participant of childbearing potential should have a negative serum pregnancy
test within 14 days (+/-2 working days) of study registration.
12. Female participants 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.
Participants of childbearing potential are those who have not been surgically
sterilized or have not been free from menses for > 1 year.
13. Male participants 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. For the surgical expansion group (Group 2): there must be at least 1 cm2 of
contrast-enhancing disease that is considered resectable by the neurosurgeon.
Exclusion Criteria. 1. Has received prior therapy with Gliadel or bevacizumab.
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 cancer directed
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 to monoclonal antibodies, 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 0.
1. Note: Participants with ≤ Grade 2 neuropathy are an exception to this criterion
and may qualify for the study.
2. Note: If participant 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 study registration,
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 within
the last three months prior to study registration -.
10. Has a known additional malignancy that is progressing or requires active treatment.
Exceptions include but are 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 cerebri, extracranial disease, or tumor localized primarily to
the brainstem or spinal cord.
12. Brain midline shift greater than 0.5 cm or pending herniation seen on baseline MRI
ABTI.
13. Tumors larger than 5 cm at 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. Participants
with vitiligo or resolved childhood asthma/atopy would be an exception to this rule.
Participants that require intermittent use of bronchodilators or local steroid
injections would not be excluded from the study. Participants 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 participant's participation, assessment of experimental
treatment toxicity or increase the participant'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
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.
18. Has known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial.
19. Is pregnant, 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 anticoagulants or antiplatelet therapy that cannot be held.
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. Participant 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.
