A Study Combining NeoVax, a Personalized NeoAntigen Cancer Vaccine, With Ipilimumab to Treat High-risk Renal Cell Carcinoma

This research study is a Phase I clinical trial, which tests the safety of an investigational
kidney cancer vaccine and also tries to define the appropriate dose of the investigational
kidney cancer vaccine to use for further studies. "Investigational" means that the kidney
cancer vaccine, in this case the Personalized Neoantigen Cancer Vaccine, is being studied. It
also means that the FDA (the U.S. Food and Drug Administration) has not approved the
Personalized Cancer Vaccine for any use in patients, including people with kidney cancer.

Poly-ICLC (also called Hiltonol) is an experimental "viral mimic" and an activator of
immunity. Poly-ICLC is an investigational drug, meaning the FDA has not approved it as a
treatment for any disease.

Personalized NeoAntigen Cancer Vaccine: The purpose of this study is to determine if it is
possible to make and administer safely a vaccine against kidney cancer by using information
gained from specific characteristics of the participant's own kidney cancer. It is known that
kidney cancers have mutations (changes in genetic material) that are specific to an
individual patient and 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 participant's body fight
any tumor cells that could cause the kidney cancer to come back in the future. The study will
examine the safety of the vaccine when given at several different time points and will
examine the participant's blood cells for signs that the vaccine induced an immune response.

Ipilimumab (Yervoy™) is an antibody that has been approved by the United States Food and Drug
Administration (FDA) for the treatment of melanoma.

In this research study, the investigators are looking at the safety and tolerability of the
Personalized NeoAntigen Cancer Vaccine combined with Ipilimumab as well as the body's immune
response to the vaccine. Ipilimumab will be delivered as an injection given underneath the
skin rather than injected in the vein in proximity to each vaccination site in order to 1)
direct anti-CTLA4 activity to the vaccine-draining lymph nodes and 2) limit potential toxic
effects.

Inclusion Criteria:

- Ability to understand and the willingness to sign a written informed consent document.

- Patient is agreeable to allow tumor and normal tissue samples to be submitted for
complete exome and transcriptome sequencing.

- Patients must have histologically confirmed renal cell carcinoma, stage III or IV
before starting study drugs per AJCC (American Joint Committee on Cancer) 7th edition
7. Patients undergoing a potentially curative metastasectomy are eligible if the
tissue from the surgery is enough to make a vaccine. Patients who are asymptomatic
from their disease and with low volume metastatic disease (5 lesions or less, all
<2cm) are eligible.

- Patients with clear cell and non-clear cell histology are allowed.

- Patient should sign the consent before their planned surgery.

- Patients who have sarcomatoid elements in addition to having renal cell carcinoma
(RCC) are allowed.

- ECOG (Eastern Cooperative Oncology Group) performance status ≤ 1

- Age ≥ 18 years.

- Participants must have normal organ and marrow function as defined below:

- leukocytes ≥3,000/mcL (microliter)

- absolute neutrophil count ≥1,500/mcL

- platelets ≥100,000/mcL

- total bilirubin within normal institutional limits

- AST (aspartate aminotransferase)(SGOT) /ALT (alanine aminotransferase)(SGPT) ≤2.5
× institutional upper limit of normal

- creatinine ≤ 1.6 mg/dL OR

- creatinine clearance ≥50 mL/min/1.73 m2 for participants with creatinine levels
above institutional normal.

- 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 and within 7
days prior to start of study medication, because the effects NeoVax on the developing
human fetus are unknown. It is the investigators' responsibility to repeat the
pregnancy test should start of treatment be delayed.

- Female patients enrolled in the study, who are not free from menses for >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 for the duration of treatment
with ipilimumab plus 5 half-lives of ipilimumab (75 days) plus 30 days (duration of
ovulatory cycle) for a total of 105 days post-treatment completion. 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 patients must agree to use an adequate method of contraception for the duration
of treatment with study drugs plus 5 half-lives of the study drug (75 days) plus 90
days (duration of sperm turnover) for a total of 165 days post-treatment

Eligibility Criteria for Secondary Registration

- ECOG performance status <1

- Participants must have normal organ and marrow function as defined below:

- leukocytes ≥3,000/mcL

- absolute neutrophil count ≥1,500/mcL

- platelets ≥100,000/mcL

- total bilirubin within normal institutional limits

- AST(SGOT)/ALT(SGPT) ≤2.5 × institutional upper limit of normal

- creatinine ≤ 1.6 mg/dL OR

- creatinine clearance ≥50 mL/min/1.73 m2 for participants with creatinine levels
above institutional normal.

- Women of childbearing potential (WOCBP) must have a negative pregnancy test (minimum
sensitivity 25 IU/L or equivalent of HCG) within 7 days prior to start of study
medication, because the effects NeoVax on the developing human fetus are unknown. It
is the investigators' responsibility to repeat the pregnancy test should start of
treatment be delayed.

- Female patients enrolled in the study, who are not free from menses for >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 4 weeks after the last dose of 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 patients must agree to use an adequate method of contraception for the duration
of treatment with study drugs plus 5 half-lives of the study drug (75 days) plus 90
days (duration of sperm turnover) for a total of 165 days post-treatment

Exclusion Criteria:

- Prior treatment with immune-modulatory agents including, but not limited to: IL-2
(interleukin-2), CTLA-4 (cytotoxic T-lymphocyte-associated protein 4) blockade, PD-1
(Programmed cell death protein 1) /PD-L1 (Programmed cell death protein ligand 1)
blockade, CD40 (cluster of differentiation 40) stimulation, or CD137 (tumor necrosis
factor receptor superfamily member 9) stimulation.

- Prior investigational ccRCC-directed cancer vaccine therapy.

- Patients with active brain metastases or leptomeningeal disease.

- Prior systemic therapy, including targeted therapy such as VEGF (vascular endothelial
growth factor) or mTOR (mammilian target of rapamycin) inhibitors unless it is >6
months between last dose of drug and first vaccination with NeoVax

- Treatment with other investigational products within the last 2 months prior to entry
into this study.

- Previous bone marrow or stem cell transplant.

- Concomitant therapy with any anti-cancer agents, other investigational anti-cancer
therapies, or immunosuppressive agents; chronic use of systemic corticosteroids with
prednisone >10 mg/day.

- Use of a non-oncology vaccine therapy for prevention of infectious diseases during the
four week period prior to enrollment to the study. Patients may not receive any
non-oncology vaccine therapy during the period of NeoVax administration and until at
least 8 weeks after the last dose of study therapy

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

- History of or current active autoimmune diseases, [e.g. including but not limited to
inflammatory bowel diseases (IBD), rheumatoid arthritis, autoimmune thyroiditis,
autoimmune hepatitis, systemic sclerosis (scleroderma and variants), systemic lupus
erythematosus, autoimmune vasculitis, autoimmune neuropathies (such as Guillain-Barre
syndrome). Vitiligo and adequately controlled endocrine deficiencies such as
hypothyroidism are not exclusionary.].

- Patients who have had a history of acute diverticulitis, intra-abdominal abscess, GI
obstruction and abdominal carcinomatosis which are known risk factors for bowel
perforation.

- Concomitant treatment with corticosteroids greater than physiologic doses (used in the
management of cancer or non-cancer-related illnesses). Topical (if not including the
proposed vaccination sites) or inhalational steroids are allowed.

- Known chronic infections with HIV, hepatitis B or C.

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

- History of current immunodeficiency disease [e.g., splenectomy or splenic
irradiation].

- 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 adverse events (AEs).

- 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 another invasive malignancy are ineligible except for
the following circumstances: a) individuals with a history of invasive malignancy are
eligible if they have been disease-free for at least 2 years and are deemed by the
investigator to be at low risk for recurrence of that malignancy; b) individuals with
any of 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.