Axelopran and Nivolumab in PD-1-Refractory Metastatic Melanoma

Inclusion Criteria: 1. Histologically confirmed, unresectable or metastatic cutaneous melanoma with documented PD-1-refractory disease, defined as disease progression during or after prior anti-PD-1-based therapy, meeting criteria for either primary or secondary (acquired) resistance, as follows57: 1. Primary resistance: Disease progression as best response, or stable disease lasting \<6 months, following at least 6 weeks (approximately two cycles) of anti-PD-1-based therapy, with progression confirmed by RECIST v1.1. 2. Secondary (acquired) resistance: Disease progression occurring after an initial objective response (complete or partial response) or durable stable disease (≥6 months) per RECIST v1.1 while receiving anti-PD-1-based therapy, or within 12 weeks of discontinuation of anti-PD-1 therapy following prior clinical benefit. 3. Note: Disease must have been histologically confirmed through prior pathology assessment conducted as per SOC. 4. Note: Prior anti-PD-1-based therapy may have been administered as monotherapy or in combination with other agents. 2. Age ≥ 18 years. 3. Eastern Cooperative Oncology Group (ECOG) Performance Scale (PS) 0-2 4. Measurable disease using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. 5. Patients must have normal organ and marrow function as defined below: 1. absolute neutrophil count ≥1,000/mcL 2. platelets ≥75,000/mcL 3. total bilirubin ≤1.5 × the institutional upper limit of normal (ULN) 4. AST(SGOT)/ALT(SGPT) ≤2.5 × institutional ULN (≤5 × the institutional ULN for patients with liver metastasis) 5. Creatinine clearance ≥40 mL/min/1.73 m2 for patients with a creatinine level above institutional normal. 6. Sexually active fertile subjects and their partners must agree to use highly effective methods of contraception prior to study entry, during the course of the study, and for 5 months after the last dose of treatment (whichever is later). In addition, men must agree not to donate sperm and women must agree not to donate eggs (ova, oocyte) for the purpose of reproduction during these same periods. 7. Female subjects of childbearing potential must not be pregnant or breastfeeding at screening. Female subjects are considered to be of childbearing potential unless one of the following criteria is met: a. Permanent sterilization (hysterectomy, bilateral salpingectomy, or bilateral oophorectomy) or documented postmenopausal status (defined as 12 months of amenorrhea in a woman \> 45 years-of-age in the absence of other biological or physiological causes). Note: Documentation may include review of medical records, medical examination, or medical history interview by study site staff. 8. Ability to understand and the willingness to sign a written informed consent document. 9. If known to have prior brain metastases, must not have evidence of active (enlarging and/or symptomatic lesions) brain disease on MRI/CT evaluation done within 28 days of start of study treatment. Exclusion Criteria: 1. Participant is not a candidate to continue anti-PD-1 therapy due to unresolved toxicities resulting from previous treatment with anti-PD-1 therapy. 2. Has an active autoimmune disease requiring systemic treatment within the past 3 months, or a syndrome that requires ongoing systemic steroids or immunosuppressive agents. Subjects with vitiligo, Graves' disease, or psoriasis not requiring systemic therapy or resolved childhood asthma/atopy would be an exception to this rule. i. Subjects that require intermittent use of bronchodilators or local steroid injections would not be excluded from the study. Subjects with stable hypothyroidism or Sjogren's syndrome will not be excluded from the study. ii. Physiological replacement doses of steroids are permitted. 3. Participant is taking a daily dose of opioids that is \>30 morphine milligram equivalents (MME) i. Daily opioid doses ≤30 MME are allowed 4. Has a history of non-infectious pneumonitis that required steroids, evidence of interstitial lung disease, or currently active non-infectious pneumonitis. 5. Prior malignancy within 2 years that in the investigator's opinion would be likely to affect the outcomes of the patients with unresectable melanoma. 6. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator. 7. Known HIV or active Hepatitis B or C. Checking viral serology will not be mandated. 8. Patients with major gastrointestinal surgery within 12 weeks prior to the first dose of study treatment. Patients who have a colostomy will be excluded from the trial. 9. Are unable to swallow pills or have known active inflammatory gastrointestinal disease, chronic diarrhea, previous gastric resection or lap band dysphagia, short-gut syndrome, gastroparesis, or other condition that limits the ingestion or gastrointestinal absorption of drugs administered orally. i. Note: Gastroesophageal reflux disease under medical treatment is allowed (assuming no drug interaction potential). 10. Subjects taking moderate to strong CYP3A inhibitors or P-gp inhibitors