Phase 2
Inclusion Criteria:
1. Age ≥ 18 years.
2. Able to understand and provide a signed informed consent that fulfills the relevant
IRB or IEC guidelines.
3. Histologically-confirmed glioblastoma in accordance with the 2021 WHO Classification
of Tumors of the CNS (WHO CNS5) that has progressed after initial therapy or
therapies. The digital image to be provided for confirmation of histology by the
Sponsor. Gliosarcoma, small cell GBM or other GBM variants, and molecular GBM are
allowed.
4. Progressive or recurrent disease will be confirmed (i.e. contrast enhanced magnetic
resonance imaging (MRI) performed within 3 weeks prior to study treatment per RANO
criteria or diagnostic biopsy).
5. Previous first line treatment with at least radiotherapy and temozolomide. Subjects
must have been off prior treatment at least 28 days prior to initiation of study
therapy. Subjects must be at least 90 days from completion of radiation to reduce
the risk of pseudoprogression being misdiagnosed as progression, unless the
recurrence is a new enhancement on MRI outside the radiation treatment field or
progression is confirmed by biopsy.
6. Subjects must have recovered from prior treatment-related toxicities to Grade 2 or
less.
7. Life expectancy > 12 weeks.
8. Karnofsky Performance Status ≥ 70.
9. Ability to attend required study visits and return for adequate follow-up, as
required by this protocol.
10. Agreement to practice effective contraception for female subjects of child-bearing
potential and non-sterile males. Female subjects of child-bearing potential must
agree 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 after
treatment. Effective contraception includes surgical sterilization (eg, vasectomy,
tubal ligation), two forms of barrier methods (eg, condom, diaphragm) used with
spermicide, intrauterine devices (IUDs), and abstinence.
11. Craniotomy must be adequately healed (at least 28 days between study treatment
initiation and surgery).
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
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.
Phase 2B Inclusion Criteria. 1. Age ≥ 22 years.
2. Able to understand and provide a signed informed consent that fulfills the relevant
Institutional 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 surgical
resection if feasible, plus radiotherapy with concurrent and/or adjuvant
temozolomide), limited to first-line progression. A second surgical resection is
allowed but not required. Gliosarcoma, small cell GBM or other GBM variants, and
molecular GBM are allowed.
4. Progressive or recurrent disease will be confirmed (ie, contrast enhanced magnetic
resonance imaging [MRI] performed within 4 weeks prior to study treatment per RANO
v02 criteria or diagnostic biopsy), or progression that does not meet RANO v02
criteria if the disease progression is otherwise obvious in the opinion of the
Investigator and is discussed with the Medical Monitor. Participants must be a
minimum of 3 months from the completion of radiotherapy to distinguish true
progression 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 any
cytotoxic chemotherapy (eg, temozolomide/nitrosoureas), 28 days since any
investigational agent, and 6 to 12 weeks since radiation before starting study
drug(s).
7. Willingness to use TTFields device. Both experimental arms require wearing the
TTFields device ≥ 18 hours a day. Participants must be willing to shave their head
twice a week and use the TTFields device as instructed. They should have no scalp
condition or implanted device that contraindicates TTFields use (eg, no non-MRI-safe
metal in the skull, ventricular peritoneal shunt is generally okay, but no active
scalp 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, as
required by this protocol.
12. Agreement to practice highly effective contraception for female participants of
childbearing potential and nonsterile males. Female participants of childbearing
potential are defined as any female who has experienced menarche and who is NOT
permanently sterile or postmenopausal. Postmenopausal is defined as 12 consecutive
months with no menses without an alternative medical cause. Female participants of
childbearing potential must have a negative pregnancy test and adhere to using a
highly effective method of contraception (eg, tubal ligation, approved hormonal
contraceptive, or an intrauterine device [IUD]) prior to screening and agree to
continue 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 must
agree to use barrier methods of birth control while on study and for 7 months post
last dose of study drug.
13. Craniotomy must be adequately healed (at least 28 days between study treatment
initiation and surgery).
Exclusion Criteria:
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
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.
