OPTIMUS PRIME: Safety and Feasibility of OPTune GIO® Integrated With MRI-gUided Laser Ablation Surgery and Pembrolizumab for Recurrent GlIoblastoMa, A randomizEd Trial

Inclusion Criteria:

1. Patient must be at least 18 years of age.

2. Diagnosis of recurrent or progressive glioblastoma, WHO Grade IV, IDH wild-Type orastrocytoma WHO grade IV.

3. Unequivocal evidence of tumor progression by brain MRI scan per RANO criteria.Patients who experience a second disease progression are eligible provided that theyhave not been previously treated with anti-angiogenic agents including bevacizumab (at the exception of bevacizumab radiation necrotic protocol)

4. A diagnostic contrast-enhanced MRI of the brain must be performed preoperatively,within 28 days prior to study enrollment.

5. There must be an interval of at least 12 weeks from the completion of radiationtherapy to study registration unless there is unequivocal evidence for tumorrecurrence per RANO criteria. When the interval is less than 12 weeks but more than 4 weeks from the completion of radiotherapy, the use of perfusion imaging and/or PETscan is allowed to differentiate between unequivocal evidence of tumor recurrenceand pseudoprogression.

6. Karnofsky performance status (KPS) ≥60%.

7. Candidate for MLA based on the size, location, and shape of the recurrent tumor asdetermined by the performing neurosurgeon. Surgical resection/debulking prior to MLAis allowed per standard of care but is not required.

8. Candidate for Optune GIO® therapy.

9. Candidate for pembrolizumab.

10. Adequate bone marrow and organ function as defined below:

11. ANC ≥ 1,500/mcL

12. Platelets ≥ 100,000/mcL

13. Hemoglobin ≥ 9 g/dL or ≥ 5.6 mmol/L (transfusion is allowed)

14. Serum creatinine ≤ 1.5 x IULN OR creatinine clearance by Cockcroft-Gault ≥ 60mL/min for patients with serum creatinine > 1.5 x IULN

15. Serum total bilirubin ≤ 1.5 x IULN OR direct bilirubin ≤ IULN for patients withtotal bilirubin > 1.5 x IULN

16. AST (SGOT) ≤ 3 x IULN

17. ALT (SGPT) ≤ 3 x IULN

18. Participants of childbearing age must use effective contraception: Women of childbearing potential (WOCBP) must be using a highly effective method ofcontraception to avoid pregnancy throughout the study and for at least 24 weeksafter the last dose of study drug to minimize the risk of pregnancy. Prior to studyenrollment, women of childbearing potential must be advised of the importance ofavoiding pregnancy during trial participation and the potential risk factors for anunintentional pregnancy.

19. WOCBP include any woman who has experienced menarche and who has not undergonesuccessful surgical sterilization (hysterectomy, bilateral tubal ligation oroophorectomy) or who is not post-menopausal. Post-menopause is defined as:

• Amenorrhea that has lasted for ≥ 12 consecutive months without anothercause, or
• For women with irregular menstrual periods who are taking hormonereplacement therapy (HRT), a documented serum follicle-stimulating hormone (FSH) level of greater than 35 mIU/mL.

2. Males with female partners of childbearing potential must agree to usephysician-approved contraceptive methods (e.g., abstinence, condoms, vasectomy)throughout the study and should avoid conceiving children for 24 weeksfollowing the last dose of study drug.

3. Ability of the patient to understand and willingness to sign an IRB approved writteninformed consent document

Exclusion Criteria:

1. Prior treatment with any anti-angiogenic agent, including bevacizumab.

2. Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, oranti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (includingipilimumab or any other antibody or drug specifically targeting T-cellco-stimulation or checkpoint pathways).

3. Prior treatment with a monoclonal antibody within 4 weeks prior to the projectedfirst dose of pembrolizumab or has not recovered (i.e. ≤ grade 1 or at baseline)from adverse events due to agents administered more than 4 weeks earlier.

4. Prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2weeks prior to the projected first dose of pembrolizumab or has not recovered (i.e. ≤ grade 1 or at baseline) from adverse events due to a previously administeredagent. Note: patients with ≤ grade 2 neuropathy are an exception to this criterion and mayqualify for the study.

5. Presence of infratentorial lesions, brainstem lesions, or lesions that are less than 5 mm from the hypophysis or cranial nerves.

6. Multifocal gliomas that are bilateral. Patients with unilateral multifocal gliomasmay be eligible if their multifocal disease can be treated effectively and safely ina single MLA procedure. Also note that corpus callosal tumors are eligible even ifthey are bilateral as long as they satisfy the size and shape limits of MLA asdetermined by the performing neurosurgeon.

7. Presence of leptomeningeal metastases beyond the cranial vault. (Focalleptomeningeal enhancement allowable at the discretion of the principalinvestigator).

8. Requires corticosteroids equivalent to > 4mg dexamethasone daily.

9. Recent (within 8 weeks) history of CNS hemorrhage unless the hemorrhage is locatedwithin the tumor that will be removed en total during surgical debulking or ablatedduring MLA.

10. Requires therapeutic doses of anticoagulants unless anticoagulation can be safelydiscontinued per standard practice (e.g. first DVT for which anticoagulation hasbeen at least 3 months and repeat imaging demonstrates resolution of DVT) or an IVCfilter can be used in place of anticoagulation.

11. Received prior local therapy (stereotactic radiosurgery, brachytherapy, orcarmustine wafers) to the proposed area of MLA treatment.

12. Received a live vaccine within 30 days prior to the projected initiation of studytreatment (Optune GIO® for Arm 1 and LITT for Arm 2).

13. Currently receiving any other investigational agents or has participated in a studyof an investigational agent or using an investigational device within 3 weeks of theprojected initiation of study treatment (Optune GIO® for Arm 1 and LITT for Arm 2).

14. Has a diagnosis of immunodeficiency or is receiving any form of immunosuppressivetherapy within 7 days prior to the first dose of trial treatment (with the exceptionof daily dexamethasone ≤ 4 mg).

15. Uncontrolled intercurrent illness including, but not limited to, ongoing or activeinfection, symptomatic congestive heart failure, unstable angina pectoris, cardiacarrhythmia, uncontrolled hypertension, or psychiatric illness/social situations thatwould limit compliance with study requirements.

16. History of active autoimmune disease requiring systemic treatment within the past 2years (i.e. with use of disease modifying agents, corticosteroids, orimmunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, orphysiologic corticosteroid replacement therapy for adrenal or pituitaryinsufficiency, etc.) is not considered a form of systemic treatment.

(Note that prior autoimmune diseases at Grade 1 or 2 per CTCAE v. 4.0 in the last 2years that were deemed related to prior use of immunotherapy, will be allowed underthis protocol, provided that continuation or subsequent resumption of immunotherapy,regardless of whether systemic treatment had been given, did not result in worseningof signs and symptoms of the aforementioned autoimmune diseases)

17. History of (non-infectious) pneumonitis within the past 3 years that requiredsteroids or current pneumonitis.

(Note that patients with a history of pneumonitis in the past 3 years that was notaggravated by immunotherapy or that has clinically resolved or improved and has notrecurred or progressed clinically with subsequent immunotherapy are eligible toparticipate in the study).

18. Pregnant and/or breastfeeding. Patient must have a negative serum or urine pregnancytest within 72 hours of study entry.

19. Known active hepatitis B (e.g., HBsAg reactive) or hepatitis C (e.g., HCV RNA [qualitative] is detected) infection.

20. Known history of active TB (bacillus tuberculosis).

21. Known history of HIV (HIV 1/2 antibodies).