Laser Interstitial Thermal Therapy and Pembrolizumab in Treating Patients with Recurrent Glioblastoma

Inclusion Criteria

• Histopathologically proven diagnosis of glioblastoma or gliosarcoma prior to registration by pathology report
• The tumor must be confined to the supratentorial compartment
• The formalin-fixed paraffin-embedded (FFPE) tumor tissue block or slides must be available to be sent 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
• Absolute neutrophil count (ANC) >= 1,500/mcL (within 7 days of registration)
• Platelets >= 100,000/mcL (within 7 days of registration)
• Hemoglobin >= 9.0 g/gL or >= 5.6 mmol/L, without recent transfusion (within 7 days of registration)
• Creatine =< 1.7 x upper limit of normal (ULN) OR measure or calculated creatinine clearance (glomerular filtration rate [GFR] can also be used in place of creatinine or creatinine clearance [CrCl]) >= 70.0 mL/min for subject with creatinine levels > 1.5 X institutional ULN (within 7 days of registration) * Creatinine clearance should be calculated per institutional standard
• Total bilirubin =< 1.5 x ULN OR direct bilirubin =< ULN for subjects with total bilirubin levels > 1.5 x ULN (within 7 days of registration)
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x ULN OR =< 5 x ULN for subjects with liver metastases (within 7 days of registration)
• International normalized ratio (INR) or prothrombin time (PT) =< 1.5 x ULN unless subject is receiving anticoagulant therapy as long as PT or partial prothrombin time (PTT) is within therapeutic range of intended use of anticoagulants (within 7 days of registration)
• Activated partial thromboplastin time (aPTT) =< 1.5 x ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants (within 7 days of registration)
• The patient must have completed chemoradiation with radiation therapy and temozolomide of the primary tumor according to standards of care
• The treating physician expects that the patient will not require more than physiologic replacement dose of steroids defined as4 mg of dexamethasone per day or its equivalent.
• Patients must have received no more than 3 prior therapies for recurrent high grade glioma (rHGG)
• Subjects must have the ability to understand and the willingness to sign a written informed consent document
• Female subject of childbearing potential should have a negative urine or serum pregnancy test within 72 hours prior to receiving the first dose of study medication; if the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
• Female subjects of childbearing potential must be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the 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 sterilized or have not been free from menses for > 1 year
• Male subjects must agree to use an adequate method of contraception for the duration of the study through 120 days after the last dose of study therapy
• Tumor diameter in the plane perpendicular to LITT trajectory must be =< 6.0 cm in diameter
• It must be the surgeon’s expectation that >= 68 % of the tumor can be treated with LITT to the yellow TdT line (i.e. 43 degrees for 2 min)
• It is permissible to plan combined LITT followed by immediate post LITT tumor debulking in the same operation for tumors at the discretion of the surgeon with goal of avoiding post-LITT swelling and ICP issues as long as >= 1 cm^3 of tumor is left as “index lesion”
• Active tumor must be Unifocal & Unilateral. Two enhancing nodules within the same fluid attenuated inversion recovery (FLAIR) hyperintense region are still eligible; 1-2 secondary enhancing or non-enhancing lesions may be present as long as they have been radiologically stable for >= 3 mo)
• Age >= 18 for two reasons: * *No dosing or adverse event data are currently available on the use of pembrolizumab in subjects’ =< 18 years of age. *GBM and GS in children have much better prognosis than adults, children, are excluded from this study.

Exclusion Criteria

• Prior use of an immunotherapy such as (but not limited to) a vaccine therapy, dendritic cell vaccine or intracavitary or convectional enhanced delivery of therapy
• Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free for a minimum of 3 years
• Patients with uncontrolled intercurrent illness including, but not limited to; * Ongoing or active infection * Symptomatic congestive heart failure * Unstable angina pectoris * 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-T elevations of >= 2 mm using the analysis of an electrocardiogram (EKG) performed within 7 days prior to registration * New York Heart Association grade II or greater congestive heart failure requiring hospitalization within 12 months prior to registration * History of stroke, cerebral vascular accident (CVA) or transient ischemic attack within 6 months prior to registration * Serious and inadequately controlled cardiac arrhythmia * Significant vascular disease (e.g., aortic aneurysm, history of aortic dissection) or clinically significant peripheral vascular disease * Known history of tuberculosis (TB) * Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration * Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy at the time of registration * Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects; note, however, that laboratory tests for additional liver function tests not listed and coagulation parameters are not required for entry into this protocol * Active connective tissue disorders, such as lupus or scleroderma, which in the opinion of the treating physician may put the patient at high risk for immunologic toxicity * Any other major medical illnesses or psychiatric impairments that in the investigator’s opinion will prevent administration or completion of protocol therapy * Has known active hepatitis B (e.g., hepatitis body surface antigen [HbsAg] reactive) or hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is detected)
• Has received a live vaccine within 30 days of planned start of study therapy. * Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed as are the current covid 19 vaccines, which are ribonucleic acid (RNA) vaccines. However intranasal influenza vaccines (e.g., Flu- Mist), which are live attenuated vaccines, are not allowed within 30 days of planned start of study therapy.
• Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent
• Acquired immune deficiency syndrome (AIDS) based upon current Centers for Disease Control and Prevention (CDC) definition; note, however, that human immunodeficiency virus (HIV) testing is not required for entry into this protocol; the need to exclude patients with AIDS from this protocol is necessary because the treatments involved in this protocol may be significantly immunosuppressive and worsen the patient’s HIV symptoms
• Has a known history of human immunodeficiency virus (HIV)(HIV 1/2 antibodies); HIV-positive subjects are ineligible because of the potential and unknown pharmacokinetic interactions
• Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment * Patients who are pregnant or breastfeeding will be excluded from the study due to the potential teratogenic or abortifacient effects that may result from pembrolizumab or LITT therapy; because there is an unknown, but potential risk for adverse events in nursing infants secondary to treatment of the mother, breastfeeding should be discontinued; these potential risks may also apply to other agents used in this study
• Patient has active infection requiring system therapy
• Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs); 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
• Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment; this exception does not include carcinomatous meningitis which is excluded regardless of clinical stability
• Has a known additional malignancy that is progressing or requires active treatment; exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer
• Patients with active autoimmune disease or history of autoimmune disease that might recur, which may affect vital organ function or require immune suppressive treatment including systemic corticosteroids, should be excluded; these include but are not limited to patients with a history of immune related neurologic disease, multiple sclerosis, autoimmune (demyelinating) neuropathy, Guillain-Barre syndrome or chronic inflammatory demyelinating polyneuropathy (CIDP), myasthenia gravis; systemic autoimmune disease such as systemic lupus erythematosus (SLE), connective tissue diseases, scleroderma, inflammatory bowel disease (IBD), Crohn’s, ulcerative colitis, hepatitis; and patients with a history of toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome, or phospholipid syndrome should be excluded * Of note, patients with vitiligo, endocrine deficiencies including thyroiditis managed with replacement hormones including physiologic corticosteroids are eligible; patients with rheumatoid arthritis and other arthropathies, Sjogren’s syndrome and psoriasis controlled with topical medication and patients with positive serology, such as antinuclear antibodies (ANA), anti-thyroid antibodies should be evaluated for the presence of target organ involvement and potential need for systemic treatment but should otherwise be eligible
• History of or active (non-infectious) pneumonitis that required steroids, evidence of interstitial lung disease or active, non-infectious pneumonitis
• Serious or non-healing wound, ulcer, or bone fracture or history of abdominal fistula, gastrointestinal perforation, intra-abdominal abscess major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to registration, with the exception of the craniotomy for tumor resection
• Evidence of bleeding diathesis or coagulopathy
• Patient must have < 1.0 cm midline shift pre-operatively
• History of severe hypersensitivity reaction to any monoclonal antibody including pembrolizumab
• Patients who cannot safely undergo MRI due to non-MRI compatible pacemaker, or other reason
• 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 are unlikely to have adequate LITT and thus ineligible for the study