N-803 and PD-L1 t-haNK Combined With Bevacizumab for Recurrent or Progressive Glioblastoma

Exclusion Criteria

• •1. Serious uncontrolled concomitant disease that would contraindicate the use of the investigational drugs used in this study or that would put the subject at high risk for treatment related complications.
• •2. Prior anticancer treatment of glioblastoma with bevacizumab or other anti-angiogenic treatment.
• •3. Current chronic daily treatment (continuous for \> 3 months) with systemic corticosteroids (dose equivalent to or greater than 8 mg/day dexamethasone), excluding inhaled steroids. Short-term steroid use to prevent intravenous (IV) contrast allergic reaction or anaphylaxis in subjects who have known contrast allergies is allowed.
• •4. History of surgery in the past 28 days or with surgical wound not healed.
• •5. History of serious hemorrhage as defined by NCI CTCAE 5.0 grading.
• •6. Evidence of \> Grade 1 CNS hemorrhage on the baseline MRI scan.
• •7. History of recent hemoptysis.
• •8. Subjects receiving therapeutic anticoagulation.
• •9. Subjects with a history or evidence of inherited bleeding diathesis or significant coagulopathy at risk of bleeding.
• •10. Systemic autoimmune disease (eg, lupus erythematosus, rheumatoid arthritis, Addison's disease) requiring any treatment within the last 5 years.
• •11. History of organ transplant requiring immunosuppression.
• •12. History of active inflammatory bowel disease (eg, Crohn's disease, ulcerative colitis).
• •13. Dyspnea at rest due to complications of advanced malignancy or other disease requiring continuous oxygen therapy.
• •14. Body weight ≤ 40 kg at screening.
• •15. Inadequate organ function, evidenced by the following laboratory results:
• •1. Absolute neutrophil count (ANC) \< 1,000 cells/mm3.
• •2. Hemoglobin \< 9 g/dL.
• •3. Platelet count \< 100,000 cells/mm3.
• •4. Total bilirubin \> 2 × upper limit of normal (ULN; unless the subject has documented Gilbert's syndrome).
• •5. Aspartate aminotransferase (AST \[SGOT\]) or alanine aminotransferase (ALT \[SGPT\]) \> 2.5 × ULN (\> 5 × ULN in subjects with liver metastases).
• •6. Alkaline phosphatase (ALP) levels \> 2.5 × ULN (\> 5 × ULN in subjects with liver metastases, or \> 10 × ULN in subjects with bone metastases).
• •7. Serum creatinine \> 2.0 mg/dL or 177 µmol/L.
• •8. Albumin \< 3.0 g/dL.
• •Note: Each study site should use its institutional Upper Limit of Normal (ULN) to determine eligibility.
• •16. Clinically significant (ie, active) cardiovascular disease or myocardial infarction within 6 months prior to first study medication; unstable angina; congestive heart failure of New York Heart Association grade 2 or higher; or serious cardiac arrhythmia. Subjects with uncontrolled hypertension should be medically managed on a stable regimen to control hypertension prior to study entry.
• •17. Current, serious, clinically significant cardiac arrhythmias, defined as the existence of an absolute arrhythmia or ventricular arrhythmias classified as Lown III, IV or V.
• •18. Known hypersensitivity to any component of the study medication(s).
• •19. Participation in an investigational drug study or receiving any investigational treatment within 28 days prior to study treatment. No wash out is necessary for subjects previously receiving Tumor treating field (TTF); TTF will be allowed to continue at the discretion of the Investigator. FDA-authorized drugs for the prevention and treatment of COVID-19 are permitted.
• •20. Assessed by the Investigator to be unable or unwilling to comply with the requirements of the protocol.
• •21. Concurrent participation in any interventional clinical trial.
• •22. Pregnant and nursing women.
• •1. Received any further therapy beyond initial first-line therapy other than surgical resection.
• •2. Prior therapy with bevacizumab for GBM.
• •3. Serious uncontrolled concomitant disease that would contraindicate the use of the investigational drugs used in this study or that would put the participant at high risk for treatment-related complications.
• •4. History of surgery in the past 28 days or with surgical wound not healed.
• •5. History of serious hemorrhage as defined by NCI CTCAE v5.0 grading.
• •6. Evidence of \> grade 1 CNS hemorrhage on the baseline MRI scan.
• •7. History of recent hemoptysis.
• •8. Participants receiving therapeutic anticoagulation or antiplatelet therapy.
• •9. Participants with a history or evidence of inherited bleeding diathesis or significant coagulopathy at risk of bleeding.
• •10. Systemic autoimmune disease (eg, lupus erythematosus, rheumatoid arthritis, Addison's disease) requiring any treatment within the last 5 years.
• •11. History of organ transplant requiring immunosuppression.
• •12. History of active inflammatory bowel disease (eg, Crohn's disease, ulcerative colitis).
• •13. Prior use of anti-PD1 or PD-L1 immunotherapy or cellular therapy targeting PD-1/PD-L1 (or any NK cell therapy) for GBM.
• •14. Prior treatment with TTFields.
• •15. Uncontrolled seizures or neurological instability.
• •16. Should not require high-dose corticosteroids (eg, dexamethasone dose of ≤ 4 mg/day, or lowest dose to manage symptoms).
• •17. Other active malignancy requiring treatment.
• •18. Body weight ≤ 40 kg at screening.
• •19. Inadequate organ function, evidenced by the following laboratory results:
• •1. ANC \< 1,000 cells/mm3.
• •2. Hemoglobin \< 8 g/dL.
• •3. Platelet count \< 100,000 cells/mm3.
• •4. Total bilirubin \> 2 × ULN. For participants with documented Gilbert's syndrome, total bilirubin must be \< 3 × ULN.
• •5. AST (SGOT) or ALT (SGPT) \> 2.5 × ULN (\> 5 × ULN in participants with liver metastases).
• •6. ALP levels \> 2.5 × ULN (\> 5 × ULN in participants with liver metastases, or \> 10 × ULN in participants with bone metastases).
• •7. Serum creatinine \> 2.0 mg/dL or 177 µmol/L. Note: Each study site should use its institutional ULN to determine eligibility.
• •20. Clinically significant (ie, active) cardiovascular disease or myocardial infarction within 6 months prior to first study medication; unstable angina; congestive heart failure of New York Heart Association grade 2 or higher; or serious cardiac arrhythmia. Participants with uncontrolled hypertension should be medically managed on a stable regimen to control hypertension prior to study entry.
• •21. Current, serious, clinically significant cardiac arrhythmias, defined as the existence of an absolute arrhythmia or ventricular arrhythmias classified as Lown III, IV or V.
• •22. Known hypersensitivity to any component of the study medication(s).
• •23. Assessed by the Investigator to be unable or unwilling to comply with the requirements of the protocol, including the use of the TTFields device as required or any psychiatric/social situation that would limit adherence to protocol.
• •24. Participation in an investigational drug study or receiving any investigational treatment within 28 days prior to study treatment or concurrent participation in any interventional clinical trial.
• •25. Pregnant and nursing women.
• •26. Active implanted medical device, a skull defect (such as, missing bone with no replacement) or bullet fragments. Examples of active electronic devices include deep brain stimulators, spinal cord stimulators, vagus nerve stimulators, pacemakers, defibrillators, and programmable shunts.
• •27. Known sensitivity to conductive hydrogels like the gel used on transcutaneous electrical nerve stimulation (TENS) electrodes.
• •28. A tumor located in the lower parts of the brain close to the spinal cord.