Inclusion Criteria:

          1. Patients must have histologically confirmed metastatic melanoma with measurable, stage
             III (lymph node or in transit lesions) or stage IVA, IVB, or IVC disease.

          2. Patients must have symptomatic or radiographic progression during or after treatment
             with a PD-(L)1 inhibitor administered either as monotherapy or in combination.

               1. The interval between last PD-(L)1 directed treatment and start of study treatment
                  should be at least 21 days.

               2. Prior BRAF or MEK inhibitor treatment is not required. However, for patients with
                  known BRAF status:

                    -  Those with BRAF wild type may have had a maximum of two previous systemic
                       regimens for the treatment of melanoma.

                    -  Those with a BRAF mutation may have had a maximum of three previous systemic
                       regimens for the treatment of melanoma.

               3. Prior ipilimumab is permitted.

               4. Previous treatment with either a PD-1 inhibitor (for patients enrolling on the
                  IMO-2125 + pembrolizumab combination) or CTLA-4 inhibitor (for patients enrolling
                  on the IMO-2125 + ipilimumab combination if applicable) should not have been
                  accompanied by DLT for which permanent discontinuation is recommended (per USPI).

                    -  Patients with a history of Grade ≥2 gastrointestinal symptoms (e.g.,
                       diarrhea, colitis) during prior checkpoint inhibitor treatment should be
                       discussed with the Idera Medical Monitor during the Screening Period before
                       starting study treatment.

          3. Phase 1 patients must have at least two measurable tumor lesions ≥ 1.0 cm that are
             accessible to biopsy. Phase 2 patients must have at least one measurable lesion (per
             RECIST v1.1) which may be the same site that is used for the intratumoral injections.

          4. Patients must be ≥ 18 years of age.

          5. Patients must have Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 2.

          6. Patients must meet the following laboratory criteria:

               1. Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L (1500/mm3)

               2. Platelet count ≥ 75 x 10^9/L (75,000/mm3)

               3. Hemoglobin ≥ 8.0 g/dL (4.96 mmol/L)

               4. Serum creatinine ≤ 1.5 x upper limit of normal (ULN) or calculated creatinine
                  clearance ≥ 60 mL/minute

               5. Aspartate aminotransferase (AST) ≤ 2.5 x ULN; alanine aminotransferase (ALT) ≤
                  2.5 x ULN; AST/ALT < 5 x ULN if liver involvement

               6. Serum bilirubin ≤ 1.5 x ULN, except in patients with Gilbert's Syndrome who must
                  have a total bilirubin < 3 mg/dL

          7. Women of childbearing potential (WOCBP) and men must agree to use effective
             contraceptive methods from Screening throughout the study treatment period and until
             at least 90 days after the last dose of IMO-2125, 3 months after the last dose of
             ipilimumab or at least 4 months after the last dose of pembrolizumab.

          8. Patients must have an anticipated life expectancy > 3 months.

        Exclusion Criteria:

          1. Patients who have received prior therapy with a TLR agonist, excluding topical agents.
             Patients who have received experimental vaccines or other investigational immune
             therapies should be discussed with the Medical Monitor to confirm eligibility.

          2. Patients who have received systemic treatment with IFN-α within the previous 6 months
             prior to enrolling into this study.

          3. Patients with known hypersensitivity to any oligodeoxynucleotide.

          4. Patients with active autoimmune disease requiring disease-modifying therapy.

          5. Patients requiring concurrent systemic steroid therapy higher than physiologic dose
             (7.5 mg/day of prednisone).

          6. Patients with any form of active primary or secondary immunodeficiency.

          7. Patients with another primary malignancy that has not been in remission for at least 3
             years.

          8. Patients with active systemic infections requiring antibiotics or active hepatitis A,
             B, or C.

          9. Patients with a known diagnosis of human immunodeficiency virus (HIV) infection.

         10. Patients who previously had a severe reaction to treatment with a human antibody.

         11. Patients with known central nervous system, meningeal, or epidural disease.

         12. Women who are pregnant or breastfeeding.

         13. Patients with impaired cardiac function or clinically significant cardiac disease.

         14. Patients with ocular melanoma.