Inclusion Criteria:

• Subjects must be willing and able to sign the informed consent and comply with the study
• protocol.
• Must be ≥18 years of age.
• Histologically confirmed metastatic melanoma with measurable (by RECIST v1.1), stage III (lymph node or in transit lesions) or stage IVA, IVB, or IVC disease that is accessible for injection.
• Confirmed progression during or after treatment with a PD-1 inhibitor (cannot be part of bi-specific antibody); e.g., nivolumab or pembrolizumab. Confirmed progression is defined as:
  • Radiological progression (confirmed at least 4 weeks after the initial scan showing PD); or
  • For progression based solely on worsening of non-target or new, non-measurable disease, confirmation by an additional scan at least 4 weeks after the initial scan unless progression is accompanied by correlative symptoms.
• In addition, all the following must hold:
  • No intervening anti-cancer therapy between the last course of PD-1 inhibitor treatment and the first dose of study treatment is allowed except for local measures (e.g., surgical excision or biopsy, focal radiation therapy);
  • The interval between last PD-1 inhibitor and start of study treatment should be at least 21 days with no residual anti-PD-1-related immune toxicities in excess of Grade 1 severity;
  • Subjects who had adjuvant anti-PD-1 treatment are eligible if they have either disease recurrence after the end of adjuvant treatment or on-treatment disease recurrence after ≥ 12 weeks of adjuvant treatment;
  • If subject BRAF mutation status is unknown, before randomization the subject must have BRAF testing performed using an approved assay method;
  • Patients with BRAF-positive tumor(s) are eligible for the study if they received prior treatment with a BRAF inhibitor (alone or in combination with a MEK inhibitor) or declined targeted therapy.
• ECOG Performance Status ≤ 1.
• Adequate baseline organ function as defined by:
  • Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L (1500/mm^3);
  • Platelet count ≥75 x 10^9/L (75,000/mm^3);
  • Hemoglobin ≥ 8.0 g/dL (4.96 mmol/L);
  • Serum creatinine ≤ 1.5 x upper limit of normal (ULN) or calculated creatinine clearance ≥ 60 mL/minute (≤ Grade 1);
  • Aspartate aminotransferase (AST) ≤ 2.5 x ULN; alanine aminotransferase (ALT) ≤ 2.5 x ULN; AST/ALT < 5 x ULN if liver involvement (≤ Grade 1);
  • Serum bilirubin ≤ 1.5 x ULN, except in subjects with Gilbert’s Syndrome who must have a total bilirubin < 3 mg/dL (≤ Grade 1).
• Women of childbearing potential (WOCBP) and men must agree to use effective contraceptive methods from screening until at least 90 days after the last dose of either ipilimumab or IMO-2125, whichever is later.
• Non-childbearing potential is defined as a woman who meets either of the following criteria:
  • postmenopausal state defined as no menses for 12 months without an alternative medical cause, or b) documented hysterectomy, bilateral tubal ligation; or
  • bilateral oophorectomy.
• Effective contraception methods are defined as one of the following:
  • True abstinence, defined as refraining from heterosexual intercourse, when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods), declaration of abstinence for the duration of a trial, and withdrawal are not acceptable methods of contraception;
  • Condoms and spermicide;
  • Diaphragm and spermicide;
  • Oral or implanted hormonal contraceptive (e.g., Implanon™);
    • NOTE: For subjects in Sweden, low dose oral contraceptives are not permitted.
  • An intra-uterine device.
• WOCBP must have a negative pregnancy test (serum or urine) according to the Schedule of Evaluations.

Exclusion Criteria:

• Ocular melanoma.
• Prior therapy with a TLR agonist, excluding topical agents.
• Prior ipilimumab with the exception of adjuvant treatment completed ≥ 6 months prior to enrollment.
• Systemic treatment with IFN-α within the previous 6 months.
• Known hypersensitivity to any oligodeoxynucleotide.
• Active autoimmune disease requiring disease-modifying therapy at the time of screening.
• Subjects with a requirement for systemic steroids receiving >10 mg/day of prednisone (or equivalent) for the 2 weeks preceding start of study treatment.
• Subjects with another primary malignancy that has not been in remission for at least 3 years with the exception of non-melanoma skin cancer, curatively treated localized prostate cancer with non-detectable prostate-specific antigen, cervical carcinoma in situ on biopsy or a squamous intraepithelial lesion on Papanicolaou (Pap) smear, and thyroid cancer (except anaplastic).
• Active systemic infections requiring antibiotics.
• Known active, hepatitis A, B, or C infection.
• Known diagnosis of human immunodeficiency virus (HIV) infection.
• Women who are pregnant or breast-feeding.
• Prior anaphylactic or other severe infusion reaction associated with human antibody administration that cannot be managed with standard supportive measures.
• Presence of known central nervous system, meningeal, or epidural metastatic disease. However, subjects with known brain metastases are allowed if the brain metastases are stable for ≥ 4 weeks before the first dose of study treatment. Stable is defined as neurological symptoms not present or resolved to baseline, no radiologic evidence of progression, and steroid requirement of prednisone ≤ 10 mg/day or equivalent.
• Impaired cardiac function or clinically significant cardiac disease.