A Phase II Trial of Sunitinib and Nivolumab for KIT-mutated Advanced Melanoma

Inclusion Criteria:

1. Unresectable stage 3 or stage 4 metastatic melanoma
2. A mutation, translocation, or fusion in the KIT gene in the patient's tumor felt to be potentially sensitive to tyrosine kinase inhibition. Expression of CD113 or other immunohistochemical test will not by itself satisfy this requirement.
3. Evidence of measurable disease by RECIST criteria 1.2 Bone lesions, ascites, peritoneal carcinomatosis or miliary lesions, pleural or pericardial effusions, lymphangitis of the skin or lung, cystic lesions, or irradiated lesions are not considered measurable. .
4. Resolution of all acute toxic effects of prior radiotherapy or surgical procedures to NCI CTCAE Version 3.0 grade ≤1.
5. Adequate organ function as defined by the following criteria:

   * Absolute neutrophil count (ANC) ≥1,000/µL
   * Platelets ≥75,000/µL
   * Hemoglobin ≥8.0 g/dL
   * Serum calcium ≤12.0 mg/dL
   * Serum creatinine ≤1.5 x ULN
   * Total serum bilirubin ≤1.5 x ULN
   * Serum aspartate transaminase (AST; serum glutamic oxaloacetic transaminase \[SGOT\]) and serum alanine transaminase (ALT; serum glutamic pyruvic transaminase \[SGPT\]) ≤2.5 x local laboratory upper limit of normal (ULN), or AST and ALT ≤5 x ULN if liver function abnormalities are due to underlying malignancy
6. Karnofsky performance status \> 60 %.
7. Male or female, 18 years of age or older.
8. Signed and dated informed consent document indicating that the subject (or legally acceptable representative) has been informed of all pertinent aspects of the trial prior to undergoing study screening procedures.
9. Subject's willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures.

Exclusion Criteria:

1. Brain metastasis requiring daily corticosteroid dosage over 7 .5mg/ day prednisone or equivalent.
2. Prior therapy with sunitinib or anti-PD-1 or anti-PDL-1 antibodies (pembrolizumab, nivolumab, etc.) Prior therapy with other KIT inhibitors (dasatinib, nilotinib, imatinib, etc.) allowed but results from these patients will be analyzed separately.
3. Major surgery or radiation therapy within 2 weeks of starting the study treatment. Prior palliative radiotherapy to metastatic lesion(s) is permitted, provided there is at least one measurable lesion that has not been irradiated.
4. NCI CTCAE Version 3.0 grade 3 hemorrhage within 4 weeks of starting the study treatment.
5. Any of the following within the 4 months prior to study drug administration: myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, symptomatic heart failure, or cerebrovascular accident.
6. Ongoing cardiac dysrhythmias of NCI CTCAE Version 3.0 grade \> 2.
7. Prolonged QTc interval on baseline EKG (\>450 msec for males or \>470 msec for females)
8. Uncontrolled hypertension (\> 170/100 mm hg despite optimal medical therapy).
9. Concurrent treatment on another clinical trial. Supportive care trials or non-treatment trials, e.g., QOL, are allowed.
10. Concomitant treatment with a drug having proarrhythmic potential (terfenadine, quinidine, procainamide, disopyramide, sotalol, probucol, bepridil, haloperidol, risperidone, indapamide and flecainide)
11. Use of potent CYP3A4 inhibitors and inducers 7 and 12 days before dosing, respectively (see below).
12. Definite history of ulcerative colitis or Crohn's disease or lupus
13. History of allogeneic transplant.
14. Pregnancy or breastfeeding. Female subjects must be surgically sterile or be postmenopausal, or must agree to use effective contraception during the period of therapy. All female subjects with reproductive potential must have a negative pregnancy test (serum or urine) prior to enrollment.