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

Phase 2 Inclusion Criteria:

1. Age ≥ 18 years.

2. Able to understand and provide a signed informed consent that fulfills the relevantIRB or IEC guidelines.

3. Histologically-confirmed glioblastoma in accordance with the 2021 WHO Classificationof Tumors of the CNS (WHO CNS5) that has progressed after initial therapy ortherapies. The digital image to be provided for confirmation of histology by theSponsor. Gliosarcoma, small cell GBM or other GBM variants, and molecular GBM areallowed.

4. Progressive or recurrent disease will be confirmed (i.e. contrast enhanced magneticresonance imaging (MRI) performed within 3 weeks prior to study treatment per RANOcriteria or diagnostic biopsy).

5. Previous first line treatment with at least radiotherapy and temozolomide. Subjectsmust have been off prior treatment at least 28 days prior to initiation of studytherapy. Subjects must be at least 90 days from completion of radiation to reducethe risk of pseudoprogression being misdiagnosed as progression, unless therecurrence is a new enhancement on MRI outside the radiation treatment field orprogression is confirmed by biopsy.

6. Subjects must have recovered from prior treatment-related toxicities to Grade 2 orless.

7. Life expectancy > 12 weeks.

8. Karnofsky Performance Status ≥ 70.

9. Ability to attend required study visits and return for adequate follow-up, asrequired by this protocol.

10. Agreement to practice effective contraception for female subjects of child-bearingpotential and non-sterile males. Female subjects of child-bearing potential mustagree to use effective contraception for up to 6 months after completion of therapy,and non-sterile male subjects must agree to use a condom for up to 6 months aftertreatment. Effective contraception includes surgical sterilization (eg, vasectomy,tubal ligation), two forms of barrier methods (eg, condom, diaphragm) used withspermicide, intrauterine devices (IUDs), and abstinence.

11. Craniotomy must be adequately healed (at least 28 days between study treatmentinitiation and surgery).

Exclusion Criteria:

1. Serious uncontrolled concomitant disease that would contraindicate the use of theinvestigational drugs used in this study or that would put the subject at high riskfor treatment related complications.

2. Prior anticancer treatment of glioblastoma with bevacizumab or other anti-angiogenictreatment.

3. Current chronic daily treatment (continuous for > 3 months) with systemiccorticosteroids (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 contrastallergies 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 significantcoagulopathy 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, ulcerativecolitis).

13. Dyspnea at rest due to complications of advanced malignancy or other diseaserequiring continuous oxygen therapy.

14. Body weight ≤ 40 kg at screening.

15. Inadequate organ function, evidenced by the following laboratory results:

16. Absolute neutrophil count (ANC) < 1,000 cells/mm3.

17. Hemoglobin < 9 g/dL.

18. Platelet count < 100,000 cells/mm3.

19. Total bilirubin > 2 × upper limit of normal (ULN; unless the subject hasdocumented Gilbert's syndrome).

20. Aspartate aminotransferase (AST [SGOT]) or alanine aminotransferase (ALT [SGPT]) > 2.5 × ULN (> 5 × ULN in subjects with liver metastases).

21. Alkaline phosphatase (ALP) levels > 2.5 × ULN (> 5 × ULN in subjects with livermetastases, or > 10 × ULN in subjects with bone metastases).

22. Serum creatinine > 2.0 mg/dL or 177 µmol/L.

23. Albumin < 3.0 g/dL. Note: Each study site should use its institutional Upper Limit of Normal (ULN) todetermine eligibility.

24. Clinically significant (ie, active) cardiovascular disease or myocardial infarctionwithin 6 months prior to first study medication; unstable angina; congestive heartfailure of New York Heart Association grade 2 or higher; or serious cardiacarrhythmia. Subjects with uncontrolled hypertension should be medically managed on astable regimen to control hypertension prior to study entry.

25. Current, serious, clinically significant cardiac arrhythmias, defined as theexistence of an absolute arrhythmia or ventricular arrhythmias classified as LownIII, IV or V.

26. Known hypersensitivity to any component of the study medication(s).

27. Participation in an investigational drug study or receiving any investigationaltreatment within 28 days prior to study treatment. No wash out is necessary forsubjects previously receiving Tumor treating field (TTF); TTF will be allowed tocontinue at the discretion of the Investigator. FDA-authorized drugs for theprevention and treatment of COVID-19 are permitted.

28. Assessed by the Investigator to be unable or unwilling to comply with therequirements of the protocol.

29. Concurrent participation in any interventional clinical trial.

30. Pregnant and nursing women.

Phase 2B Inclusion Criteria

1. Age ≥ 22 years.

2. Able to understand and provide a signed informed consent that fulfills the relevantInstitutional Review Board (IRB) or Independent Ethics Committee (IEC) guidelines.

3. Histologically-confirmed GBM in accordance with the 2021 WHO CNS5 (grade 4 Glioma,IDH-wildtype) that has progressed after initial therapy or therapies (prior surgicalresection if feasible, plus radiotherapy with concurrent and/or adjuvanttemozolomide), limited to first-line progression. A second surgical resection isallowed but not required. Gliosarcoma, small cell GBM or other GBM variants, andmolecular GBM are allowed.

4. Progressive or recurrent disease will be confirmed (ie, contrast enhanced magneticresonance imaging [MRI] performed within 4 weeks prior to study treatment per RANOv02 criteria or diagnostic biopsy), or progression that does not meet RANO v02criteria if the disease progression is otherwise obvious in the opinion of theInvestigator and is discussed with the Medical Monitor. Participants must be aminimum of 3 months from the completion of radiotherapy to distinguish trueprogression from pseudoprogression.

5. Previous first-line treatment with at least radiotherapy and temozolomide.

6. Have received and recovered from standard treatments. At least 4 weeks since anycytotoxic chemotherapy (eg, temozolomide/nitrosoureas), 28 days since anyinvestigational agent, and 6 to 12 weeks since radiation before starting studydrug(s).

7. Willingness to use TTFields device. Both experimental arms require wearing theTTFields device ≥ 18 hours a day. Participants must be willing to shave their headtwice a week and use the TTFields device as instructed. They should have no scalpcondition or implanted device that contraindicates TTFields use (eg, no non-MRI-safemetal in the skull, ventricular peritoneal shunt is generally okay, but no activescalp infections or wounds).

8. Life expectancy ≥ 12 weeks.

9. ECOG performance status of 0 to 2.

10. Have recovered from prior treatment-related toxicities to grade 2 or less.

11. Ability to attend required study visits and return for adequate follow-up, asrequired by this protocol.

12. Agreement to practice highly effective contraception for female participants ofchildbearing potential and nonsterile males. Female participants of childbearingpotential are defined as any female who has experienced menarche and who is NOTpermanently sterile or postmenopausal. Postmenopausal is defined as 12 consecutivemonths with no menses without an alternative medical cause. Female participants ofchildbearing potential must have a negative pregnancy test and adhere to using ahighly effective method of contraception (eg, tubal ligation, approved hormonalcontraceptive, or an intrauterine device [IUD]) prior to screening and agree tocontinue its use during the study or be surgically sterilized (eg, hysterectomy)while on study and for 7 months post last dose of study drug. Male participants mustagree to use barrier methods of birth control while on study and for 7 months postlast dose of study drug.

13. Craniotomy must be adequately healed (at least 28 days between study treatmentinitiation and surgery).

Exclusion Criteria:

1. Received any further therapy beyond initial first-line therapy other than surgicalresection.

2. Prior therapy with bevacizumab for GBM.

3. Serious uncontrolled concomitant disease that would contraindicate the use of theinvestigational drugs used in this study or that would put the participant at highrisk 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 orsignificant 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, ulcerativecolitis).

13. Prior use of anti-PD1 or PD-L1 immunotherapy or cellular therapy targetingPD-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:

20. ANC < 1,000 cells/mm3.

21. Hemoglobin < 8 g/dL.

22. Platelet count < 100,000 cells/mm3.

23. Total bilirubin > 2 × ULN. For participants with documented Gilbert's syndrome,total bilirubin must be < 3 × ULN.

24. AST (SGOT) or ALT (SGPT) > 2.5 × ULN (> 5 × ULN in participants with livermetastases).

25. ALP levels > 2.5 × ULN (> 5 × ULN in participants with liver metastases, or > 10 × ULN in participants with bone metastases).

26. Serum creatinine > 2.0 mg/dL or 177 µmol/L. Note: Each study site should useits institutional ULN to determine eligibility.

27. Clinically significant (ie, active) cardiovascular disease or myocardial infarctionwithin 6 months prior to first study medication; unstable angina; congestive heartfailure of New York Heart Association grade 2 or higher; or serious cardiacarrhythmia. Participants with uncontrolled hypertension should be medically managedon a stable regimen to control hypertension prior to study entry.

28. Current, serious, clinically significant cardiac arrhythmias, defined as theexistence of an absolute arrhythmia or ventricular arrhythmias classified as LownIII, IV or V.

29. Known hypersensitivity to any component of the study medication(s).

30. Assessed by the Investigator to be unable or unwilling to comply with therequirements of the protocol, including the use of the TTFields device as requiredor any psychiatric/social situation that would limit adherence to protocol.

31. Participation in an investigational drug study or receiving any investigationaltreatment within 28 days prior to study treatment or concurrent participation in anyinterventional clinical trial.

32. Pregnant and nursing women.

33. Active implanted medical device, a skull defect (such as, missing bone with noreplacement) or bullet fragments. Examples of active electronic devices include deepbrain stimulators, spinal cord stimulators, vagus nerve stimulators, pacemakers,defibrillators, and programmable shunts.

34. Known sensitivity to conductive hydrogels like the gel used on transcutaneouselectrical nerve stimulation (TENS) electrodes.

35. A tumor located in the lower parts of the brain close to the spinal cord.