A Phase I Study of a Personalized NeoAntigen Cancer Vaccine with Radiotherapy Plus Pembrolizumab/ MK-3475 Among Newly Diagnosed Glioblastoma Patients

This research study is studying a new type of vaccine as a possible treatment for patients
with glioblastoma. This research study is a Phase I clinical trial, which tests the safety of
an investigational intervention and also tries to define the appropriate dose of the
intervention to use for further studies. "Investigational" means that the intervention is
being studied and that research doctors are trying to find more about it. It also means that
the FDA (U.S. Food and Drug Administration) has not approved the Personalized NeoAntigen
Cancer Vaccine for any use in patients, including people with glioblastoma.

The purpose of the initial study cohort (Cohort 1) is to determine if it is possible to make
and administer safely a vaccine against glioblastoma by using information gained from
specific characteristics of the participants tumor. It is known that glioblastomas have
mutations (changes in genetic material) that are specific to an individual patient's tumor.
These mutations can cause the tumor cells to produce proteins that appear very different from
the body's own cells. It is possible that these proteins used in a vaccine may induce strong
immune responses, which may help the body fight any tumor cells that could cause the
glioblastoma to come back in the future.

Three additional cohorts (1a, 1b, & 1c) were added to the study following completion of
accrual to the original study cohort (cohort 1). Each new cohort receives NeoVax and
radiation therapy as administered to cohort 1 and will also receive pembrolizumab: cohort 1a
patients will start pembrolizumab w/in 2 weeks after start of RT, and continue every 3 weeks
for up to 2 years; cohort 1b patients will start pembrolizumab 2-4 weeks after completion of
NeoVax priming, and continue every 3 weeks for up to 2 years; cohort 1c patients will receive
a single dose of pembrolizumab administered within 2 weeks after start of RT, re-start 2-4
weeks after completion of NeoVax priming, and continue every 3 weeks for up to 2 years. The
rationale for adding these new cohorts is: 1) to assess the safety and feasibility of NeoVax
when administered with pembrolizumab; and 2) to determine if the timing of anti-PD-1
administration impacts the immunogenicity of NeoVax.

An additional sub-study cohort (1d) is being added for patients whose tumor is
MGMT-methylated. Cohort 1d will enroll patients with tumors for which the MGMT status is
methylated or partially methylated; patients on cohort 1d will receive standard daily
temozolomide during radiation and as adjuvant therapy for up to six cycles following
completion of radiation therapy. The rationale for adding cohort 1d is to determine the
safety and feasibility of NeoVax when administered with pembrolizumab and temozolomide.

I. Inclusion Criteria:

Participants must meet the following criteria on screening examination to be eligible to
participate in the study (labs/tests/assessments within 14 days prior to initial study
registration unless otherwise specified)

- Participant is willing and able to give written informed consent

- Pathologically confirmed WHO grade IV glioblastoma or variants (gliosarcoma,
glioblastoma with oligodendroglial features, giant cell glioblastoma) with adequate
tumor material for genomic sequencing. Participants will be eligible if the original
diagnosis was a lower grade glioma and a subsequent histologic diagnosis of
glioblastoma or its variants was made, and patient received no prior therapy other
than surgery

- Patients with a diagnosis of astrocytoma with molecular features of glioblastoma
will be considered eligible for trial.

- In addition, patients with IDH-mutated tumors will also continue to be eligible
for trial, despite the release of updated WHO disease classifications in 2021.

- The tumor must be primarily supratentorial in location as determined by diagnostic
imaging performed preoperatively

- Radiographic contrast enhancement attributable to residual tumor on post-operative
imaging performed within 72 hours of resection must not exceed 1 cm in maximal
diameter in biperpendicular plances (greater than 1 cm in one plane but less than 1 cm
in other planes will be allowed)

- CT or MRI within 14 days prior to start of study therapy (NOTE: This criterion does
not apply to Cohort 1d participants who are registering after having initiated
standard of care therapy.)

- Age ≥18 years

- Karnofsky performance status ≥ 70

- Participant is a candidate for, and agrees to receive conventional external beam
radiotherapy. (Patients screening for Cohort 1d can be actively receiving - or already
completed - their first line conventional external beam radiotherapy.)

- No corticosteroid dosing within 5 days of radiation therapy initiation (Cohorts 1a,
1b, 1c, & 1d).

- Normal hematologic, renal and hepatic function as defined below:

- ANC: greater or equal to 1,000 /mcl

- Platelets: greater than or equal to 100,000 /mcl

- Hemoglobin: greater than or equal to 9 gm/dl or ≥5.6 mmol/L without transfusion
or EPO dependency (within 7 days of assessment)

- International normalized ratio (INR) or prothrombin time: less than or equal to
1.5 times institutional ULN unless subject is receiving anticoagulant therapy as
long as PT or PTT is within therapeutic range of intended use of anticoagulants

- Activated partial thromboplatin time (aPTT): less than or equal to 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

- Serum creatinine: less than or equal to 1.5 X institutional ULN OR Measured or
calculated creatinine clearance ≥60 mL/min for subject with creatinine levels >
1.5 X institutional ULN

- Total bilirubin: less than or equal to 1.5 X institutional ULN (or less than or
equal to 3.0 X institutional ULN for Gilbert's Syndrome) OR Direct bilirubin ≤
institutional ULN for subjects with total bilirubin levels > 1.5 institutional
ULN

- AST (SGOT) and ALT (SGPT): less than or equal to 2.5 X institutional ULN (or less
than or equal to 5.0 X institutional ULN for Gilbert's Syndrome)

- MGMT promoter methylation status determined by an institutional CLIA-approved
laboratory using a methylation specific PCR assay

- Adequate tumor content as determined by institutional pathologist for nucleic acid
extraction and DNA sequence analysis

- Patients unable to undergo magnetic resonance (MR) imaging because of non-compatible
devices can be enrolled, provided CT scans are obtained and are of sufficient quality.
Patients without non-compatible devices may not have CT scans performed to meet this
requirement

- An interval of at least 3 weeks between prior surgical resection to start of study
therapy (or one week for stereotactic biopsy to start of study treatment);

- Women of childbearing potential (WOCBP) must have a negative pregnancy test (minimum
sensitivity 25 IU/L or equivalent of HCG) before entry onto the trial, because the
effects NeoVax on the developing human fetus are unknown

- Participants cannot be breast feeding;

- Female participants enrolled in the study, who are not free from menses for greater
than or equal to 2 years, post hysterectomy/oophorectomy, or surgically sterilized,
must be willing to use either 2 adequate barrier methods or a barrier method plus a
hormonal method of contraception to prevent pregnancy or to abstain from sexual
activity throughout the study, starting with visit 1 through 120 days after the last
dose of the study therapy;

- Approved contraceptive methods include for example; intra uterine device, diaphragm
with spermicide, cervical cap with spermicide, male condoms, or female condom with
spermicide. Spermicides alone are not an acceptable method of contraception;

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

II. Exclusion Criteria:

Participants who exhibit any of the following conditions at either screening timepoint will
not be eligible for admission into or continuation on the study

- Stereotactic biopsy (without further resection);

- Tumor primarily localized in the infratentorial compartment or spinal cord - tumors
with limited infratentorial compartment or spinal cord involvement are eligible;

- Radiographic or cytologic evidence of diffuse leptomeningeal extension - tumors with
limited subependymal involvement are eligible;

- Participants who have received or plan to receive any additional treatment for
glioblastoma aside from surgical resection and conventional radiotherapy (Cohort 1)
and pembrolizumab (cohorts 1a, 1b and 1c) and temozolomide (cohort 1d), including -
but not limited to - temozolomide (cohorts 1, 1a, 1b and 1c), stereotactic
radiosurgery, placement of Gliadel (carmustine; BCNU) wafers, any other intratumoral
or intracavitary treatment, brachytherapy, Novo-Tumor Treating Fields (Optune), or
investigational therapeutic agents. (Cohort 1d participants may have already initiated
or completed their RT with concomitant TMZ, and may have initiated their adjuvant TMZ
at the time of study entry as long as they do not have evidence of progressive disease
and have undergone a leukopheresis or blood draw with adequate mononuclear cell
collection.)

- Concomitant therapy with any anti-cancer agents, other investigational anti-cancer
therapies, or immunosuppressive agents including but not limited to methotrexate,
chloroquine, azathioprine, etc. within six months of study participation;

- History of severe allergic reactions attributed to any vaccine therapy for the
prevention of infectious diseases;

- Active, known, or suspected autoimmune disease or immunosuppressive conditions that
has required systemic treatment in the past 2 years (i.e. with use of disease
modifying agents, corticosteroids or immunosuppressive drugs) with the exception of
vitiligo, type 1 diabetes, residual autoimmune-related hypothyroidism requiring
hormone replacement, or psoriasis not requiring systemic treatment. Replacement
therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy
for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic
treatment.

- Known chronic infections with HIV, hepatitis B (HBV) or C (HCV), Hepatitis B virus DNA
and testing for HCV RNA must be undetectable.

- Uncontrolled intercurrent illness including, but not limited to ongoing or active
infection requiring treatment, symptomatic congestive heart failure, unstable angina
pectoris, cardiac arrhythmia;

- Any underlying medical condition, psychiatric condition or social situation that in
the opinion of the investigator would compromise study administration as per protocol
or compromise the assessment of AEs;

- Planned major surgery;

- Pregnant women are excluded from this study because personalized neoantigen peptides
and poly-ICLC are agents with unknown risks to the developing fetus. Because there is
an unknown but potential risk of adverse events in nursing infants secondary to
treatment of the mother with personalized neoantigen peptides and poly-ICLC, nursing
women are excluded from this study;

- Individuals with a history of an invasive malignancy are ineligible except for the
following circumstances; a) individuals with a history of invasive malignancy are
eligible if disease-free for at least 3 years and are deemed by the investigator to be
at low risk for recurrence of that malignancy; b) individuals with the following
cancers are eligible if diagnosed and treated - carcinoma in situ of the breast, oral
cavity or cervix and basal cell or squamous cell carcinoma of the skin;

Coh 1a/1b/1c/1d Exclusions:

- Hypersensitivity to pembrolizumab or any of its excipients.

- Is currently participating and receiving study therapy or has participated in a study
of an investigational agent and received study therapy or used investigational device
within 4 weeks of the first dose of treatment. (NOTE: Participation in a clinical
trial evaluating interventions for purposes other than GBM therapy is not a basis for
exclusion, and may be permitted pending prospective approval of Principal Investigator
or designee.)

- Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study
Day 1 or who has not recovered (i.e., less than or equal to Grade1 or at baseline)
from adverse events due to agents administered more than 4 weeks earlier.

- Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy
within 2 weeks prior to study Day 1 or who has not recovered (i.e., less than or equal
to Grade 1 or at baseline) from adverse events due to a previously administered agent.

- Note: Subjects with less than or equal to Grade 2 neuropathy are an exception to
this criterion and may qualify for the study.

- Note: If subject received major surgery, subject must have recovered adequately
from the toxicity and/or complications from the intervention prior to starting
therapy.

- Note: Cohort 1d participants may have already received their radiation therapy
with concomitant temozolomide, and may have initiated their adjuvant
temozolomide, at the time of study entry as long as they do not have evidence of
progressive disease and have undergone a leukopheresis or blood draw with
adequate mononuclear cell collection.

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

- Has known active central nervous system (CNS) metastases and/or carcinomatous
meningitis. Subjects with previously treated brain metastases may participate proved
the disease is stable (without evidence of progression by imaging for at least four
weeks prior to the first dose of trial treatment and any neurologic symptoms have
returned to baseline), have no evidence of new or enlarging brain metastases, and are
not using steroids for at least 7 days prior to trial treatment. This exception does
not include carcinomatous meningitis which is excluded regardless of clinical
stability;

- Has known history of non-infectious pneumonitis/ interstitial lung disease that
required steroids or has current pneumonitis/interstitial lung disease.

- Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.

- Has received a live vaccine within 30 days of planned start of study therapy. Examples
of live vaccines include, but are not limited to, the following: measles, mumps,
rubella, varicella/zoster, yellow fever, rabies, BCG, and Typhoid vaccine.

- Note: Seasonal influenza vaccines for injection are generally inactivated flu
vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist)
are live attenuated vaccines, and are not allowed