Laser Interstitial Thermotherapy (LITT) Combined With Checkpoint Inhibitor for Recurrent GBM (RGBM)

Inclusion Criteria:

• Histopathologically proven diagnosis of glioblastoma or gliosarcoma prior toregistration by pathology report;

• The tumor must be confined to the supratentorial compartment

• The Formaldehyde Fixed-Paraffin Embedded tumor tissue block must be available to besent for retrospective central pathology review after registration).

• History/physical examination within 7 days prior to registration

• Karnofsky performance status ≥ 60 within 7 days prior to registration

• Adequate Organ Function Laboratory Values

• Absolute neutrophil count (ANC) ≥1,500/mcL

• Platelets ≥100,000/mcL

• Hemoglobin ≥9.0 g/gL or ≥5.6 mmol/L, without recent transfusion

• Creatine ≤1.7 x upper limit of normal (ULN) or Measure or Calculated creatinineclearance ≥ 60.0mL/min for subject with creatinine levels > 1.5 X institutionalULN (GFR can also be used in place of creatinine or CrCl)

• Total bilirubin ≤ 1.5 x ULN or Direct bilirubin ≤ ULN for subjects with totalbilirubin levels > 1.5 x ULN

• AST (SGOT) and ALT (SGPT) ≤ 2.5 x ULN or ≤ 5 x ULN for subjects with livermetastases

• International Normalized Ratio (INR) or Prothrombin Time (PT) ≤ 1.5 x ULNunless subject is receiving anticoagulant therapy as long as PT or PTT iswithin therapeutic range of intended use of anticoagulants

• Activated Partial Thromboplastin Time (aPTT) ≤ 1.5 x ULN unless subject isreceiving anticoagulant therapy as long as PT or PTT is within therapeuticrange of intended use of anticoagulants

• Adequate hematologic function based on complete blood count (CBC)/differentialwithin 7 days prior to registration defined as follows:

• Absolute neutrophil count ≥ 1,500 cells/mm3;

• Platelet count ≥ 100,000 cells/mm3

• Hgb > 9 g/dL (can be achieved with transfusion)

• Adequate renal function within 7 days prior to registration defined as follows:

• Blood Urea Nitrogen (BUN) ≤ 30 mg/dl and

• Serum creatinine ≤ 1.7 mg/dl

• Adequate hepatic function within 7 days prior to registration defined as follows:

• Total bilirubin (except patients with Gilbert's Syndrome, who are eligible forthe study but exempt from the total bilirubin eligibility criterion) ≤ 2.0mg/dl and

• Alanine Aminotransferase (ALT) and Aspartate Amino Transferase (AST) ≤ 2.5 xULN

• The patient must have completed chemoradiation with Radiotherapy and Temozolomide ofthe primary tumor according to standards of care

• The treating physician expects that the patient will not require more thanphysiologic replacement dose of steroids defined as 4 mg of dexamethasone per day orits equivalent.

• Patients must have received no more than 3 prior therapies for Recurrent High GradeGlioma

• Subjects must have the ability to understand and the willingness to sign a writteninformed consent document.

• Female subject of childbearing potential should have a negative urine or serumpregnancy test within 72 hours prior to receiving the first dose of studymedication. If the urine test is positive or cannot be confirmed as negative, aserum pregnancy test will be required.

• Female subjects of childbearing potential should be willing to use 2 methods ofbirth control or be surgically sterile, or abstain from heterosexual activity forthe course of the study through 120 days after the last dose of study medication.Subjects of childbearing potential are those who have not been surgically sterilizedor have not been free from menses for > 1 year.

• Male subjects should agree to use an adequate method of contraception starting withthe first dose of study therapy through 120 days after the last dose of studytherapy.

• Tumor diameter in the plane perpendicular to LITT trajectory must be ≤ 6.0 cm indiameter

• It must be the surgeon's expectation that ≥ 90 of the tumor can be treated with LITTto the yellow thermal damage threshold (TdT) line (ie, 43 degrees for 2 min)

• Tumor must be Unifocal & Unilateral-Two enhancing nodules within the same FLAIRhyperintense region are still eligible; 1-2 secondary enhancing or non-enhancinglesions may be present as long as they have been radiologically stable for greaterthan or equal to 3 months.

Exclusion Criteria:

• Use of an immunotherapy such as a vaccine therapy, dendritic cell vaccine orintracavitary or convectional enhanced delivery of therapy in the past

• Prior invasive malignancy (except non-melanomatous skin cancer) unless disease freefor a minimum of 3 years

• Severe, active co-morbidity defined as follows:

• Unstable angina within the last 6 months prior to registration

• Transmural myocardial infarction within the last 6 months prior to registration

• Evidence of recent myocardial infarction or ischemia by the findings of S-Televations of ≥ 2 mm using the analysis of an EKG performed within 7 days priorto registration

• New York Heart Association grade II or greater congestive heart failurerequiring hospitalization within 12 months prior to registration

• History of stroke, cerebral vascular accident (CVA) or transient ischemicattack within 6 months prior to registration

• Serious and inadequately controlled cardiac arrhythmia

• Significant vascular disease (e.g., aortic aneurysm, history of aorticdissection) or clinically significant peripheral vascular disease

• Evidence of bleeding diathesis or coagulopathy

• Serious or non-healing wound, ulcer, or bone fracture or history of abdominalfistula, gastrointestinal perforation, intra-abdominal abscess major surgicalprocedure, open biopsy, or significant traumatic injury within 28 days prior toregistration, with the exception of the craniotomy for tumor resection.

• Known history of Tuberculosis

• Acute bacterial or fungal infection requiring intravenous antibiotics at thetime of registration

• Chronic obstructive pulmonary disease exacerbation or other respiratory illnessrequiring hospitalization or precluding study therapy at the time ofregistration

• Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects

• Acquired immune deficiency syndrome (AIDS) based upon current Center forDisease Control and Prevention (CDC) definition; note, however, that HIVtesting is not required for entry into this protocol. The need to excludepatients with AIDS from this protocol is necessary because the treatmentsinvolved in this protocol may be significantly immunosuppressive and worsen thepatient's HIV symptoms.

• Active connective tissue disorders, such as lupus or scleroderma, which in theopinion of the treating physician may put the patient at high risk forimmunologic toxicity.

• History of (non-infectious) pneumonitis that required steroids, evidence ofinterstitial lung disease or active, non-infectious pneumonitis

• Patients with active autoimmune disease or history of autoimmune disease thatmight recur, which may affect vital organ function or require immunesuppressive treatment including systemic corticosteroids, should be excluded.These include but are not limited to patients with a history of immune relatedneurologic disease, multiple sclerosis, autoimmune (demyelinating) neuropathy,Guillain-Barre syndrome or Chronic Inflammatory Demyelinating Polyneuropathy,myasthenia gravis; systemic autoimmune disease such as Systemic LupusErythematosus, connective tissue diseases, scleroderma, inflammatory boweldisease (IBD), Crohn's, ulcerative colitis, hepatitis; and patients with ahistory of toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome, orphospholipid syndrome should be excluded because of the risk of recurrence orexacerbation of disease.

• Of note, patients with vitiligo, endocrine deficiencies including thyroiditismanaged with replacement hormones including physiologic corticosteroids areeligible. Patients with rheumatoid arthritis and other arthropathies, Sjögren'ssyndrome and psoriasis controlled with topical medication and patients withpositive serology, such as antinuclear antibodies (ANA), anti-thyroidantibodies should be evaluated for the presence of target organ involvement andpotential need for systemic treatment but should otherwise be eligible.

• Any other major medical illnesses or psychiatric impairments that in theinvestigator's opinion will prevent administration or completion of protocoltherapy.

• Has a known additional malignancy that is progressing or requires activetreatment. Exceptions include basal cell carcinoma of the skin or squamous cellcarcinoma of the skin that has undergone potentially curative therapy or insitu cervical cancer.

• Has known active central nervous system (CNS) metastases and/or carcinomatousmeningitis. Subjects with previously treated brain metastases may participateprovided they are stable (without evidence of progression by imaging for atleast four weeks prior to the first dose of trial treatment and any neurologicsymptoms have returned to baseline), have no evidence of new or enlarging brainmetastases, and are not using steroids for at least 7 days prior to trialtreatment. This exception does not include carcinomatous meningitis which isexcluded regardless of clinical stability.

• Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids orimmunosuppressive drugs). Replacement therapy (eg, thyroxine, insulin, orphysiologic corticosteroid replacement therapy for adrenal or pituitaryinsufficiency, etc.) is not considered a form of systemic treatment.

• Has known history of, or any evidence of active, non-infectious pneumonitis.

• Has an active infection requiring systemic therapy?

• Has a history or current evidence of any condition, therapy, or laboratoryabnormality that might confound the results of the trial, interfere with thesubject's participation for the full duration of the trial, or is not in thebest interest of the subject to participate, in the opinion of the treatinginvestigator.

• Has known psychiatric or substance abuse disorders that would interfere withcooperation with the requirements of the trial

• Is pregnant or breastfeeding, or expecting to conceive or father childrenwithin the projected duration of the trial, starting with the pre-screening orscreening visit through 120 days after the last dose of trial treatment.

• Has received prior therapy with an anti-Programmed Death 1 (PD-1), anti-Programmed Death-ligand 1 (PD-L1), or anti- Programmed Death-ligand 1 (PD-L2)agent.

• Has a known history of Human Immunodeficiency Virus (HIV) (HIV ½ antibodies).

• Has known active Hepatitis B (e.g., HbsAg reactive) or Hepatitis C (eg, HCV RNA [qualitative] is detected).

• Has received a live attenuated vaccine within 30 days of planned start of studytherapy.

• Note: Seasonal influenza vaccines for injection are generally inactivatedflu vaccines and are allowed; however Intranasal influenza vaccines (e.g.,Flu-Mist®) are live attenuated vaccines, and are not allowed.

• Patient must have < 1.0 cm midline shift pre-operative

• History of severe hypersensitivity reaction to any monoclonal antibody includingpembrolizumab.

• Patients who cannot safely undergo MRI due to non-MRI compatible pacemaker, or otherreason.

• Patients who have tumors for which the Gd-enhancing mass appears to be covered ≤ 90%using 2 catheters and assuming a 3.0 cm diameter based on pre-operative planning areunlikely to have adequate LITT and thus ineligible for the study.