• Has histologically or cytologically confirmed melanoma.

• Has unresectable Stage III or Stage IV melanoma, per AJCC 8th Edition Staging Criteria, not amenable to local therapy.

• Male or female participants who are at least 18 years of age on the day of signing informed consent

• Male participants must agree to use a reliable method of contraception (refer to Section 6.4.1) during the treatment period and for at least 120 days after the last dose of study drug and must refrain from donating sperm during this period.

• Female participants must not be pregnant or breast feeding and meet at least one of the following conditions:

∙ Not a woman of childbearing potential (WOCBP)

‣ A WOCBP must agree to use a reliable method of contraception (refer to Section 6.4.1) during the treatment period and for at least 120 days after the last dose of study treatment.

• Participants must have received an anti-PD-1/PD-L1 mAb as part of their most recent line of therapy prior to enrollment in the study.

• Participants must have progressed on or after treatment with an anti-PD-1/PD-L1 mAb administered either as monotherapy or in combination with other checkpoint inhibitors or other therapies in their most recent line of therapy. PD 1 treatment progression is defined by meeting all of the following criteria:

∙ Has received at least 8 weeks of an anti-PD-1/PD-L1 mAb

‣ Has demonstrated progression after anti-PD-1/PD-L1 mAb therapy as defined by RECIST v.1.1. The initial evidence of progressive disease (PD) is to be confirmed by a second assessment no less than 4 weeks from the date of the first documented PD, in the absence of rapid clinical progression (as defined in 7.c)

‣ Progressive disease has been documented within 6 months from the last dose of anti-PD-1/L1 mAb.

• i. Progressive disease must be determined according to iRECIST ii. This determination is made by the investigator. Once PD is confirmed, the initial date of PD documentation will be considered the date of disease progression.

• d. Patients who progress while receiving or within 6 months of receiving the last dose of anti-PD-1/L1 mAb in the neoadjuvant or adjuvant setting will be included. Inclusion of patients who progress within 6 months of stopping neoadjuvant or adjuvant anti-PD-1/L1 mAb will be capped at 20% of the total study population. Inclusion of patients who progress while still receiving neoadjuvant or adjuvant anti-PD-1/L1 mAB will not be capped.

• The participant provides written informed consent for the trial

• Measurable disease based on RECIST v.1.1. Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions

∙ Multiple target lesions will be allowed and will be selected based on standard RECIST criteria.

‣ The following cutaneous lesions will be considered measurable lesions: lesions ≥ 10 mm in longest diameter or multiple melanoma lesions which in aggregate have a longest diameter of ≥ 10 mm, when measured by caliper.

⁃ Have available archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion. Formalin-fixed, paraffin embedded (FFPE) tissue blocks are preferred to slides.

• Newly obtained biopsies are preferred to archived tissue, but archived sample can be used at baseline provided that the patient has only had anti-PD-1/L1 based regimen since obtaining the sample.

∙ Biopsies may be taken from any amenable lesion, but it is preferable to use the same lesion throughout.

∙ Biopsy may be taken from previously irradiated lesions only if they have progressed since radiation therapy.

∙ Patient may still be eligible for study if tumor is not amenable to safe biopsy or biopsy is judged by patient or treating physician to not be in their best interest.

⁃ Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2. Evaluation of ECOG must be performed within 7 days prior to C1D1.

⁃ Adequate organ function as defined below. Specimens must have been collected within 7 days prior to the start of study treatment:

• Absolute neutrophil count (ANC) ≥1500/µL

∙ Platelets ≥100,000/µL

∙ Hemoglobin ≥9.0 g/dL or ≥5.6 mmol/La

∙ Creatinine OR measured or calculated creatinine clearance (GFR can be used in place of CrCl) ≤1.5 x ULN OR ≥45 mL/min for participant with creatinine levels \>1.5 x institutional ULN

∙ Total bilirubin ≤1.5 x ULN OR direct bilirubin ≤ULN for participants with total bilirubin levels \> 1.5 x ULN

∙ AST (SGOT) and ALT (SGPT) ≤2.5 x ULN (≤5 x ULN for participants with liver metastases)

∙ International normalized ratio (INR) OR prothrombin time (PT) ≤1.5 x ULN unless participant is receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulants

∙ Activated partial thromboplastin time (aPTT) ≤1.5 x ULN unless participant is receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulants NOTE: Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) transfusion within the last 2 weeks NOTE: Creatinine clearance (CrCl) should be calculated per institutional standard

⁃ Prior adverse events from anticancer therapy must be resolved to ≤ grade 1, with the exception of alopecia or endocrinopathies, which may be on replacement therapy. Prednisone equivalent of ≤ 10 mg is allowed.