Radiation Therapy Plus Temozolomide and Pembrolizumab With and Without HSPPC-96 in Newly Diagnosed Glioblastoma (GBM)

Background:

- Malignant gliomas are unfortunately, in most cases, a uniformly fatal tumor. Despite
aggressive surgery, radiation treatment (RT) and chemotherapy at initial diagnosis these
tumors almost always recur.

- Many clinical trials in glioblastoma (GBM) have evaluated the addition of agent(s) to
standard therapy which consists of concurrent radiation with temozolomide chemotherapy
after maximal surgical resection in patients with newly diagnosed disease and salvage
chemotherapy with either rechallenge with temozolomide or an alternative alkylating
agent such as CCNU or cisplatin. To date, none of the combination strategies have
demonstrated clinical benefit. Furthermore, in subjects with an unmethylated MGMT
(O6-methylguanine-DNA methyltransferase) promoter temozolomide has only modest benefit
and salvage therapies have not demonstrated a significant impact in this subject group
underscoring the need for more research.

- Immunotherapy offers the promise of improving outcomes for patients with GBM by evoking
specific immune responses that may produce a more sustained and less toxic effect than
conventional therapy. Heat-shock proteins (HSPs), which function as intracellular
chaperones, can be used to deliver a variety of tumor antigens to antigen presenting
cells for immune stimulation.

- Heat Shock Protein-Peptide Complex-96 (HSPPC-96) consists of the heat shock protein
glycoprotein-96 (HSP gp-96) and a wide array of chaperoned proteins, including
autologous antigenic peptides (aka vaccine ). Heat shock proteins (HSP) are molecules
that respond to cellular stress and counteract abnormal protein folding. They are known
to modulate immune responses, especially the HSP gp-96. In a stressful environment, such
as a tumor, HSPs are upregulated and highly expressed on tumor cells. This protects the
tumor and leads to resistance to therapy. HSP expression is associated with cellular
proliferation, apoptosis evasion, tissue invasion, metastasis, and angiogenesis.

- Pembrolizumab is a potent and highly selective humanized monoclonal antibody (mAb) of
the IgG4/kappa isotype designed to directly block the interaction between PD-1 and its
ligands, PD-L1 and PD-L2. Additionally, pembrolizumab is thought to also have activity
in the peripherally circulating T-effector cells by reversing lymphocyte exhaustion. It
is currently FDA approved for use in patients with unresectable or metastatic melanoma
and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF
inhibitor and NSCLC with elevated PDL1 in the tumor. recurrent or metastatic HNSCC with
disease progression on or after platinum-containing chemotherapy. It is also FDA
approved for with advanced (metastatic) non-small cell lung cancer (NSCLC) whose disease
has progressed after other treatments and with tumors that express a protein called
PD-L1 and for the treatment of patients with recurrent or metastatic head and neck
squamous cell carcinoma (HNSCC) with disease progression on or after platinum-containing
chemotherapy

- This study will be the first to evaluate this combination of vaccine (HSPPC-96) and PD-
1 inhibition (pembrolizumab) in newly diagnosed GBM patients whose tumors are MGMT
promoter unmethylated and are isocytrate dehydrogenase (IDH) wildtype; and will provide
important data on immune-modulatory effect of this combination. This may be of
particular value in patients with high peripheral PD-L1 expression, but also the value
of PD-1 added to standard GBM therapy. As vaccine needs to be generated from the patient
s tumor, patients will need to be identified prior to surgery.

Eligibility:

- MRI findings consistent with a suspected GBM or histologically confirmed newly diagnosed
GBM that has not been treated and would benefit from further surgical resection.

- Tumor must be supratentorial.

- GBM diagnosis must be made by surgical excision (stereotactic biopsy will not be allowed
unless there is plan for second surgery to remove greater than or equal to 80 % of the
tumor) and patients tumors must not have MGMT promoter methylation and must be IDH
wildtype.

- No prior treatment with radiation or chemotherapy for their GBM.

- Age greater than or equal to 18 years on day of signing informed consent

Objective:

- The primary endpoint is to determine whether the one year overall survival (OS) rate is
improved in newly diagnosed GBM patients whose tumors have an unmethylated MGMT promoter and
are IDH wildtype treated with RT + TMZ + Pembrolizumab followed by TMZ + Pembrolizumab +
HSPPC-96 vaccine or Placebo vaccine x 6 cycles (1 cycle is 9 weeks).

Design:

- This will be a randomized, double blind phase II trial RT + TMZ + Pembrolizumab followed
by TMZ + Pembrolizumab +/- HSPPC-96 in newly diagnosed GBM patients whose tumors have an
unmethylated MGMT promotor and are IDH wildtype.

- Subjects will be assigned to intervention based on tumor resection and ability to
generate vaccine as follows:

- If < 80 % of tumor removed, <7 g of tumor is resected or HSPPC-96 cannot be
generated, subjects will be treated on the ancillary cohort of RT+TMZ
+Pembrolizumab followed by TMZ+ Pembrolizumab.

- If greater than or equal to 80% of contrasting enhanced tumor removed (based on T1
Post contrast MRI using cross sectional measurement), greater than or equal to 7 g
of tumor is resected and sufficient HSPPC-96 is generated, subjects will be
included in the main cohort and will be randomized on a 1:1 basis to receive:

1. RT+TMZ +Pembrolizumab followed by TMZ+Pembrolizumab + Placebo

OR

2. RT+TMZ +Pembrolizumab followed by TMZ+Pembrolizumab+HSPPC-96

- Approximately 8 potentially eligible patients are seen per month, and it is anticipated
that at least 1-2 per month will be accrued per site.

- INCLUSION CRITERIA:

Pre Surgery (Step 1)

- MRI findings consistent with a suspected GBM or a histologically confirmed newly
diagnosed GBM that has not been treated and would benefit from further surgical
resection. As vaccine needs to be generated from the patient s tumor, patients will
need to be identified prior to definitive surgery.

- Age greater than or equal to 18 years on day of signing informed consent.

- Karnofsky performance status greater than or equal to 70%.

- Tumor must be supratentorial only.

- Stereotactic biopsy will not be allowed unless there is plans for second surgery to
remove greater than or equal to 80 % of the tumor.

- No prior treatment with radiation or chemotherapy for their GBM.

- No prior treatment with carmustine wafers.

Post-Surgery for vaccine or placebo (Step 2):

- Pathology must be a GBM, MGMT promoter region determined to be unmethylated and IDH
wild type. Greater than or equal to 80 % resection of contrast enhanced tumor on post
operative MRI is required for randomization, otherwise treatment will occur on the
ancillary arm.

- Treatment must be initiated greater than or equal to 14 days and < 6 weeks from
surgery.

- Craniotomy site must be adequately healed and free of drainage or cellulitis, and the
underlying cranioplasty must appear intact at the time of radiation. Radiation must
start within 6 weeks of surgery.

- Dexamethasone dose should be less than or equal to 4 mg/day or steroid equivalent
prior to starting treatment. If higher doses are needed, consult with Study Chair.

- Female subjects of childbearing potential should have a negative urine or serum
pregnancy within 7 days prior to receiving the first dose of study medication. If the
urine test is positive or cannot be confirmed as negative, a negative serum pregnancy
test will be required.

- Patients must have adequate organ and bone marrow function within 14 days prior to
step 2 registration, as defined below:

- Absolute neutrophil count (ANC) > 1.5 (SqrRoot) 10(9)/L; platelet count > 100
(SqrRoot) 10(9)/L; and hemoglobin (Hb) >9.0 g/dL within 7 days prior to
enrollment. Note: The use of transfusion or other intervention to achieve Hb
greater than or equal to 9.0 g/dL is acceptable.

- Total bilirubin < 1.5 (SqrRoot) ULN (except in patients diagnosed with Gilbert s
disease)

- AST (SGOT), ALT (SGPT), and alkaline phosphatase (ALP) < 2.5 (SqrRoot) ULN

- Serum creatinine < 1.5 (SqrRoot) ULN

- International normalized ratio (INR), prothrombin time (PT), or activated partial
thromboplastin time (APTT) as follows: In the absence of therapeutic intent to
anticoagulate the patient: INR < 1.5 or PT < 1.5(SqrRoot) ULN or aPTT <
1.5(SqrRoot) ULN. In the presence of therapeutic intent to anticoagulate the
patient: INR or PT and aPTT within therapeutic limits (according to the medical
standard in the institution) and the patient has been on a stable dose of
anticoagulants for at least 2 weeks before registration.

- Females of child-bearing potential (FOCBP) and males must agree to use two adequate
contraception methods (give examples, e.g. hormonal or barrier method of birth
control; abstinence) prior to study entry, for the duration of study participation,
and for 120 days following completion of therapy. Should a female patient become
pregnant or suspect she is pregnant while participating in this study, she should
inform her treating physician immediately. Male patients who father a child should
notify the treating physician.

NOTE: A FOCBP is any woman (regardless of sexual orientation, having undergone a tubal
ligation, or remaining celibate by choice) who meets the following criteria:

1. Has not undergone a hysterectomy or bilateral oophorectomy

2. Has had menses at any time in the preceding 12 consecutive months (and therefore has
not been naturally postmenopausal for > 12 months)

- Patients must have the ability to understand and the willingness to sign a
written informed consent prior to registration on study.

- Diagnosis must be made by surgical excision.

- Patients should not be on antibiotics for any infection but post operative
antibiotics are allowed if used prophylactically but should be completed prior to
starting RT.

EXCLUSION CRITERIA:

- Patients who are receiving any other investigational agents.

- Known history of immunodeficiency (HIV). This medical entity can be exacerbated by
PD-1 blockade.

- Any form of immunosuppressive therapy within 7 days prior to the first dose of trial
treatment excluding steroids. Attempts should be made to have patient on lowest
possible dose of steroids. These medical entities can be exacerbated by PD-1 blockade.

- History of another malignancy in the previous 3 years, with a disease-free interval of
< 3 years. 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. Patients who have undergone a bne marrow or stem-cell transplant for
any malignancy are excluded.

- 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 chronic systemic steroids or immunosuppressive agents. Subjects with vitiligo
or resolved childhood asthma/atopy would be an exception to this rule. Subjects that
require intermittent use of bronchodilators or local steroid injections will not be
excluded from the study. Subjects with hypothyroidism stable on hormone replacement or
Sjorgen s syndrome will not be excluded from the study.

- Has a history of interstitial lung disease, non-infectious pneumonitis or pneumonitis.

- Has an active infection requiring systemic antibiotics within 10 days of surgery.

- 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:

- Hypertension (defined as 160/95) that is not controlled on medication

- Ongoing or active infection requiring systemic treatment

- Symptomatic congestive heart failure

- Unstable angina pectoris

- Cardiac arrhythmia

- Psychiatric illness/social situations or substance abuse disorders that would limit
compliance with study requirements

- Any other illness or condition that the treating investigator feels would interfere
with study compliance or would compromise the patient s safety or study endpoints.

- Is pregnant or breastfeeding, or expecting to conceive or father children within
the projected duration of the trial, starting with the pre-screening or screening
visit through 120 days after the last dose of trial treatment.

- The effects of pembrolizumab and HSPPC-96 on the developing human fetus are
unknown. For this reason and because checkpoint inhibitors and immunotherapeutic
vaccines as well as other therapeutic agents used in this trial are known to be
teratogenic, women of child-bearing potential and men must agree to use adequate
contraception (hormonal or barrier method of birth control; abstinence) prior to
study entry,and for the duration of study participation. Should a woman become
pregnant or suspect she is pregnant while she or her partner is participating in
this study, she should inform her treating physician immediately.

- 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).

- On treatment for Hepatitis B or Hepatitis C or history of TB.

- Has received a live vaccine within 30 days prior to the first dose of trial
treatment

- Patients who have a history of allergic reactions attributed to compounds of
similar chemical or biologic composition to Pembrolizumab are not eligible. Known
hypersensitivity to any excipients of Pembrolizumab.