Study Testing The Safety and Efficacy of Adjuvant Temozolomide Plus TTFields (Optune®) Plus Pembrolizumab in Patients With Newly Diagnosed Glioblastoma (2-THE-TOP)

Patients with newly-diagnosed GBM who undergo maximal safe resection (biopsy alone is
eligible) followed by standard chemoradiation will be eligible for this trial.

Four weeks after completing chemoradiation, patients will undergo baseline standard of care
MRI. Four to six weeks after finishing chemoradiation, patients will start monthly cycles of
adjuvant TMZ. A minimum of 6 and maximum of 12 cycles of adjuvant TMZ will be given.
Treatment with Optune will start at approximately the same time as the first cycle of
adjuvant TMZ and continue until second disease progression or a maximum of 2 years. Within
one week after starting Cycle 2 of adjuvant TMZ and Optune therapy, patients will begin
open-label treatment with pembrolizumab every 3 weeks until first disease progression or
unacceptable toxicities or 2 years, whichever comes first.

At first progression, patients will be allowed to continue with Optune therapy combined with
any other therapy, which may include pembrolizumab, per standard of care at the discretion of
the treating physician. Surgical resection or biopsy of first recurrent tumor for
confirmation of recurrence is allowed within the protocol.

All patients will be seen before Cycle 1 of TMZ, before cycle 2 of TMZ, before starting the
second dose of pembrolizumab, and every 3 weeks before each subsequent pembrolizumab dose at
an outpatient clinic until they complete all 12 cycles of adjuvant TMZ or discontinue TMZ due
to toxicity or first progression.

Medical follow-up will continue for 30 days after treatment termination. After this visit,
mortality will be assessed based on telephone interviews with the patients or the patients'
caregivers every 3 months.

Inclusion Criteria:

- Histologic confirmation of glioblastoma, WHO Grade IV (GBM variants are allowed; Lower
grade gliomas that have been transformed to GBM will be considered newly diagnosed GBM
if the lower-grade tumor was not previously treated, and the standard treatment for
GBM including radiation and temozolomide is now planned).

- MGMT methylation status if available (indeterminate methylation status will be
considered unmethylated).

- Karnofsky performance status (KPS) ≥70%.

- Patients must be at least 18 years of age.

- Received maximal safe resection (biopsy only allowed) and radiotherapy concomitant
with temozolomide:

1. Gliadel wafers placement at the time of surgical resection is allowed.

2. Any additional treatment directed at GBM will be considered exclusionary.

3. Minimum dose for concomitant radiotherapy is 40 Gy.

- Candidate for adjuvant high dose temozolomide and Optune therapy.

- Life expectancy of at least 3 months.

- Adequate bone marrow and organ function as defined below:

1. ANC ≥ 1,500/mcL

2. Platelets ≥ 100,000/mcL

3. Hemoglobin ≥ 9 g/dL or ≥ 5.6 mmol/L (transfusion is allowed)

4. Serum creatinine ≤ 1.5 x IULN OR creatinine clearance by Cockcroft-Gault ≥ 60
mL/min for patients with serum creatinine > 1.5 x IULN

5. Serum total bilirubin ≤ 1.5 x IULN OR direct bilirubin ≤ IULN for patients with
total bilirubin > 1.5 x IULN

6. AST (SGOT) and ALT (SGPT) ≤ 3 x IULN

- Participants of childbearing age must use effective contraception:

- Women of childbearing potential (WOCBP) must be using a highly effective method
of contraception to avoid pregnancy throughout the study and for at least 24
weeks after the last dose of study drug to minimize the risk of pregnancy. Prior
to study enrollment, women of childbearing potential must be advised of the
importance of avoiding pregnancy during trial participation and the potential
risk factors for an unintentional pregnancy. Refer to Appendix D for guidance on
highly effective contraceptive methods.

- WOCBP include any woman who has experienced menarche and who has not undergone
successful surgical sterilization (hysterectomy, bilateral tubal ligation or
oophorectomy) or who is not post-menopausal. Post-menopause is defined as:

- Amenorrhea that has lasted for ≥ 12 consecutive months without another cause, or

- For women with irregular menstrual periods who are taking hormone replacement
therapy (HRT), a documented serum follicle-stimulating hormone (FSH) level of
greater than 35 mIU/mL.

- Males with female partners of childbearing potential must agree to use
physician-approved contraceptive methods (e.g., abstinence, condoms, vasectomy)
throughout the study and should avoid conceiving children for 24 weeks following
the last dose of study drug.

- Ability of the patient or their legally authorized representative (LAR) to understand
and willingness to sign an IRB approved written informed consent document

- Steroid dose equivalent to dexamethasone dose of ≤ 4mg daily at the time of starting
adjuvant treatment

- Optune and temozolomide treatment start date will be at least 4 weeks but not more
than 6 weeks from the later of last dose of concomitant temozolomide or radiotherapy.
Although Optune and temozolomide should be started simultaneously, it is not required
as long as both are started within this time frame

Exclusion Criteria:

- Prior treatment with anti-angiogenic agents including bevacizumab.

- History of malignancy (other than glioblastoma) during the last two years except
non-melanoma skin cancer, in situ cervical cancer, indolent neoplasm not requiring
active treatment, or cured, early-stage prostate cancer not requiring active treatment
or treated with local treatment only.

- Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or
anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including
ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation
or checkpoint pathways).

- Progressive disease (according to RANO criteria). Advanced imaging is allowed to
further investigate suspected pseudoprogression if deemed necessary.

- Actively participating in another clinical treatment trial intended to treat GBM.

- Multifocal gliomas defined as distinct tumors that do not have overlapping T2/FLAIR
signal.

- Presence of leptomeningeal metastases.

- Implanted pacemaker, programmable shunts, defibrillator, deep brain stimulator, other
implanted electronic devices in the brain, or documented clinically significant
arrhythmias.

- Tumor is entirely located in the infra-tentorial region.