Carboplatin and Paclitaxel With or Without Sorafenib Tosylate in Treating Patients With Stage III or Stage IV Melanoma That Cannot Be Removed by Surgery

PRIMARY OBJECTIVES:

I. To compare the overall survival of patients with unresectable stage III or stage IV
melanoma treated with carboplatin, paclitaxel and placebo versus carboplatin, paclitaxel and
sorafenib (sorafenib tosylate).

II. To compare progression-free survival, response rate, and safety of patients with
unresectable stage III or stage IV melanoma treated with carboplatin, paclitaxel and placebo
versus carboplatin, paclitaxel and sorafenib.

III. To analyze the pharmacokinetic and pharmacogenetic properties of sorafenib including
angiogenesis, monooxygenases polymorphisms and multidrug resistance (MDR).

IV. To assess the association of expression markers in the patient tumor with clinical
outcome.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

Arm I: Patients receive paclitaxel intravenously (IV) over 3 hours and carboplatin IV over
30 minutes on day 1. Patients also receive sorafenib tosylate orally (PO) twice daily (BID)
(approximately every 12 hours) on days 2-19.

Arm II: Patients receive paclitaxel and carboplatin as in Arm I. Patients also receive
placebo PO BID (approximately every 12 hours) on days 2-19.

In both arms, treatment repeats every 21 days for 10 courses in the absence of disease
progression or unacceptable toxicity. Patients with stable disease or who achieve a partial
response or complete response may continue to receive sorafenib tosylate or placebo alone
BID (approximately every 12 hours) on days 1-21. Courses with sorafenib tosylate or placebo
repeat every 21 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed every 3 months for 2 years and
then every 6 months for 3 years.

Inclusion Criteria:

- Histological or cytological confirmed melanoma that is metastatic or unresectable;
patients must have a history of cutaneous, mucosal or unknown primary site

- Patients who have received prior systemic cytotoxic chemotherapy for treatment of
melanoma are ineligible; the following groups are eligible with regard to prior
systemic therapy either in the adjuvant or metastatic disease setting:

- No prior therapy

- Immunotherapy consisting of interferon, interleukin-2, granulocyte macrophage
colony-stimulating factor (GM-CSF) or vaccine

- One prior investigational therapy (cannot be chemotherapy or an inhibitor of rat
sarcoma [Ras], serine/threonine kinase [Raf], or mitogen-activated protein
kinase kinase [MEK])

- NOTE: Chemotherapy given via isolated limb perfusion is allowed

- Prior radiation therapy is allowed; however, if radiation has been administered to a
lesion, there must be radiographic evidence of progression of that lesion in order
for that lesion to constitute measurable disease or to be included in the measured
target lesions

- All sites of disease must be evaluated within 4 weeks of registration; patients must
have measurable disease as defined by Response Evaluation Criteria in Solid Tumors
(RECIST)

- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

- White blood count >= 3,000/mm^3

- Absolute granulocyte count >= 1,500/mm^3

- Platelet count >= 100,000/mm^3

- Serum creatinine =< 2.0 x upper limit of normal (ULN) or serum creatinine clearance
(CrCl) >= 40 ml/min (neither drug is cleared by the kidney)

- Total bilirubin =< 1.5 x ULN (< 3.0 x ULN in the presence of Gilbert's disease)

- Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 x ULN (=< 5.0
ULN in the presence of liver metastases)

- International normalized ratio (INR) =< 1.5 and a partial thromboplastin time (PTT)
within normal limits (patients who are on therapeutic anticoagulation with warfarin
should have documentation of a normal prothrombin time [PT]/PTT prior to initiating
that therapy)

- Patients must not have ocular melanoma

- Patients must have discontinued immunotherapy or radiation therapy at least 4 weeks
prior to initiation of treatment and recovered from adverse events due to those
agents

- Patients must not receive any other investigational agents during the period on study
or the four weeks prior to initiation of treatment

- Patients must not have a history or clinical evidence of brain metastasis; patients
must be evaluated with a head magnetic resonance imaging (MRI) within 4 weeks prior
to enrollment

- Patients must not have other current malignancies, other than basal cell skin cancer,
squamous cell skin cancer, in situ cervical cancer, ductal or lobular carcinoma in
situ of the breast; patients with other malignancies are eligible if they have been
continuously disease-free for >= 5 years prior to the time of randomization

- Patients must not have any evidence of bleeding diathesis

- Patients must not have a serious intercurrent illness including, but not limited to,
ongoing or active infection requiring parenteral antibiotics, clinically significant
cardiovascular disease (e.g. uncontrolled hypertension, myocardial infarction,
unstable angina), New York Heart Association grade II or greater congestive heart
failure, serious cardiac arrhythmia requiring medication, or grade II or greater
peripheral vascular disease within 1 year prior to study entry, or psychiatric
illness/social situations that would limit compliance with study requirements

- Patients must not be taking cytochrome P450 enzyme-inducing antiepileptic drugs
(phenytoin, carbamazepine or phenobarbital), rifampin or St. John's Wort

- Women must not be pregnant or breast-feeding

- All females of childbearing potential must have a blood test or urine study within 4
weeks prior to registration to rule out pregnancy

- Women of child-bearing potential and men must agree to use adequate contraception
(hormonal or barrier method of birth control; abstinence) prior to study entry and
for the duration of study participation; should a woman become pregnant while
participating in this study, she should inform her treating physician immediately; if
a man impregnates a woman while participating in this study, he should inform his
treating physician immediately as well

- Human immunodeficiency virus (HIV)-positive patients are excluded from the study