Overview

This research study is studying the drugs called NeoVax (a new type of personalized neoantigen vaccine) in combination with CDX-301 and Nivolumab as a possible treatment for melanoma.

The names of the study drugs involved in this study are:

• Personalized Neoantigen peptides (which combined with poly-ICLC make the vaccine NeoVax)
• Poly-ICLC (Hiltonol)
• CDX-301
• Nivolumab (Opdivo)

Eligibility

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 IV
                  cutaneous melanoma (mucosal melanoma or uveal melanoma are excluded) that is
                  surgically resected, is deemed surgically resectable, or is unresectable; tumor
                  tissue for sequence analysis must be available from either previous melanoma
                  resection/biopsy or at least one site of disease must be amenable to surgical or
                  core biopsy
               -  Age ≥ 18 years
               -  ECOG performance status of 0 or 1
               -  Recovered from all toxicities associated with prior treatment, to acceptable
                  baseline status (as to Lab toxicity see below limits for inclusion) or a National
                  Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE)
                  version 5.0, Grade of 0 or 1, except for toxicities not considered a safety 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, who can
                       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 creatinine
                       levels above 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 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 to the
             start of Nivolumab, because the effects of NeoVax plus Montanide and Nivolumab on the
             developing human fetus are unknown
          -  Because there is an unknown but potential risk for adverse events in nursing infants
             secondary to treatment of the mother with study agents, breastfeeding should be
             discontinued if the mother is treated Nivolumab, Personalized Neoantigen vaccine, and
             CDX-301
          -  Female participants enrolled in the study, who are not free from menses for >2 years,
             post hysterectomy / oophorectomy, or surgically sterilized, should 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 5 months 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. Should a
             woman become pregnant or suspect she is pregnant while she or her partner is
             participating in this study, she should inform her treating physician immediately.The
             investigational product will be permanently discontinued in an appropriate manner.
          -  Male participants should agree to use an adequate method of contraception starting
             with 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 with
             unresectable melanoma who have received PD-1 inhibition therapy as adjuvant therapy
             and stopped receiving PD-1 inhibition for a period of ≥ 6 months before starting
             treatment with Nivolumab are allowed to participate.
          -  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
          -  Active brain metastases or leptomeningeal metastases
          -  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) during the 4 week period prior to first dose of Nivolumab. Participants may
             not receive any non-oncology vaccine therapy during the period of Nivolumab 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 the
             prevention of infectious diseases
          -  Active, known or suspected autoimmune disease. Subjects are permitted to enroll if
             they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to
             autoimmune condition only requiring hormone replacement, psoriasis not requiring
             systemic treatment, or conditions not expected to recur in the absence of an external
             trigger
          -  A condition requiring systemic treatment with either corticosteroids (> 10 mg daily
             prednisone equivalents) or other immunosuppressive medications within 14 days of study
             drug administration. Inhaled or topical steroids and adrenal replacement doses > 10 mg
             daily prednisone equivalents are permitted in the absence of active autoimmune
             disease. Corticosteroids used as pre-medication for imaging studies are allowed.
          -  Test positive for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus
             ribonucleic acid (HCV antibody) indicating acute or chronic infection
          -  Known history of testing positive for human immunodeficiency virus (HIV) or known
             acquired immunodeficiency syndrome (AIDS).
          -  Known sensitivity or allergy to Nivolumab or CDX-301
          -  Uncontrolled intercurrent illness including, but not limited to ongoing or active
             infection requiring treatment, symptomatic
          -  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 (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, 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 Nivolumab, 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 they have been 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, localized prostate cancer, basal cell or squamous cell
             carcinoma of the skin
          -  Prisoners, or subjects who are compulsory detained are not eligible to participate