Naltrexone and Propranolol in Combination with Standard of Care Ipilimumab and Nivolumab for the Treatment of Stage II-III Melanoma

Inclusion Criteria

• Age ≥ 18, able to understand and sign the informed consent form
• Histologically confirmed, unresectable stage III/IV melanoma
• Being considered for standard of care therapy with ipilimumab 3 mg/kg + nivolumab 1 mg/kg
• Eastern Cooperative Oncology Group (ECOG) performance status 0-1
• Treatment-naïve or any number of prior lines of therapy. Prior targeted therapy is allowed. Prior small molecule inhibitors must be discontinued within 2 weeks before starting study
• Life expectancy of at least 6 months
• At least 1 site of disease must be accessible 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 to not be feasible. 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
• Absolute neutrophil count (ANC) >= 1500/mcL
• Platelets >= 100,000/mcL
• Hemoglobin (Hb) >= 9 g/dL
• Albumin >= 2.5 mg/dL
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 X upper limit of normal (ULN)
• Serum total bilirubin =< 1.5X ULN or direct bilirubin =< ULN for subjects with total bilirubin levels > 1.5 X ULN
• Female subjects of childbearing potential should have a negative serum pregnancy within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
• Female subjects of childbearing potential should be willing to use a highly effective contraception (hormonal or intrauterine device [IUD]) along with a condom in their male partner, or be surgically sterile or abstain from heterosexual activity for a period of at least 6 months after the last dose of study drug. Subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year
• Male subjects should agree to use an adequate method of contraception starting with the first dose of study therapy through at least 6 months after the last dose of study drug
• Patients must have at least one measurable lesion at baseline by computed tomography (CT) or magnetic resonance imaging (MRI) as per RECIST v1.1 criteria. Tumor sites situated in a previously irradiated area, or in an area subjected to other loco-reginal therapy, are not considered measurable unless there has been demonstrated progression in the lesion
• Prior focal radiotherapy is allowed

Exclusion Criteria

• Untreated brain metastases are excluded. (Exceptions: after discussion with the PI, untreated brain metastases may be allowed in patients who are treatment-naïve ONLY provided the brain metastases are =< 10 mm, asymptomatic, do not have significant edema, hemorrhage, cause shift, or require steroids or anti-seizure medications and are not in eloquent areas. These patients may be potentially eligible to forego initial local treatment of the brain metastases and have them reassessed at 6-8 weeks after consultation with the Neurosurgery and Radiation Oncology teams)
• Use of corticosteroids to control immune related adverse events at enrollment will not be allowed, and patients who previously required corticosteroids for symptom control must be off steroids for at least 2 weeks. Low-dose steroid use (≤ 10 mg of prednisone or equivalent) as corticosteroid replacement therapy for primary or secondary adrenal insufficiency is allowed
• Has not recovered (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
• Has active autoimmune disease unrelated to use of immune checkpoint inhibitors that has required systemic treatment in the past year (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
• Has contraindications to 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 betablocker; 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: Has contraindications to use of naltrexone including: 1) patients currently receiving opioid analgesics or who are anticipated to require opioid analgesics in the near future; 2) patients currently dependent on opioids, including those currently maintained on opiate agonists (e.g., methadone) or partial agonists (e.g., buprenorphine); 3) patients in acute opioid withdrawal; 4) Any individual with a history of sensitivity to naltrexone
• Pregnancy or breast feeding. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with nivolumab, ipilimumab, propranolol, and naltrexone, breastfeeding must be discontinued if the mother is enrolled on this trial
• Patients may not be receiving any other investigational agents and may not have participated in a study of an investigational agent or using an investigational device within 4 weeks of the first dose of treatment
• Either a concurrent condition (including medical illness, such as active infection requiring treatment with intravenous antibiotics or the presence of laboratory abnormalities) or history of a prior condition that places the patient at unacceptable risk if he/she were treated with the study drug or a medical condition that confounds the ability to interpret data from the study
• Concurrent, active malignancies in addition to those being studied (other than cutaneous squamous cell carcinoma or basal cell carcinoma)
• Active (non-infectious) pneumonitis
• Has Hepatitis B (HBV) or Hepatitis C (HCV) acute or chronic infection
• Has received a live vaccine within 30 days prior to the first dose of trial treatment