A Pilot Surgical Trial To Evaluate Early Immunologic Pharmacodynamic Parameters For The PD-1 Checkpoint Inhibitor, Pembrolizumab (MK-3475), In Patients With Surgically Accessible Recurrent/Progressive Glioblastoma

PD-1 works to help tumor cells continue to grow and multiply. Pembrolizumab (MK-3475) is a
humanized monoclonal antibody. Humanized monoclonal is an antibody that is designed to block
the action of the receptor, PD-1.

The FDA (the U.S. Food and Drug Administration) has not approved Pembrolizumab for
Glioblastoma but it has been approved for other uses.

Inclusion Criteria:

- Have histologically confirmed World Health Organization Grade IV malignant glioma
(glioblastoma or gliosarcoma). Participants will be eligible if the original histology
was low-grade glioma and a subsequent histological diagnosis of glioblastoma or
variants is made.

- Be willing and able to provide written informed consent/assent for the trial.

- Be 18 years of age on day of signing informed consent.

- Have a Karnofsky performance status (KPS) ≥ 70 (Appendix A).

- Previous first line therapy with at least radiotherapy.

- Be at first or second relapse. Note: Relapse is defined as progression following
initial therapy (i.e., radiation ± chemotherapy). For participants who had prior
therapy for a low-grade glioma, the surgical diagnosis of a high-grade glioma will be
considered the first relapse.

- Participants must have shown unequivocal evidence for tumor progression by MRI or CT
scan.

- Demonstrate adequate organ function as defined in Table 1, all screening labs should
be performed within 14 days of registration.

Table 1 Adequate Organ Function Laboratory Values

- System Laboratory Value

- Hematological

- Absolute neutrophil count (ANC) ≥1,500 /mcL

- Platelets ≥100,000 / mcL

- Hemoglobin ≥9 g/dL or ≥5.6 mmol/L without transfusion or EPO dependency (within 7
days of assessment)

- Renal

- Serum creatinine OR Measured or calculated creatinine clearance (GFR can also be
used in place of creatinine or CrCl) ≤1.5 X institutional upper limit of normal
(ULN) OR ≥60 mL/min for subject with creatinine levels > 1.5 X institutional ULN
Hepatic

- Serum total bilirubin ≤ 1.5 X institutional ULN OR Direct bilirubin ≤
institutional ULN for subjects with total bilirubin levels > 1.5 institutional
ULN

- AST (SGOT) and ALT (SGPT) ≤ 2.5 X institutional ULN OR ≤ 5 X institutional ULN
for subjects with Gilberts syndrome

- Albumin >2.5 mg/dL

- Coagulation

- International Normalized Ratio (INR) or Prothrombin Time (PT)

- Activated Partial Thromboplastin Time (aPTT) ≤1.5 X institutional ULN unless
subject is receiving anticoagulant therapy as long as PT or PTT is within
therapeutic range of intended use of anticoagulants

≤1.5 X institutional ULN unless subject is receiving anticoagulant therapy as
long as PT or PTT is within therapeutic range of intended use of anticoagulants

- Creatinine clearance should be calculated per institutional standard.

- CT or MRI within 14 days prior of registration.

- An interval of at least 4 weeks (to registration) between prior surgical resection or
one week for stereotactic biopsy.

- An interval of at least 12 weeks from the completion of radiation therapy to
registration unless there is unequivocal histologic confirmation of tumor progression.

- Participants must have recovered to grade 0 or 1 or pre-treatment baseline from
clinically significant toxic effects of prior therapy (including but not limited to
exceptions of alopecia, laboratory values listed per inclusion criteria, and
lymphopenia which is common after therapy with temozolomide).

- From registration, the following time periods must have elapsed: 5 half-lives from any
investigational agent, 4 weeks from cytotoxic therapy (except 23 days for temozolomide
and 6 weeks from nitrosoureas), 6 weeks from antibodies, or 4 weeks (or 5 half-lives,
whichever is shorter) from other anti-tumor therapies (including vaccines). No
wash-out period required from TTF.

- Participants must have sufficient tissue from prior surgery revealing glioblastoma or
variants for submission following registration. The following amount of tissue is
required:

- 1 formalin-fixed paraffin-embedded (FFPE) tumor tissue block (preferred) OR

- 10 FFPE unstained slides (5 μm thick)

- Patients must be undergoing surgery that is clinically indicated as determined by
their care providers. Patients must be eligible for surgical resection with the
expectation that the surgeon is able to resect at least 400mg of tumor with low risk
of inducing neurological injury.

- Female subject of childbearing potential must have a negative urine or serum pregnancy
within 72 hours prior to registration. If the urine test is positive or cannot be
confirmed as negative, a serum pregnancy test will be required. Women are considered
post-menopausal and not of child bearing potential if they have had 12 months of
natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g., age
appropriate, history of vasomotor symptoms) or six months of spontaneous amenorrhea
with serum FSH levels > 40 mIU/mL and estradiol < 20 pg/mL or have had surgical
bilateral oophorectomy (with or without hysterectomy) at least six weeks ago. In the
case of oophorectomy alone, only when the reproductive status of the woman has been
confirmed by follow up hormone level assessment is she considered not of child bearing
potential.

- Women of child-bearing potential (WOCBP), defined as all women physiologically capable
of becoming pregnant, must agree to use highly effective contraception during study
treatment and for 120 days after study discontinuation. Highly effective contraception
is defined as either:

- True Abstinence: When this is in line with the preferred and usual lifestyle of
the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal,
post-ovulation methods) and withdrawal are not acceptable methods of
contraception.

- Sterilization: Surgical bilateral oophorectomy (with or without hysterectomy) or
tubal ligation at least six weeks ago. In case of oophorectomy alone, only when
the reproductive status of the woman has been confirmed by follow up hormone
level assessment (as described in item 3.1.16 above).

- Male Partner Sterilization (with the appropriate post-vasectomy documentation of
the absence of sperm in the ejaculate). For female subjects on the study, the
vasectomised male partner must be the sole partner for that participant.

- Use of a combination of any two of the following:

- Placement of an intrauterine device (IUD) or intrauterine system (IUS)

- Barrier methods of contraception: Condom or Occlusive cap (diaphragm or
cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal
suppository

- Appropriate hormonal contraceptives (including any registered and marketed
contraceptive agent that contains an estrogen and/or a progestational agent
- including oral, subcutaneous, intrauterine, or intramuscular agents)

- Male subjects must agree to use adequate method of contraception starting with the
first dose of study therapy through 120 days after the last dose of therapy.

Exclusion Criteria:

- Current or planned participation in a study of an investigational agent or using an
investigational device.

- Has a diagnosis of immunodeficiency.

- Has tumor primarily localized to the brainstem or spinal cord.

- Has presence of diffuse leptomeningeal disease or extracranial disease.

- Has received systemic immunosuppressive treatments, aside from systemic
corticosteroids (such as methotrexate, chloroquine, azathioprine, etc) within six
months of registration.

- Has received anti-angiogenic or anti-VEGF targeted agents (e.g. bevacizumab,
cediranib, aflibercept, vandetanib, XL-184, sunitinib, etc).

- Requires treatment with high dose systemic corticosteroids defined as dexamethasone >
4 mg/day or bioequivalent for at least 3 consecutive days within 2 weeks of
registration.

- Has received prior interstitial brachytherapy, implanted chemotherapy, stereotactic
radiosurgery or therapeutics delivered by local injection or convection enhanced
delivery.

- Has history of known coagulopathy that increases risk of bleeding or a history of
clinically significant hemorrhage within 12 months of registration.

- Has a known history of active TB (Bacillus Tuberculosis).

- Has gastrointestinal bleeding or any other hemorrhage/bleeding event CTCAE Grade > 3
within 6 months of registration.

- Has a known additional malignancy that is progressing or requires active treatment
within 3 years of registration. Exceptions include basal cell carcinoma of the skin,
squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone
potentially curative therapy.

- Has 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 (eg., thyroxine, insulin, or physiologic corticosteroid
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a
form of systemic treatment.

- Has known history of, or any evidence of active non-infectious pneumonitis.

- Has an active infection requiring systemic therapy.

- Has a history or current evidence of any condition, therapy, or laboratory abnormality
that might confound the results of the trial, interfere with the subject's
participation for the full duration of the trial, or is not in the best interest of
the subject to participate, in the opinion of the treating investigator. Examples
include but are not limited to symptomatic congestive heart failure, unstable angina
pectoris, cardiac arrhythmia or psychiatric illness/social situations that would limit
compliance with study requirements.

- Has known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial.

- Has received prior therapy 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).

- Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).

- Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA
[qualitative] is detected).

- Has received a live vaccine within 30 days prior to registration.

- Has a known hypersensitivity to any of the study therapy products.