NeoVax + CDX-301 and Nivolumab or Pembrolizumab in Melanoma

Inclusion Criteria:

Eligibility to participate will be assessed at one timepoint: prior to initial core needle/surgical biopsy (Initial Registration).

• Inclusion Criteria

• Participant is willing and able to give written informed consent

• Participants must have histologically confirmed stage IIIB/C/D or stage IVcutaneous melanoma (mucosal melanoma or uveal melanoma are excluded) that issurgically resected, is deemed surgically resectable, or is unresectable; tumortissue for sequence analysis must be available from either previous melanomaresection/biopsy or at least one site of disease must be amenable to surgicalor core 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 aNational Cancer Institute Common Terminology Criteria for Adverse Events (NCICTCAE) version 5.0, Grade of 0 or 1, except for toxicities not considered asafety risk, such as alopecia 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, whocan have 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 creatininelevels above institutional normal (if using the Cockcroft-Gault formulabelow):

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

Male CrCl = (140 - age in years) x weight in kg x 1.00 72 x serum creatinine in 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 or Pembrolizumab, because the effects of NeoVax plusMontanide and Nivolumab (or Pembrolizumab) on 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 Nivolumab or Pembrolizumab, PersonalizedNeoantigen vaccine, and CDX-301

• 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 5 months after the last dose of studytherapy. Approved contraceptive methods include for example: intra uterine device,diaphragm with spermicide, cervical cap with spermicide, male condoms, or femalecondom with spermicide. Spermicides alone are not an acceptable method ofcontraception. Should a woman become pregnant or suspect she is pregnant while sheor her partner is participating in this study, she should inform her treatingphysician immediately.The investigational product will be permanently discontinuedin an appropriate manner.

• Male participants should agree to use an adequate method of contraception startingwith visit 1 through 7 months after the last dose of study therapy

Exclusion Criteria:

• Prior immunotherapy for metastatic melanoma except for anti-CTLA-4. Patients withunresectable melanoma who have received PD-1 inhibition therapy as adjuvant therapyand stopped receiving PD-1 inhibition for a period of ≥ 6 months before startingtreatment with Nivolumab or Pembrolizumab are allowed to participate.

• 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 (withthe exception of vaccination against the SARS-CoV-2 virus for the prevention ofCOVID-19 disease) during the 4 week period prior to first dose of Nivolumab orPembrolizumab.

Participants may not receive any non-oncology vaccine therapy during the period of Nivolumab (or Pembrolizumab) or NeoVax plus CDX-301 administration and until at least 8 weeks after the last dose of study therapy. 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 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. Corticosteroids used as pre-medication for imaging studies areallowed.

• 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).

• Known sensitivity or allergy to Nivolumab, Pembrolizumab, or CDX-301

• 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 (except for surgery for resection of melanoma if applicable).

• Patients with known mutations/amplifications in Flt-3

• 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

• Prisoners, or subjects who are compulsory detained are not eligible to participate