Pembrolizumab +/- Bevacizumab for Recurrent GBM

Pembrolizumab (MK-3475) is a humanized monoclonal antibody. An antibody is a common type of
protein made in the body in response to a foreign substance. Antibodies attack foreign
substances and protect against infection. Antibodies can also be produced in the laboratory
for use in treating patients, an antibody that is made in the lab is also known as a
humanized monoclonal antibody. There are now several approved antibodies for the therapy of
cancer and other disease. Pembrolizumab (MK-3475) has been studied in lab experiments and in
other types of cancer. Information from these studies suggests that Pembrolizumab (MK-3475)
may be beneficial in your type of cancer. Bevacizumab, also known as Avastin, is approved by
the FDA for treating recurrent GBM. Bevacizumab is an anti-angiogenic medicine, which means
it blocks blood vessels from forming that could supply the tumor with nutrients and oxygen.

There is a safety lead-in to evaluate pembrolizumab in combination of with bevacizumab
(cohort A) expected to enroll up to 18 participants. Three dose levels (DL) are evaluated for
pembrolizumab administered at 200 mg (flat dosing) under various dose intervals: every 3 (DL
0), 4 (DL -1) or 6 (DL -2) weeks. A standard 3+3 design is used starting at DL 0.
De-escalation may occur depending on observation of dose-limiting toxicity (DLT). At least 6
participants will be evaluated for DLT at DL 0. The Phase II study randomizes participants to
cohort A: pembrolizumab (using the MTD determined in the safety lead-in) and bevacizumab or
cohort B: pembrolizumab monotherapy (using the MTD determined in the safety lead-in). Accrual
goals are established for each cohort: A n=50 and B n=30 participants. The two cohorts are
evaluated independently against a historical control and not compared. All participants
treated at the safety lead-in established MTD dose level will be rolled into the Phase II
cohort.

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.

- Previous first line therapy with at least radiotherapy and temozolomide

- Be at first or second relapse.

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

- CT or MRI within 14 days prior to start of study drug.

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

- An interval of at least 12 weeks from the completion of radiation therapy to start of
study drug unless there is a new area of enhancement consistent with recurrent tumor
outside the radiation field or 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 the projected start of scheduled study treatment, 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.

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 within 6 months of start of study
drug

- 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 start of
study drug.

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

- Requires therapeutic anticoagulation with warfarin at baseline; patients must be off
warfarin or warfarin-derivative anti-coagulants for at least 7 days prior to starting
study drug; however, therapeutic or prophylactic therapy with low-molecular weight
heparin is allowed.

- Has history of known coagulopathy that increases risk of bleeding or a history of
clinically significant hemorrhage within 12 months of start of study drug

- Has evidence of intratumoral or peritumoral hemorrhage on baseline MRI scan other than
those that are grade ≤ 1 and either post-operative or stable on at least 2 consecutive
MRI scans.

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

- Has a known additional malignancy that is progressing or requires active treatment
within 3 years of start of study drug. 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 an active autoimmune disease requiring systemic treatment within the past 3 months
or a documented history of clinically severe autoimmune disease, or a syndrome that
requires systemic steroids or immunosuppressive agents.

- Has evidence of interstitial lung disease or 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.

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

- Is pregnant or breastfeeding, or expecting to conceive within the projected duration
of the trial

- Has a known history of HIV

- Has known active Hepatitis B or Hepatitis C

- Has received a live vaccine within 30 days prior to the first dose of study drug.

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

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

- Has a history of non-healing wounds or ulcers, or bone refractures within 3 months of
fracture

- Has a history of arterial thromboembolism within 12 months of start of study drug.

- Has inadequately controlled hypertension

- Has a history of hypertensive crisis or hypertensive encephalopathy

- Has had clinically significant cardiovascular disease within 12 months of start of
study drug

- Has a history of abdominal fistula, gastrointestinal perforation, or intra-abdominal
abscess within 6 months prior to start of study drug.