A Phase I Study combining NeoVax, a Personalized NeoAntigen Cancer Vaccine, with Ipilimumab to Treat high-risk Renal Cell Carcinoma

This research study is evaluating a new type of Kidney Cancer vaccine called "Personalized
NeoAntigen Cancer Vaccine"as a possible treatment for Kidney Cancer.

The following intervention will be involved in this study:

- Personalized Neoantigen Vaccine

- Poly-ICLC (Hiltonol)

- Ipilimumab

Inclusion Criteria for Initial Registration:

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

- Patients should have suspected stage III or stage IV clear cell renal cell carcinoma
(ccRCC), with anticipation that all disease can be surgically resected. Confirmation
of clear cell histology, final stage (III or IV), and removal of all disease will be
done after the surgery, and will be required for further participation of the trial.

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

- Patients undergoing a potentially curative metastatectomy are eligible if the tumor
tissue from the surgery is enough to make a vaccine.

- 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

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

- creatinine clearance ≥40 mL/min/(calculated using the Cockroft-Gault equation)

- 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

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

- creatinine ≥40 mL/min/(calculated using the Cockroft-Gault equation)

- Patients must have histologically confirmed clear cell renal cell carcinoma (ccRCC),
stage III or fully resected stage IV (no evidence of disease), before starting study
drugs per AJCC 8th edition.

- No evidence of disease (NED) at secondary registration.

- 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,
CTLA-4 blockade, PD-1/PD-L1 blockade, CD40 stimulation, or CD137 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 or mTOR inhibitors
unless it is >6 months between last dose of drug and first vaccination with NeoVax.
Systemic therapy is allowed only if prior therapy was not immune therapy (i.e. VEGF
TKI), and it was >6 months ago.

- 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 for ACTIVE cancer treatment, 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 (with the
exception of vaccination against the SARS-CoV-2 virus for the prevention of COVID-19
disease) is not allowed for 4 weeks prior to day 1, until 8 weeks after last study
dose. Given the severity of the COVID-19 pandemic, vaccination specifically against
the SARS-CoV-2 virus for the prevention of COVID-19 is ALLOWED in this study.

- 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 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 enfants 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.