Nivolumab plus Axitinib for the Treatment of Stage III or IV Melanoma

Inclusion Criteria

• Be willing and able to provide written informed consent for the trial
• Be >= 18 years of age on day of signing informed consent
• 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 response evaluation criteria in solid tumors (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 eastern cooperative oncology group (ECOG) performance scale
• Absolute neutrophil count (ANC) >= 1,000 /mcL (within 14 days of treatment initiation)
• Platelets >= 50,000 / mcL (within 14 days of treatment initiation)
• Hemoglobin >= 7 g/dL without transfusion or erythropoietin (EPO) dependency (within 7 days of assessment) (within 14 days of treatment initiation)
• Serum creatinine =< 1.5 X upper limit of normal (ULN) OR measured or calculated creatinine clearance (glomerular filtration rate [GFR] can also be used in place of creatinine or creatinine clearance [CrCl]*) >= 60 mL/min for subject with creatinine levels > 1.5 X institutional ULN (within 14 days of treatment initiation) * Creatinine clearance should be calculated per institutional standard
• Serum total bilirubin =< 1.5 X ULN OR direct bilirubin =< ULN for subjects with total bilirubin levels > 1.5 ULN (within 14 days of treatment initiation)
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X ULN OR =< 5 X ULN for subjects with liver metastases (within 14 days of treatment initiation)
• International normalized ratio (INR) or prothrombin time (PT) =< 1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or partial thromboplastin time (PTT) is within therapeutic range of intended use of anticoagulants (within 14 days of treatment initiation)
• Activated partial thromboplastin time (aPTT) =< 1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants (within 14 days of treatment initiation)
• Patients with brain metastases are permitted if they are asymptomatic or previously treated with central nervous system (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 must have a negative urine or serum pregnancy test within 7 days from the time of registration. Also, within 24 hours prior to receiving the first dose of study medication then every 4 weeks while on treatment
• Female subjects of childbearing potential should be willing to use 2 methods of birth control or be surgically sterile or abstain from heterosexual activity for the course of the study and for 5 months after the last dose of study medication. 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 7 months after the last dose of study therapy * Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject

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
• Has a 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 are excluded regardless of grade * Patients with prior Guillain-Barre syndrome, encephalitis, meningitis, or transverse myelitis are excluded regardless of grade * Patients with prior Stevens-Johnson syndrome or toxic epidermal necrolysis are excluded regardless of grade
• Has 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 * Note: measurement of screening blood pressure (BP) reading is based on an average of 3 readings at least 2 minutes apart if the subject has an initial BP >= 150/90. Subjects with initial screening BP >= 150/90 mmHg can be treated with anti-hypertensive medication to achieve a well-controlled status and are eligible with reassessed sex hormone-binding globulin (SBP)/ peroxisomal multifunctional enzyme type 2 (DBP) of < 160/100 mm Hg
• 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 * Note: Subjects with =< Grade 2 neuropathy are an exception to this criterion and may qualify for the study * Note: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy
• Has had radiation within 2 weeks of randomization
• Has current use or anticipated need for treatment with drugs or foods that are known strong cytochrome P450 (CYP34A4/5) inhibitors including but not limited to atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, troleandomycin, voriconazole, and grapefruit or grapefruit juice. NOTE: The topical use of these medications, such as 2% ketoconazole cream is allowed
• Has current use or anticipated need for treatment with drugs known to be strong CYP3A4/5 inducers, including but not limited to carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, and St. John’s wort
• Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy, in situ cervical cancer, in situ colon cancer, or nonmetastatic prostate cancer not on systemic therapy
• Has known active CNS metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least 2 weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability
• Has 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 or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment
• Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis
• Has an active infection requiring systemic IV antibiotic therapy
• Has had any of the following within the past 6 months * Myocardial infarction or unstable angina * Ventricular arrythmia * Acute decompensated heart failure * Cerebrovascular accident * Hypertensive emergency requiring intensive care unit (ICU) admission
• Presence of a disorder that may impact absorption of axitinib, such as inability to take oral medication, requirement for IV alimentation, prior gastric resection, treatment for active peptic ulcer confirmed by endoscopy within the past 3 months, active gastrointestinal (GI) bleed, malabsorption syndrome
• 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
• Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
• Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 5 months after the last dose of trial treatment for females and 7 months after the last dose of trial treatment for males
• Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies) if the CD4 count is less than 350 mm3 or serum HIV viral load is < 25,000 IU/mL
• Has a known history of or is positive for hepatitis B (hepatitis B surface antigen [HBsAg] reactive) or hepatitis C (hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is detected). * Note: Without known history, testing only needs to be performed if there is clinical suspicion for hepatitis B or C
• Is currently incarcerated or otherwise detained
• Has received a live vaccine within 30 days of planned start of study therapy * Note: seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal iNinfluenza vaccines (e.g., Flu-Mist) are live attenuated vaccines, and are not allowed