Efineptakin Alfa and Pembrolizumab for the Treatment of Recurrent Glioblastoma

Inclusion Criteria:

• Age >= 18 years

• Disease characteristics:

• Tissue-confirmed progressive or recurrent World Health Organization (WHO) GradeIV IDH wildtype glioblastoma (including molecular glioblastoma and gliosarcoma)

• Previously treated with maximum feasible resection or biopsy, radiation, andtemozolomide

• Have an enhancing mass on magnetic resonance imaging (MRI) amenable to resection orbiopsy of the tumor (as determined by the neurosurgeon pre-operatively) andhistological diagnosis of glioblastoma from a prior biopsy or surgery

• Willing to undergo clinically indicated biopsy and/or resection of theirglioblastoma at Mayo Clinic in Rochester, Minnesota (MN).

• Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 or 1 andKarnofsky Performance Scale (KPS) >= 70 NOTE: PS must be assessed (again) within 7days prior to first dose of study drug

• Hemoglobin >= 9.0 g/dL (obtained =< 15 days prior to registration) (withouttransfusion or erythropoietin [EPO] dependency =< 7 days prior to assessment)

• Absolute neutrophil count (ANC) >= 1500/mm^3 (obtained =< 15 days prior toregistration)

• Platelet count >= 100,000/mm^3 (obtained =< 15 days prior to registration)

• Creatinine =< 1.5 x upper limits of normal (ULN) OR measured or calculatedcreatinine 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 totalbilirubin 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)

• Prothrombin time (PT)/international normalized ratio (INR)/activated partialthromboplastin time (aPTT) =< 1.5 x ULN OR if patient is receiving anticoagulanttherapy then INR or aPTT is within target range of therapy (obtained =< 15 daysprior to registration)

• Negative pregnancy test done =< 7 days prior to registration, for persons ofchildbearing potential only (POCBP) Note: If testing done for eligibility is > 72hours prior to first dose, then pregnancy testing must be repeated, and result mustbe negative for patient to receive treatment.

• POCBP or able to father a child must be willing to use adequate contraceptionstarting with first dose through 180 days after last dose

• Provide written informed consent

• Willing to return to enrolling institution for follow-up (during the activemonitoring phase of the study).

• Willing to provide tissue and blood samples for correlative research purposes

Exclusion Criteria:

• Any of the following because this study involves an investigational agent for whichgenotoxic, mutagenic, and teratogenic effects on the developing fetus and newbornare unknown:

• Pregnant persons

• Nursing persons

• Persons of childbearing potential or able to father a child who are unwillingto employ adequate contraception

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

• Prior treatment

• Received bevacizumab (AVASTIN) =< 4 months prior to registration

• Note: Bevacizumab is allowed for symptom control during the adjuvant phaseof the study

• Received a live vaccine =< 30 days prior to registration.

• Requirement for dexamethasone dose of > 2mg/day =< 2 days prior to registration

• Failure to recover from any adverse events related to any of the following therapiesreceived 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 thejudgment of the investigator, would make the patient inappropriate for entry intothis study or interfere significantly with the proper assessment of safety andtoxicity of the prescribed regimens

• Known history of human immunodeficiency virus (HIV) infection

• Uncontrolled intercurrent illness including, but not limited to, ongoing or activeinfection, symptomatic congestive heart failure, unstable angina pectoris, cardiacarrhythmia, or psychiatric illness/social situations (e.g., drug addiction) thatwould limit compliance with study requirements

• Receiving any other investigational agent

• Other active malignancy requiring systemic treatment =< 1 year prior to registration

• History of myocardial infarction =< 6 months prior to registration, or congestiveheart failure requiring use of ongoing maintenance therapy for life-threateningventricular arrhythmias

• Active autoimmune disease that has required systemic treatment (i.e., with use ofdisease modifying agents, corticosteroids, or immunosuppressive drugs) =< 2 yearsprior to registration NOTE: Replacement therapy (e.g., thyroxine, insulin, orphysiologic corticosteroid replacement therapy for adrenal or pituitaryinsufficiency, 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 Cvirus [HCV] ribonucleic acid [RNA] [qualitative] detected by polymerase chainreaction [PCR])

• Note: No testing for Hepatitis B and Hepatitis C is required unless mandated bylocal health authority

• NOTE: Patients with known Hepatitis B OR Hepatitis C may be enrolled if theymeet the following criteria:

• Hepatitis B: Patients who are HBsAG positive are eligible if they havereceived HBV antiviral therapy for at least 4 weeks and have undetectableHBV viral load prior to randomization. Patients should remain onanti-viral therapy throughout the treatment phase of the trial and shouldfollow local guidelines for HBV anti-viral therapy after completing studytreatment

• Hepatitis C: Patients with history of Hepatitis C infection are eligibleif HCV viral load is undetectable at screening. Patients must havecompleted curative anti-viral therapy at least 4 weeks prior toregistration

• Known history of active TB (Bacillus Tuberculosis)

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

• Hypersensitivity to pembrolizumab or any of its excipients

• Received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent within < 12 months prior to registration

• NOTE: If such therapy was given ≥ 12 months prior to registration, patient iseligible

• History of allogenic tissue/solid organ transplant