Inclusion Criteria:

          -  1) Signed Written Informed Consent The signed informed consent form prior to the
             performance of any study related procedures that are not considered part of standard
             of care.

             2) Target Population

               1. Subjects who are ipilimumab naïve with progressive unresectable Stage III or
                  Stage IV melanoma; eligible patients may have had prior adjuvant therapy, but not
                  including ipilimumab, and been treated with up to 3 prior treatments for
                  metastatic melanoma [eg, chemotherapy, other biologic or targeted therapy or
                  Interleukin-2 (IL-2)].

               2. Histologic or cytologic confirmation of stage III or stage IV melanoma

               3. Measurable disease at baseline as assessed by CT and/or MRI

               4. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1

               5. Screening laboratory values must meet the following criteria and should be
                  obtained within 7 days prior to registration • White blood cell (WBC) ≥ 2000/μL •
                  Neutrophils ≥ 1500/μL

                    -  Platelets ≥ 100 x103/μL

                    -  Hemoglobin > 9.0 g/dL

                    -  Serum creatinine ≤ 1.5 x upper limit of normal (ULN) or creatinine clearance
                       (CrCl) ≥ 40 mL/min (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

                    -  Aspartate aminotransferase (AST)/Alanine aminotransferase (ALT) ≤ 3 x ULN
                       Total Bilirubin ≤ 1.5 x ULN (except subjects with Gilbert Syndrome, who can
                       have total bilirubin < 3.0 mg/dL)

                       3) Age and Reproductive Status Men and women ≥ 18 years old

               1. Men and women of childbearing potential (WOCBP) must be using an acceptable
                  method of contraception to avoid pregnancy throughout the study, and for women at
                  least 23 weeks after the last dose of investigational product and for men at
                  least 31 weeks after the last dose of investigational product in such a manner
                  that the risk of pregnancy is minimized. See Section 3.3.3 for the definition of
                  WOCBP.

               2. Women must have a negative serum pregnancy test (minimum sensitivity 25 IU/L or
                  equivalent units of HCG) within 24 hours prior to the start of investigational
                  product.

                  Exclusion Criteria:

          -  1) Target Disease Exceptions

             a) Subjects with known or suspected brain metastasis, or brain as the only site of
             disease are excluded with the following exceptions.

             i) Subjects with controlled brain metastasis (no radiographic progression at least 4
             weeks following radiation and/or surgical treatment, off steroids for at least 4
             weeks, and have no new or progressing neurological signs or symptoms) will be allowed.

             b) Subjects with a history of prior malignancy with the exception of carcinoma in situ
             of the cervix or other malignancy diagnosed > 2 years ago that has undergone
             potentially curative therapy with no evidence of disease for the last ≥ 2 years and
             that is deemed by the investigator to be at a low risk of recurrence.

             2) Medical History and Concurrent Diseases

             a) Active autoimmune disease or a history of known or suspected autoimmune disease
             with the exception of subjects with isolated vitiligo, treated thyroiditis or resolved
             childhood asthma/atopy.

             b) Known human immunodeficiency virus (HIV), active hepatitis A, or hepatitis B or C
             infection.

             c) Evidence of active infection that requires anti-bacterial, anti-viral, or
             anti-fungal therapy ≤ 7 days prior to initiation of study drug therapy d) History of
             acute diverticulitis within the last 6 months, or current chronic diarrhea e) Active
             peptic ulcer disease even if asymptomatic f) Prior organ allograft or allogenic bone
             marrow transplantation g) Uncontrolled or significant cardiovascular disease
             including, but not limited to, any of the following: i) Myocardial infarction within
             the past 6 months ii) Uncontrolled angina within the past 6 months iii) Any history of
             clinically significant ventricular arrhythmias (such as ventricular tachycardia,
             ventricular fibrillation or Torsades de pointes). Controlled atrial fibrillation by
             itself is not an exclusion criterion.

             h) Baseline toxicities from prior anti-cancer treatments > Grade 1. i) Inability to be
             venipunctured and/or tolerate venous access. j) Any major surgery within 4 weeks or a
             diagnostic procedure (eg incision, needle biopsy) within 1 day of study drug
             administration.

             k) Known drug or alcohol abuse. l) Presence of underlying medical condition that in
             the opinion of the Investigator or Sponsor could adversely affect the ability of the
             subject to comply with or tolerate study procedures and/or study therapy, or confound
             the ability to interpret the tolerability of combined administration of DS-8273A and
             nivolumab in treated subjects.

             3) Allergies and Adverse Drug Reaction

             a) History of allergy to components of nivolumab or DS-8273A, or known allergy to
             other antibody therapies.

             4) Sex and Reproductive Status

               1. WOCBP who are unwilling or unable to use an acceptable method to minimize the
                  risk of pregnancy for the entire study period and for at least 23 weeks after the
                  last dose of investigational product.

               2. Women who are pregnant or breastfeeding.

               3. Women with a positive pregnancy test on enrollment or prior to investigational
                  product administration.

               4. Sexually active fertile men not using effective birth control if their partners
                  are WOCBP.

                  5) Prohibited Prior Treatments and/or Therapies

             a) Exposure to any investigational drug within 4 weeks of study drug administration.

             b) Any anti-cancer therapy (eg, chemotherapy, biologics, radiotherapy, or hormonal
             treatment) within 4 weeks or at least 5 half-lives (whichever is longer) of study drug
             administration.

             c) Prior therapy with an anti-PD-1/PD-L1 antibody or a TRAIL-DR5 antibody d)
             Concurrent chemotherapy, hormonal therapy, immunotherapy regimens, or radiation
             therapy, standard or investigational.

             6) Other Exclusion Criteria

               1. Prisoners or subjects who are involuntarily incarcerated

               2. Subjects who are compulsorily detained for treatment of either a psychiatric or
                  physical (eg, infectious disease) illness