Pazopanib and Paclitaxel as First-Line Treatment for Subjects With Unresectable Stage III and Stage IV Melanoma

Inclusion Criteria: 1. Subjects must provide written informed consent prior to performance of study-specific procedures or assessments, and must be willing to comply with treatment and follow up. Procedures conducted as part of the subject's routine clinical management (e.g., blood count, imaging study) and obtained prior to signing of informed consent may be utilized for screening or baseline purposes provided these procedures are conducted as specified in the protocol. Note: It is not necessary that informed consent be obtained within the protocol-specified screening window. 2. Histologically confirmed cutaneous melanoma with 1) unresectable Stage III disease, or 2) Stage IV disease by American Joint Committee on Cancer (AJCC) criteria. 3. Must have measurable disease \[i.e. with at least one measurable lesion, per RECIST\]. A measurable lesion is defined as a lesion that can be accurately measured in at least one dimension with the longest diameter ≥20mm using conventional techniques or ≥10mm with spiral CT scan. Note: Subjects should be excluded if all baseline measurable lesions are within previously irradiated areas. Subjects participating in the exploratory analysis shall not have the biopsied lesion(s) as the only sites of measurable disease. 4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 5. Age 18 years old or older 6. A female is eligible to enter and participate in this study if she is of: Non-childbearing potential (i.e., physiologically incapable of becoming pregnant), including any female who has had: * A hysterectomy * A bilateral oophorectomy (ovariectomy) * A bilateral tubal ligation * Is post-menopausal Subjects not using hormone replacement therapy (HRT) must have experienced total cessation of menses for ≥1 year and be greater than 45 years in age, OR, in questionable cases, have a follicle stimulating hormone (FSH) value \>40 milliinternational unit (mIU)/mL and an estradiol value \<40pg/mL (\<140 pmol/L). Subjects must discontinue HRT prior to study enrollment due to the potential for inhibition of Cytochrome P450 (CYP) enzymes that metabolize estrogens and progestins. For most forms of HRT, at least 2-4 weeks must elapse between the cessation of HRT and determination of menopausal status; length of this interval depends on the type and dosage of HRT. If a female subject is determined not to be post-menopausal, they must use adequate contraception, as defined immediately below. Childbearing potential, including any female who has had a negative serum pregnancy test within 2 weeks prior to the first dose of study treatment, preferably as close to the first dose as possible, and agrees to use adequate contraception. Acceptable contraceptive methods, when used consistently and in accordance with both the product label and the instructions of the physician, are as follow: * An intrauterine device with a documented failure rate of less than 1% per year. * Vasectomized partner who is sterile prior to the female subject's entry and is the sole sexual partner for that female. * Complete abstinence from sexual intercourse for 14 days before exposure to investigational product, through the dosing period, and for at least 21 days after the last dose of investigational product. * Double-barrier contraception (condom with spermicidal jelly, foam suppository, or film; diaphragm with spermicide; or male condom and diaphragm with spermicide). Note: Oral contraceptives are not reliable due to potential drug drug interactions. Female subjects who are lactating should discontinue nursing prior to the first dose of study drug and should refrain from nursing throughout the treatment period and for 14 days following the last dose of study drug. A male with a female partner of childbearing potential is eligible to enter and participate in the study if he uses a barrier method of contraception or abstinence during the study. 7. Adequate organ system functions as defined below: System:Laboratory Values Hematologic * Absolute neutrophil count (ANC) \>= .5 X 10\^9/L * Hemoglobin \>= 9 g/dL * International normalized ratio (INR) \<= 1.2 X upper limit of normal (ULN) * Partial thromboplastin time (PTT) \<= 1.2 X ULN Hepatic * Total bilirubin \<= 1.5 X ULN * Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) \<=2.5 x ULN Renal * Calculated creatinine clearance \>= 30 mL/min Note: Subjects may not have had a transfusion within 7 days of screening assessment. * Platelets \>= 100 X 10\^9/L * Urine Protein to Creatinine Ratio (UPC) \< 1 Note: If UPC is more than 1, then a 24-hour urine protein must be assessed. Subjects must have a 24-hour urine protein value \<1g to be eligible. 8. Corrected serum calcium concentration within normal range per local clinical laboratory standard. 9. Left ventricular ejection fraction (LVEF) more or equal lower limit of normal (LLN) as assessed by echocardiography or multigated acquisition (MUGA) scan. Exclusion Criteria: * Subjects meeting any of the following criteria must not be enrolled in the study: 1. Prior treatment with cytotoxic anti-cancer therapy. (Previous cytokine or investigational immunotherapy are permitted, but must be completed 28 days prior to first dose of study medication). 2. Prior use of other investigational or licensed tyrosine kinase inhibitors (TKIs), or agents which target vascular endothelial growth factor (VEGF) or VEGF receptors (ie. bevacizumab, VEGF-Trap). 3. Known history of dose-limiting hypersensitivity reactions to paclitaxel/Cremophor EL. 4. Pregnant or lactating female. Female subjects who are lactating are eligible if they discontinue nursing prior to the first dose of study drug and refrain from nursing throughout the treatment period and for 14 days following the last dose of study drug. 5. Melanoma of ocular origin. 6. History of another malignancy. Note: Subjects who have had another malignancy and have been disease-free for 3 years, or subjects with a history of completely resected non-melanomatous skin carcinoma or successfully treated in situ carcinoma are eligible. 7. Life expectancy less than 3 months. 8. History or clinical evidence of central nervous system (CNS) metastases or leptomeningeal carcinomatosis except for subjects who have previously-treated CNS metastases (surgery with or without radiotherapy, radiosurgery, or gamma knife) and meet all 3 of the following criteria: 1. Are asymptomatic 2. Have had no evidence of active CNS metastases for more or equal 6 months prior to enrollment 3. Have no requirement for steroids or enzyme-inducing anticonvulsants (EIAC) 9. Clinically significant gastrointestinal abnormalities including, but not limited to: 1. Malabsorption syndrome 2. Major resection of the stomach or small bowel that could affect the absorption of study drug 3. Active peptic ulcer disease 4. Inflammatory bowel disease 5. Ulcerative colitis, or other gastrointestinal conditions with increased risk of perforation 6. History of abdominal fistula, gastrointestinal perforation, or intra abdominal abscess within 28 days prior to beginning study treatment. 10. Presence of uncontrolled infection. 11. Prolongation of corrected QT interval (QTc) \>480 milliseconds (ms). 12. History of any one or more of the following cardiovascular conditions within the past 6 months: 1. Cardiac angioplasty or stenting 2. Myocardial infarction 3. Unstable angina 4. Symptomatic peripheral vascular disease 5. Class III or IV congestive heart failure, as defined by the New York Heart Association (NYHA) 13. History of cerebrovascular accident, pulmonary embolism or untreated deep venous thrombosis (DVT) within the past 6 months. Subjects with recent DVT who have been treated with therapeutic anti-coagulating agents for at least 6 weeks are eligible. 14. Poorly controlled hypertension \[defined as systolic blood pressure (SBP) of ≥150 millimeters of mercury (mmHg)or diastolic blood pressure (DBP) of ≥ 90 mmHg\]. Note: Initiation or adjustment of antihypertensive medication(s) is permitted prior to study entry. Blood pressure must be re-assessed on two occasions that are separated by a minimum of 24 hours. The mean SBP/DBP values from each blood pressure assessment must be less or equal 150 systolic and 90 diastolic mmHg in order for a subject to be eligible for the study. 15. Prior major surgery or trauma within 14 days of the first dose of study drug and/or presence of any non-healing wound, fracture, or ulcer. 16. Evidence of active bleeding or bleeding diathesis 17. Hemoptysis within 6 weeks of first dose of study drug. 18. Any serious and/or unstable pre-existing medical, psychiatric, or other conditions that could interfere with subject's safety, obtaining informed consent or compliance to the study. 19. Use of any prohibited medications within 14 days of the first dose of study medication. 20. Radiation therapy within 28 days of the first dose of study drug. 21. Any ongoing toxicity from prior anti-cancer therapy that is \>Grade 1 and/or that is progressing in severity. 22. Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to pazopanib.