Inclusion Criteria.
- - Signed and dated informed consent.
- - Male or female subjects aged ≥ 18 years on the day of signing informed consent.
- - Has histologically confirmed supratentorial World Health Organization Grade 4
recurrent astrocytoma to include recurrent glioblastoma (IDH-wildtype grade 4
astrocytoma) recurrent IDH-mutant WHO 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 and a subsequent histological diagnosis of recurrent glioblastoma
or variants is made.
- - Karnofsky Performance Score (KPS) of >70 at trial entry.
- - Must be at least 12 weeks from receiving conformal radiation, unless RANO criteria for
early progression are met.
- - A baseline brain MRI must be obtained no more than 30 days prior to study registration.
- - 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").
- - 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).
- - 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.
- - 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.
- - Female subject of childbearing potential should have a negative serum pregnancy test
within 14 days (+/-2 working days) of study registration.
- - 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.
- - 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.
- - For the surgical expansion group (Group 2): Have evaluable or measurable disease of
>1cm2 of contrast enhancing disease at a surgically accessible site at baseline.
- - For the surgical expansion group (Group 2): Have a tumor that is judged to be
surgically resectable by the treating neurosurgeon.
Exclusion Criteria.
- - Has received prior therapy with Gliadel® wafers.
- - Has received prior interstitial brachytherapy, implanted chemotherapy, or therapeutics
delivered by local injection or convection enhanced delivery.
- - 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.
- - Has known severe hypersensitivity to monoclonal antibodies, any history of
anaphylaxis, or recent, within 5 months, history of uncontrolled asthma.
- - 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.
- - Has a diagnosis of immunodeficiency or is receiving any immunosuppressive therapy
within 7 days prior to study registration.
- - Has had prior chemotherapy or targeted small molecule therapy within 2 weeks prior to
study Day 0.
a. Note: Subjects with ≤ Grade 2 neuropathy are an exception to this
criterion and may qualify for the study. b. 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.
- - Has had prior radiation therapy less than 12 weeks prior to study registration, unless
RANO criteria for early progression are met.
- - 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.
- - 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.
- - Has known gliomatous cerebri, extracranial disease, or tumor localized primarily to
the brainstem or spinal cord.
- - Midline shift greater than 0.5 cm or pending herniation.
- - Tumors larger than 5 cm at greatest diameter.
- - 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.
- - Has evidence of interstitial lung disease or active, non-infectious pneumonitis.
- - 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.
- - 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.
- - Has known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial.
- - 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.
- - Has received a live vaccine within 30 days prior to the first dose of trial treatment.
- - Has a contraindication for undergoing MRIs.
- - Has evidence of bleeding diathesis or coagulopathy.
- - Is on full dose anticoagulants or antiplatelet therapy.
- - Has significant hemorrhage on baseline MRI defined as >1 cm diameter of acute blood.
- - 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).
- - 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.
