Pembrolizumab and Standard Therapy in Treating Patients With Glioblastoma

PRIMARY OBJECTIVES:

I. To assess the 18 month overall survival rate of pembrolizumab in combination with standard
therapy (surgery, external beam radiation therapy and temozolomide [TMZ] chemotherapy) in
patients with newly diagnosed glioblastoma multiforme (GBM).

SECONDARY OBJECTIVES:

I. To assess adverse events (AE) and toxicity profile of pembrolizumab in combination with
standard therapy in patients with newly diagnosed GBM.

II. To assess time to progression in patients treated with pembrolizumab in combination with
standard therapy in patients with newly diagnosed GBM.

III. To assess progression-free survival in patients treated with pembrolizumab in
combination with standard therapy in patients with newly diagnosed GBM.

IV. To assess time to treatment failure in patients treated with pembrolizumab in combination
with standard therapy in patients with newly diagnosed GBM.

TERTIARY OBJECTIVES:

I. To assess the tumor PD-1/PD-L1 expression and inflammatory microenvironment profile by
comparing PD-1/PD-L1 expression and T lymphocyte/monocytic infiltrates before and after
administration of pembrolizumab treatment.

II. To assess the peripheral immunophenotype profile and GBM-associated antigen-specific T
cell responses before and after receiving pembrolizumab treatment in combination with
standard therapy.

OUTLINE:

NEOADJUVANT (COURSE 1): Patients receive pembrolizumab intravenously (IV) over 30 minutes on
day 1.

SURGERY (COURSE 2): Patients undergo standard of care surgery within days 4-7.

CONCURRENT (COURSE 3): Starting 21-35 days after surgery, patients receive pembrolizumab IV
over 30 minutes on days 1, 22, and 43 and temozolomide orally (PO) daily on days 8-54.
Patients also undergo external beam radiation therapy every 5 days per week on days 8-54.

ADJUVANT (COURSE 4-8): Within 3-5 weeks after completing radiation therapy, patients receive
pembrolizumab IV over 30 minutes on days 1, 22, and 43 and temozolomide PO daily on days 1-5
every 28 days. Treatment repeats every 63 days for up to 5 courses in the absence of disease
progression or unexpected toxicity.

After completion of study treatment, patients are followed up at 30 days and then every 3-4
months thereafter.

Inclusion Criteria:

- Histological confirmation of supratentorial glioblastoma (also known as astrocytoma
grade IV, gliosarcoma) amenable to surgical resection =< 28 days prior to registration

- Have an enhancing mass on magnetic resonance imaging (MRI) amenable to > 90% resection
of contrast-enhancing tumor (as determined by the neurosurgeon pre-operatively) and
histological diagnosis of glioblastoma from a prior stereotactic biopsy

- Willing to undergo craniotomy and resection of their glioblastoma

- Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1

- Absolute neutrophil count (ANC) >= 1500/mm^3

- Platelet count >= 100,000/mm^3

- Hemoglobin >= 9.0 g/dL without transfusion or erythropoietin (EPO) dependency (=< 7
days prior to assessment)

- Prothrombin time (PT) =< 1.5 x upper limit of normal (ULN) unless patient is receiving
anticoagulant therapy and PT or partial prothrombin time (PTT) is within therapeutic
range of intended use of coagulants

- Activated partial thromboplastin time (aPTT) =< 1.5 x ULN unless patient is receiving
anticoagulant therapy and PT or PTT is within therapeutic range of intended use of
coagulants

- Albumin >= 2.5 mg/dL

- Total bilirubin =< 1.5 x ULN OR direct bilirubin =< ULN for patients with total
bilirubin levels > 1.5 x ULN

- Aspartate transaminase (AST) AND alanine transaminase (ALT) =< 2.5 x ULN

- Creatinine =< 1.0 x ULN OR measured or calculated creatinine clearance (per
institutional standard) must be >= 60 ml/min

- Negative pregnancy test done =< 7 days prior to registration, for persons of
childbearing potential only (POCBP)

- NOTE: Serum or urine pregnancy test allowed; if urine test is positive or cannot
be confirmed as negative, a serum pregnancy test will be required

- POCBP must be willing to use adequate contraception starting with first dose through
120 days after last dose

- Provide written informed consent

- Willing to return to enrolling institution for follow-up (during the active monitoring
phase of the study)

- Note: During the active monitoring phase of a study (i.e., active treatment and
observation), participants must be willing to return to the consenting
institution for follow-up

- Willing to provide tissue and blood samples for correlative research purposes

Exclusion Criteria:

- Any of the following because this study involves an investigational agent whose
genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are
unknown:

- Pregnant women

- Nursing women

- Men or women of childbearing potential who are unwilling to employ adequate
contraception

- Signs or symptoms of life-threatening raised intracranial pressure: as defined by the
treating neurosurgeon, including severe headache, nausea, decreasing level of
consciousness, precluding 4-7 day delay in scheduling neurosurgery

- Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment
of the investigator, would make the patient inappropriate for entry into this study or
interfere significantly with the proper assessment of safety and toxicity of the
prescribed regimens

- Immunocompromised patients and patients known to be human immunodeficiency virus (HIV)
positive and currently receiving antiretroviral therapy

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements

- Receiving any other investigational agent which would be considered as a treatment for
the primary neoplasm

- Other active malignancy =< 5 years prior to registration

- EXCEPTIONS: Non-melanotic skin cancer or carcinoma-in-situ of the cervix

- NOTE: If there is a history or prior malignancy, the patient must not be
receiving other specific treatment for their cancer

- History of myocardial infarction =< 6 months prior to registration, or congestive
heart failure requiring use of ongoing maintenance therapy for life-threatening
ventricular arrhythmias

- 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

- Known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or
hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is
detected)

- Known history of active TB (Bacillus tuberculosis)

- Received a live vaccine =< 30 days prior to registration

- History of (non-infectious) pneumonitis that required steroids or current pneumonitis

- Hypersensitivity to pembrolizumab or any of its excipients

- Received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent