This phase II trial compares the effect of GI-102 alone and in combination with pembrolizumab given before surgery in treating patients with IDH wildtype glioblastoma and IDH mutated grade 4 astrocytoma that has come back after a period of improvement (recurrent) or that is growing, spreading, or getting worse (progressive). Glioblastoma is the most common and the most aggressive primary brain tumor in adults. Current standard of care includes surgical resection, radiation and chemotherapy. Treatment is often given before surgery (neoadjuvant therapy) to shrink the tumor and make it easier to remove. Treatment with GI-102, a bispecific fusion protein, may induce changes in body's immune system and may interfere with the ability of tumor cells to grow and spread. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the tumor, and may interfere with the ability of tumor cells to grow and spread. Giving GI-102 alone and in combination with pembrolizumab between neoadjuvant therapy and surgery may be safe, tolerable, and effective in treating patients with recurrent or progressive IDH wildtype glioblastoma and IDH mutated grade 4 astrocytoma.

Inclusion Criteria:

• Age ≥ 18 years

• Disease characteristics

  • Tissue-confirmed progressive or recurrent World Health Organization (WHO) grade IV IDH wildtype glioblastoma (including molecular glioblastoma and gliosarcoma); and IDH mutated WHO grade 4 astrocytoma
  • Candidates for surgical resection

• Measurable or non-measurable disease as defined by Response Assessment in Neuro-Oncology (RANO) 2.0

• Willing to undergo clinically indicated biopsy followed by resection of high-grade glioma at Mayo Clinic in Rochester, Minnesota (MN)

• Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0,1, or 2 and Karnofsky performance status (KPS) ≥ 60

  • NOTE: PS must be assessed (again) ≤ 7 days prior to first dose of study drug

• Hemoglobin ≥ 9.0 g/dL (obtained ≤ 15 days prior to registration)

• Absolute neutrophil count (ANC) ≥ 1500/mm^3 (obtained ≤ 15 days prior to registration)

• Platelet count ≥ 100,000/mm^3 (obtained ≤ 15 days prior to registration)

• Creatinine ≤ 1.5 x upper limit of normal (ULN) OR measured or calculated creatinine clearance (per institutional standard) must be ≥ 45 ml/min (obtained ≤ 15 days prior to registration)

• Total bilirubin ≤ 1.5 x ULN OR direct bilirubin ≤ ULN for patients with total bilirubin levels > 1.5 x ULN (obtained ≤ 15 days prior to registration)

• Aspartate transaminase (AST) AND alanine transaminase (ALT) ≤ 2.5 x ULN (obtained ≤ 15 days prior to registration)

• Amylase and lipase ≤ ULN (obtained ≤ 15 days prior to registration)

• Left ventricular ejection fraction (LVEF) ≥ 50% (obtained ≤ 29 days prior to registration)

• Negative pregnancy test done ≤ 8 days prior to registration, for persons of childbearing potential only

• Persons of childbearing potential (POCBP) or able to father a child must be willing to use adequate contraception starting with first dose through 180 days after last dose

• Provide written informed consent

• Willingness to provide blood specimens for correlative research

• Willingness to provide tissue specimens for correlative research

• Willingness to provide written informed consent for the neuro-oncology biorepository (IRB 12-003458) for archiving of tissue, cerebrospinal fluid (CSF), and/or blood samples collected on this protocol

• Willingness to return to enrolling institution for follow-up (during the active monitoring phase of the study)

Exclusion Criteria:

• Any of the following because this study involves an investigational agent, the genotoxic, mutagenic, and teratogenic effects of which on the developing fetus and newborn are unknown:

  • Pregnant persons
  • Nursing persons
  • Persons of childbearing potential or able to father a child who are unwilling to employ adequate contraception

• Signs or symptoms of life-threatening raised intracranial pressure: as determined by the treating neurosurgeon, including severe headache, nausea, decreasing level of consciousness, precluding 4-7-day delay in scheduling neurosurgery (i.e., immediate surgery is indicated, and patient cannot wait)

• Prior treatment

  • Received bevacizumab (AVASTIN) < 30 days prior to registration

    • NOTE: Bevacizumab is allowed for symptom control during the adjuvant phase of the study

  • Increasing dexamethasone dose prior to registration

    • NOTE: Patients currently on dexamethasone must be on dose ≤ 4 mg/day at time of registration

  • Received chemotherapy < 30 days prior to registration

  • Received a live vaccine < 30 days prior to registration

• Failure to recover from any adverse events related to any of the following therapies received prior to registration:

  • Major surgery < 28 days prior to registration
  • Radiation therapy < 14 days prior to registration

• Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens

• Uncontrolled intercurrent illness including, but not limited to:

  • Ongoing or active infection requiring IV antibiotics
  • Symptomatic congestive heart failure
  • Unstable angina pectoris
  • Cardiac arrhythmia
  • Or psychiatric illness/social situations (e.g., drug addiction) that would limit compliance with study requirements

• Receiving any other investigational agent at the time of registration

• History of myocardial infarction ≤ 6 months, or congestive heart failure requiring use of ongoing maintenance therapy for life-threatening ventricular arrhythmias

• Active autoimmune disease that has required systemic treatment (i.e., with use of disease modifying agents, corticosteroids, or immunosuppressive drugs) ≤ 2 years prior to registration

  • NOTE: Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment

• Concurrent known active hepatitis B (i.e., known positive hepatitis B virus [HBV] surface antigen [HBsAg] reactive) AND known active hepatitis C (i.e., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] detected by polymerase chain reaction [PCR]). Note: No testing for hepatitis B and hepatitis C is required unless mandated by local health authority

  • NOTE: Patients with known hepatitis B OR hepatitis C may be enrolled if they meet the following criteria:

    • Hepatitis B: Patients who are HBsAG positive are eligible if they have received HBV antiviral therapy for at least 4 weeks and have undetectable HBV viral load prior to randomization. Patients should remain on anti-viral therapy throughout the treatment phase of the trial and should follow local guidelines for HBV anti-viral therapy after completing study treatment
    • Hepatitis C: Patients with history of hepatitis C infection are eligible if HCV viral load is undetectable at screening. Patients must have completed curative anti-viral therapy at least 4 weeks prior to registration

• Known history of active TB (Bacillus tuberculosis)

• History of (non-infectious) pneumonitis or interstitial lung disease that required steroids, or current pneumonitis or interstitial lung disease

• Hypersensitivity to pembrolizumab, IL-2, GI-102 or any of its excipients

• History of allogeneic tissue/solid organ transplant