Inclusion Criteria:
* Age of 18 years or older and able to understand and sign the informed consent form.
* Histologically confirmed diagnosis of unresectable stage III or stage IV melanoma.
* Candidate for standard of care therapy with ipilimumab 3 mg/kg + nivolumab 1 mg/kg.
* Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
* Treatment-naïve or has received any number of prior lines of therapy. Prior targeted therapy is allowed, but small molecule inhibitors must be discontinued within two weeks before starting the study.
* Life expectancy of at least 6 months.
* Presence of at least one accessible site of disease to provide an on-study biopsy for tumor tissue. The biopsy may be waived after discussion with the Principal Investigator (PI) if it is deemed unfeasible. The site may be a target lesion as long as it will not be rendered unmeasurable by the biopsy procedure.
* Willingness to undergo tumor biopsy (if archival tumor is not available) prior to initiation of therapy and while on the study.
* Willingness to provide an archival specimen block, if available, for research purposes.
* Normal organ function, defined as:
1. Absolute neutrophil count (ANC) \>1500/mcL
2. Platelets \>100,000/mcL
3. Hemoglobin (Hb) \>9 g/dL
4. Albumin \>2.5 mg/dL
5. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) \<2.5 times the upper limit of normal (ULN)
6. Serum total bilirubin \<1.5 times ULN or direct bilirubin \< ULN for subjects with total bilirubin levels \>1.5 times ULN.
* Female participants of childbearing potential should have a negative serum pregnancy test within 72 hours prior to receiving the first dose of study medication.
* Female participants of childbearing potential should be willing to use a highly effective form of contraception (hormonal or intrauterine device) along with a condom in their male partner, or be surgically sterile, or abstain from heterosexual activity for a period of at least six months after the last dose of study medication.
* Male participants should agree to use an adequate method of contraception starting with the first dose of study therapy through at least six months after the last dose of study drug.
* Participants must have at least one measurable lesion at baseline by computed tomography (CT) or magnetic resonance imaging (MRI) as per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria. Tumor sites situated in a previously irradiated area or in an area subjected to other loco-regional therapy are not considered measurable unless there has been demonstrated progression in the lesion.
* Prior focal radiotherapy is allowed.
Exclusion Criteria:
* Presence of untreated brain metastases, unless discussed with the Principal Investigator (PI) and meet specific criteria for inclusion (treatment-naïve patients with brain metastases \<10 mm, asymptomatic, without significant edema, hemorrhage, shift, or requirement for steroids or anti-seizure medications, and not in eloquent areas). These patients may potentially forego initial local treatment of the brain metastases and have them reassessed after consultation with the Neurosurgery and Radiation Oncology teams.
* Use of corticosteroids to control immune-related adverse events at enrollment. Participants who previously required corticosteroids for symptom control must be off steroids for at least two weeks. Low-dose steroid use (=10 mg of prednisone or equivalent) as corticosteroid replacement therapy for primary or secondary adrenal insufficiency is allowed.
* Failure to recover (i.e., Grade 1 or at baseline) from adverse events due to prior treatment.
* History of grade 3-4 neurologic or cardiac toxicity or life-threatening liver toxicity poorly responsive to steroids with prior anti-PD-1 therapy.
* Presence of leptomeningeal disease.
* Active autoimmune disease unrelated to the use of immune checkpoint inhibitors that has required systemic treatment in the past year (e.g., 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) is not considered a form of systemic treatment.
* Contraindications to the use of propranolol, including:
1. Cardiogenic shock.
2. Sinus bradycardia greater than first-degree block.
3. Severe bronchial asthma.
4. Known hypersensitivity to propranolol.
5. Requirement for current use of an alternative beta-blocker.
6. Uncontrolled diabetes.
7. Uncontrolled depression.
8. Unstable angina or myocardial infarction within 3 months of Day 1 Cycle 1.
* For enrollment into Cohort 2-4 ONLY: Contraindications to the use of naltrexone, including:
1. Participants currently receiving opioid analgesics or anticipated to require opioid analgesics in the near future.
2. Participants currently dependent on opioids, including those currently maintained on opiate agonists (e.g., methadone) or partial agonists (e.g., buprenorphine).
3. Participants in acute opioid withdrawal.
4. Individuals with a history of sensitivity to naltrexone.
* Pregnancy or breastfeeding. If a woman becomes pregnant or suspects she is pregnant while participating in this study, she should inform her treating physician immediately. Breastfeeding must be discontinued if the mother is enrolled in this trial due to the potential risk for adverse events in nursing infants.
* Receipt of any other investigational agents or participation in a study of an investigational agent or use of an investigational device within four weeks of the first dose of treatment.
* Concurrent condition (including medical illness, active infection requiring treatment with intravenous antibiotics, or presence of laboratory abnormalities) or history of a prior condition that places the patient at unacceptable risk if treated with the study drug or confounds the ability to interpret data from the study.
* Concurrent, active malignancies in addition to those being studied, except for cutaneous squamous cell carcinoma or basal cell carcinoma.
* Active (non-infectious) pneumonitis.
* Hepatitis B (HBV) or Hepatitis C (HCV) acute or chronic infection.
* Receipt of a live vaccine
