Neoantigen Vaccine Plus Locally Administered Ipilimumab and Systemic Nivolumab in Advanced Melanoma

Inclusion Criteria:

• Participant is willing and able to give written informed consent

• Participants must have histologically confirmed cutaneous melanoma that isunresectable stage III or stage IV; at least one site of disease must be resectable,partially-resectable, or amenable to core biopsies to provide tumor tissue forsequence analysis. Participants with mucosal or uveal melanoma are excluded.

• Participants must have measurable disease by RECIST v1.1 that has not been treatedwith local therapy within the last 12 months of study treatment. The measurablelesion and the lesion used for surgical or core biopsies can be identical as long asit remains measurable after biopsy

• Age ≥ 18 years

• ECOG performance status of 0 or 1

• Recovered from all toxicities associated with prior treatment, to acceptablebaseline status (as to Lab toxicity see below limits for inclusion) or a NationalCancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4, Grade of 0 or 1, except for toxicities not considered a safety risk, such asalopecia or vitiligo

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

• WBC ≥3,000/µL

• ANC ≥1,500/µL

• Platelets ≥100,000/µL

• Hemoglobin ˃ 9.0 g/dL

• Total Bilirubin ≤ 1.5 x ULN (except subjects with Gilbert Syndrome, who canhave total bilirubin < 3.0 mg/dL)

• AST(SGOT)/ALT(SGPT) ≤ 3 x ULN

• Creatinine ≤ 1.5 x ULN OR

• Creatinine clearance ≥40 mL/min/1.73 m2 for participants with creatinine levelsabove institutional normal (if using the Cockcroft-Gault formula below):

• Female CrCl = (140 - age in years) x weight in kg x 0.85 72 x serum creatininein mg/dL

• Male CrCl = (140 - age in years) x weight in kg x 1.00 72 x serum creatinine inmg/dL

• Women of childbearing potential (WOCBP) should have a negative serum pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior tothe start of Nivolumab, because the effects of NeoVax plus Montanide and Nivolumabon the developing human fetus are unknown

• Because there is an unknown but potential risk for adverse events in nursing infantssecondary to treatment of the mother with study agents, breastfeeding should bediscontinued if the mother is treated with Ipilimumab, Nivolumab and PersonalizedNeoantigen vaccine + Montanide.

• Female participants enrolled in the study, who are not free from menses for >2years, post hysterectomy / oophorectomy, or surgically sterilized, should be willingto use either 2 adequate barrier methods or a barrier method plus a hormonal methodof contraception to prevent pregnancy or to abstain from sexual activity throughoutthe study, starting with visit 1 through 23 weeks (30 days plus the time requiredfor Nivolumab to undergo five half-lives) after the last dose of study therapy.Approved contraceptive methods include for example: intra uterine device, diaphragmwith spermicide, cervical cap with spermicide, male condoms, or female condom withspermicide. Spermicides alone are not an acceptable method of contraception. Shoulda woman become pregnant or suspect she is pregnant while she or her partner isparticipating in this study, she should inform her treating physician immediately.

• Male participants should agree to use an adequate method of contraception startingwith visit 1 through 31 weeks after the last dose of study therapy

• Eligibility Criteria for Secondary Registration

• ECOG performance status of 0 or 1

• Screening laboratory values must meet the following criteria and should be obtainedwithin 7 days prior to registration

• WBC ≥ 3000/μL

• Neutrophils ≥ 1500/μL

• Platelets ≥ 100 x103/μL

• Hemoglobin > 9.0 g/dL

• Serum creatinine ≤ 1.5 x ULN or creatinine clearance (CrCl) ≥ 40 mL/min (ifusing the Cockcroft-Gault formula below):

• Female CrCl = (140 - age in years) x weight in kg x 0.85 72 x serum creatininein mg/dL

• Male CrCl = (140 - age in years) x weight in kg x 1.00 72 serum creatinine inmg/dL

• AST/ALT ≤ 3 x ULN

• Total Bilirubin ≤ 1.5 x ULN (except subjects with Gilbert Syndrome, who canhave total bilirubin < 3.0 mg/dL)

• Women of childbearing potential (WOCBP) should have a negative serum pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior tothe start of Nivolumab, because the effects of NeoVax plus Montanide and Nivolumabon the developing human fetus are unknown

• Because there is an unknown but potential risk for adverse events in nursing infantssecondary to treatment of the mother with study agents, breastfeeding should bediscontinued if the mother is treated with Ipilimumab, Nivolumab and PersonalizedNeoantigen vaccine + Montanide.

• Female participants enrolled in the study, who are not free from menses for >2years, post hysterectomy / oophorectomy, or surgically sterilized, should be willingto use either 2 adequate barrier methods or a barrier method plus a hormonal methodof contraception to prevent pregnancy or to abstain from sexual activity throughoutthe study, starting with visit 1 through 23 weeks (30 days plus the time requiredfor Nivolumab to undergo five half-lives) after the last dose of study therapy.Approved contraceptive methods include for example: intra uterine device, diaphragmwith spermicide, cervical cap with spermicide, male condoms, or female condom withspermicide. Spermicides alone are not an acceptable method of contraception

• Male participants should agree to use an adequate method of contraception startingwith visit 1 through 31 weeks after the last dose of study therapy

Exclusion Criteria:

• Prior immunotherapy for metastatic melanoma except anti-CTLA-4

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

• Active brain metastases or leptomeningeal metastases

• Use of a non-oncology vaccine therapy for prevention of infectious diseases duringthe 4 week period prior to first dose of Nivolumab. Participants may not receive anynon-oncology vaccine therapy during the period of Nivolumab or NeoVax plus Montanideadministration and until at least 8 weeks after the last dose of study therapy

• History of severe allergic reactions attributed to any vaccine therapy for theprevention of infectious diseases

• Active, known or suspected autoimmune disease. Subjects are permitted to enroll ifthey have vitiligo, type I diabetes mellitus, residual hypothyroidism due toautoimmune condition only requiring hormone replacement, psoriasis not requiringsystemic treatment, or conditions not expected to recur in the absence of anexternal trigger

• A condition requiring systemic treatment with either corticosteroids (> 10 mg dailyprednisone equivalents) or other immunosuppressive medications within 14 days ofstudy drug administration. Inhaled or topical steroids and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of activeautoimmune disease

• test positive for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virusribonucleic acid (HCV antibody) indicating acute or chronic infection

• Known history of testing positive for human immunodeficiency virus (HIV) or knownacquired immunodeficiency syndrome (AIDS)

• Uncontrolled intercurrent illness including, but not limited to ongoing or activeinfection requiring treatment, symptomatic

• Any underlying medical condition, psychiatric condition or social situation that inthe opinion of the investigator would compromise study administration as perprotocol or compromise the assessment of AEs

• Planned major surgery

• Pregnant women are excluded from this study because Nivolumab, personalizedneoantigen peptides and poly-ICLC are agents with unknown risks to the developingfetus. Because there is an unknown but potential risk of adverse events in nursinginfants secondary to treatment of the mother with Nivolumab, personalized neoantigenpeptides and poly-ICLC, nursing women are excluded from this study

• Individuals with a history of an invasive malignancy are ineligible except for thefollowing circumstances: a) individuals with a history of invasive malignancy areeligible if they have been disease-free for at least 3 years and are deemed by theinvestigator to be at low risk for recurrence of that malignancy; b) individualswith the following cancers are eligible if diagnosed and treated - carcinoma in situof the breast, oral cavity or cervix, localized prostate cancer, basal cell orsquamous cell carcinoma of the skin