Inclusion Criteria:

- Must provide written informed consent for the study;

- Must be able to comply with the Protocol as judged by the Investigator;

- Are ≥ 18 years of age on day of signing informed consent;

- Have histologically confirmed Stage 3 (unresectable) or Stage 4 (metastatic) CM, as per the American Joint Committee on Cancer staging system, eighth edition;

- Have documented radiological progression on prior systemic therapy;

- Have previously received anti-PD-1/L1 as monotherapy or in combination. A maximum of 2 prior lines of systemic therapy is allowed for BRAF wild-type disease and a maximum of 3 prior lines of systemic therapy is allowed for BRAFV600 positive disease;

- Have measurable disease based on RECIST;

- Have a performance status of 0 or 1 on the ECOG Performance Status;

- Have adequate organ functions as defined per protocol;

- Female patients of childbearing potential must have a negative serum pregnancy test at the Screening Visit and a negative (urine or serum) pregnancy test within 72 hours
prior to study Day 1. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required and must be negative for the patient to be eligible;

- Female patients who are not postmenopausal, and who have not undergone surgical sterilization, must agree to use highly effective methods of contraception during the
treatment period and for 6 months after the last dose of study drug. They must also agree not to donate eggs (ova, oocytes) during the same timeframe; and

- Male patients with partners of childbearing potential must agree to use highly effective methods of contraception and barrier contraception (condom) during the treatment period and for 6 months after the last dose of study drug. They must also agree not to donate sperm during the same timeframe.

Exclusion Criteria:

- Have received investigational agent (including investigational device) within 4 weeks or an interval of 5 half-lives of the respective investigational agent prior to study
Day 1, whichever is longer, with the exclusion of an anti-PD-1/anti-PD-L1 antibody given as either a single agent or non-CTLA-4 antibody containing combination (e.g.,
anti-lymphocyte-activation gene 3 antibody);

- Have a known hypersensitivity to ANV419 or to any of the excipients, such as sucrose, histidine or polysorbate 80. For combination arms only: Have hypersensitivity to
pembrolizumab or ipilimumab or any of their excipients;

- For combination arms only: Have previously discontinued ipilimumab, pembrolizumab or any other PD-1/PD-L1 inhibitors due to unacceptable drug-related toxicity (defined as toxicities that required second line immunosuppression, ie, not controlled by steroids alone);

- Have an LDH level of ≥ 2 × upper limit of normal;

- Have not recovered (i.e., ≤Grade 1 or at baseline with the exception of alopecia or fatigue [up to Grade 2 allowed]) from AEs resulting from prior immunotherapies.  Patients who have autoimmune AEs controlled by replacement therapy (i.e., hypothyroidism) due to previous treatment are eligible provided replacement therapy has been initiated and toxicity has returned to Grade 1;

- Have not recovered (i.e., ≤ Grade 1 or at baseline) from toxicities due to a previously administered prior chemotherapy, targeted small molecule therapy, or radiation
therapy.

Note: If the patient received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting study drug. Major surgery is defined as any surgery requiring entrance into a body cavity (eg, chest, abdomen, or brain), organ removal, normal anatomy alteration, or joint replacement. Minor surgery is defined as any surgery in which skin, mucosa,
or connective tissue sections are altered (e.g., biopsy, cataract, endoscopic procedures, etc).

- Have been diagnosed with uveal/ocular or mucosal melanoma;

- Have a known additional malignancy (including all in-situ carcinoma) that is progressing or required active treatment within ≤ 2 years prior to enrollment.  Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that have undergone potentially curative therapy or in situ cervical cancer or patients who completed cancer-directed therapy and have no evidence of disease;

- Have active central nervous system metastases and/or carcinomatous meningitis.  Patients with previously treated brain metastases may participate provided they are
stable (without evidence of progression by imaging for at least 4 weeks prior to study Day 1 and any neurologic symptoms have returned to baseline or have been stable for at least 7 days), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to study drug. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability;

- Have a diagnosis of immunodeficiency or is receiving immunosuppressive therapy within 7 days prior to study Day 1;

- Are receiving systemic steroid > 10 mg of prednisone daily or equivalent or any other immunosuppressive medication at any dose level. Local steroid therapies (e.g., otic,
ophthalmic, intra-articular, or inhaled medications) are acceptable;

- Have an active autoimmune disease that has required systemic treatment in the past 2 years (i.e., with use of disease modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment;

- Have evidence of active, non-infectious pneumonitis;

- Have active (measurable) and uncontrolled (unresponsive to current therapy) infectious disease (bacterial, fungal, viral, or protozoic);

- Have a history of an acute coronary event (e.g., myocardial infarction) within 3 months prior to study Day 1, uncontrolled and symptomatic coronary artery disease or congestive heart failure New York Heart Association Class III/IV;

- Have an average QTcF interval > 470 msec at Screening;

- Have a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the patient's
participation for the full duration of the study, or it is not in the best interest of the patient to participate, in the opinion of the treating Investigator;

- Have known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the study;

- Are pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the study, starting with the Screening Visit through 6 months after the last dose of study drug;

- Are known to be human immunodeficiency virus (HIV) positive (or tests positive for HIV 1 or 2 at Screening), unless the following criteria are met: CD4+ lymphocyte count
> 350 µL; Had no history of acquired immunodeficiency syndrome (AIDS)-defining opportunistic infections within the past 12 months; Have been on established anti-retroviral therapy for at least 4 weeks; and Have an HIV viral load of < 400 copies/mL prior to study Day 1.

Note: Patients on strong cytochrome P450 (CYP)3A4
inhibitors or strong CYP3A4 inducers must be switched to an alternate effective anti-retroviral therapy regimen prior to study treatment or are excluded if regimen prior to study Day 1 cannot be altered.

- Have uncontrolled hepatitis B infection or hepatitis C infection; or Note: Patients with hepatitis B (positive hepatitis B surface antigen) who have controlled infection (serum hepatitis B virus DNA by polymerase chain reaction that is below the limit of detection and receiving anti-viral therapy for hepatitis B) are permitted. Patients with controlled infections must undergo periodic monitoring of hepatitis B virus DNA. 

Note: Patients with hepatitis C (positive hepatitis C virus antibody) who have controlled infection (undetectable hepatitis C virus RNA by polymerase chain reaction either spontaneously or in response to a successful prior course of anti-hepatitis C
virus therapy) are permitted.

- Have received a live vaccine within 30 days of study Day 1; Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however, intranasal influenza vaccines (eg, Flu-Mist®) are live attenuated vaccines, and are not allowed.

- For combination arms only: Have received solid organ or hematopoietic stem cell transplant.

Note: Other protocol defined Inclusion/Exclusion Criteria may apply.

Eligibility last updated 9/27/23. Questions regarding updates should be directed to the study team contact.