DISEASE CHARACTERISTICS:

• Histologically confirmed melanoma

  • Unresectable stage IV disease
  • Mucosal and unknown primary disease allowed

• Measurable disease, defined as at least one lesion that can be measured in at least one dimension as ≥ 20 mm (or as ≥ 10 mm if the CT slice thickness is ≤ 5 mm)

  • Measurable lesion must be outside a previously treated area
• Must have 1 paraffin block of primary tumor and/or metastatic tissue available for analysis of MGMT
• No ocular melanoma
• No bleeding skin metastases
• No CNS metastases (even if previously treated) by brain MRI

PATIENT CHARACTERISTICS:

• WHO performance status 0-2
• ANC ≥ 1.5 x 10^9/L
• Platelet count ≥ 100 x 10^9/L
• Hemoglobin ≥ 90 g/L (transfusion allowed)
• Serum total bilirubin ≤ 1.5 times upper limit of normal (ULN)
• ALT and alkaline phosphatase ≤ 2.5 times ULN (5 times ULN in patients with liver metastases)
• Serum creatinine < 177 μmol/L
• Proteinuria < 2+ by urine dipstick OR urine protein ≤ 1 g by 24-hour urine collection
• INR ≤ 1.5
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception during and for 12 months after completion of study treatment
• No other primary tumors within the past 5 years, except adequately controlled limited basal cell or squamous cell skin cancer or carcinoma in situ of the cervix
• No history or evidence of CNS disease unrelated to cancer (e.g., uncontrolled seizures) by physical/neurological examination, unless adequately treated with standard medical therapy
• No frequent vomiting or any other pre-existing medical condition that would preclude swallowing and/or absorption of oral medication
• No history or evidence of inherited bleeding diathesis or coagulopathy with risk of bleeding
• No uncontrolled hypertension (i.e., systolic blood pressure > 150 mm Hg and/or diastolic blood pressure > 100 mm Hg, measured repeatedly, despite adequate treatment with at least two different antihypertensive drugs)

• No clinically significant (i.e., active) cardiovascular disease, including any of the following:

  • Cerebrovascular accident/stroke or myocardial infarction within the past 6 months
  • Unstable angina
  • New York Heart Association (NYHA) class II or greater congestive heart failure
  • Serious cardiac arrhythmia (i.e., ventricular arrhythmia, high-grade atrioventricular-block) that requires medication during the study, interferes with regularity of the study treatment, or is uncontrolled by medication
• No serious non-healing wound, active peptic ulcer, or non-healing bone fracture
• No abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the past 6 months
• No significant traumatic injury within the past 30 days
• No uncontrolled active infection
• No known HIV infection
• No known hypersensitivity to any of the study drugs or excipients
• No evidence of any other disease, metabolic or psychological dysfunction, psychiatric disorder, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug, or that may affect patient compliance with study routines, or places the patient at high risk from treatment-related complications

PRIOR CONCURRENT THERAPY:

• At least 4 weeks since prior adjuvant cytokine therapy (e.g., interleukin, interferon) or vaccine therapy and recovered

  • Prior vaccine therapy for stage IV disease allowed
• Prior perfusion therapy (limb and liver) for loco-regional disease allowed
• No prior chemotherapy for metastatic disease
• No prior bevacizumab or other angiogenic inhibitors
• No prior radiotherapy to lesion(s) selected for measurement
• More than 30 days since prior treatment in a clinical trial
• More than 30 days since prior major surgery with high risk of bleeding
• More than 24 hours since prior minor surgery

• More than 10 days since prior and no concurrent full-dose oral or parenteral anticoagulants or thrombolytic agents for therapeutic purposes

  • Prophylactic use of anticoagulants is allowed (e.g., maintenance of venous catheter)
• More than 10 days since prior and no concurrent acetylsalicylic acid (> 325 mg/day) or clopidogrel (> 75 mg/day)
• No other concurrent non-steroidal anti-inflammatory drugs (NSAIDs)
• No concurrent dipyridamole
• No concurrent major surgery
• No concurrent radiotherapy to the target lesions
• No other concurrent experimental drugs or anticancer therapy