Nivolumab Plus Axitinib in Patients With Anti-PD1 Refractory Advanced Melanoma

Inclusion Criteria

• Have unresectable (stage III) or advanced (stage IV) cutaneous or mucosal melanoma. Patients with uveal melanoma are not eligible.
• Progressed on prior anti-PD1 therapy with or without anti-CTLA4 therapy. Patients may have progressed in the adjuvant setting if treated within the last 6 months. Prior treatment with BRAF/MEK inhibitors permitted, however, not required. Progression must be radiographic, and progression of disease will be confirmed by a radiologist. Patients must have progressed during anti-PD-1 therapy, defined as unequivocal progression on or within 3 months of the last dose of anti-PD-1 therapy if treated in the metastatic setting, or within 6 months if treated in the adjuvant setting.
• Have measurable disease based on RECIST 1.1.
• Patients do not have to have biopsiable disease to be eligible. However, patients with biopsiable disease must undergo biopsy at study entry and at week 12.
• Have a performance status of 0 or 1 on the ECOG Performance Scale.
• Demonstrate adequate organ function, per protocol
• Patients with brain metastases are permitted if they are asymptomatic or previously treated with CNS directed therapy with stable CNS disease for at least 2 weeks. Stable is defined as asymptomatic or not progressing on imaging.
• Female patients of childbearing potential - negative pregnancy testing; use of birth control, surgically sterile or abstain from heterosexual activity during study and for 5 months after the last dose of study medication.
• Male subjects - agree to use an adequate contraception starting with the first dose of study therapy through 7 months after the last dose of study therapy; abstinence acceptable

Exclusion Criteria

• Prior history of Grade 3 or 4 immune-related adverse events or immune-related adverse events requiring discontinuation of prior therapies.
• History of hypertensive crisis or hypertensive encephalopathy.
• Significant thrombotic (e.g. deep vein thrombosis or pulmonary embolism) or hemorrhagic event within 6 months prior to enrollment.
• History of prior immune-related adverse event due to an anti-PD1 or anti-CTLA4 that has not resolved to grade 1 on a steroid dose of prednisone 10 mg or less at the time of study entry (excluding vitiligo and endocrine toxicity).
• Patients with prior myocarditis or other immune-mediated cardiac adverse events, prior Guillain-Barre syndrome, encephalitis, meningitis, or transverse myelitis, prior Stevens-Johnson syndrome or toxic epidermal necrolysis are excluded regardless of grade.
• Poorly controlled hypertension defined as systolic blood pressure (SBP) > 160 and/or diastolic blood pressure (DBP) > 100 despite antihypertensives. If subject is above this goal, treatment with anti-hypertensives to achieve better blood pressure control is permitted. Ambulatory blood pressure assessment is permitted if there is concern for discrepant blood pressure readings while patients are in clinic.
• Has Class III or IV heart failure based on the New York Heart Association.
• Has had major surgery within 4 weeks of randomization. This does not include outpatient surgeries that do not require post-operative admission.
• Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy (greater than the equivalent of prednisone 10 mg daily, unless for prior endocrine toxicity) or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment (premedication with steroids for contrast imaging studies is permitted).
• Has a known history of active TB (Bacillus Tuberculosis).
• Hypersensitivity to nivolumab or axitinib, or any of their excipients.
• Has had prior chemotherapy or targeted small molecule therapy within 1 week prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to a previously administered agent.
• Has had radiation within 2 weeks of randomization.
• Has current use or anticipated need for treatment with drugs or