A Two Arm Trial of Axitinib and Carboplatin/Paclitaxel in Melanoma

Inclusion Criteria

• Histologically or cytologically proven melanoma with Stage IV or unresectable stage III disease.
• Male or female, age ≥ 18 years.
• Resolution of all acute toxic effects of prior radiotherapy, chemotherapy or surgical procedures to NCI CTCAE Version 4.0 grade ≤1.
• May have ≤ 2 prior chemotherapy treatments and any prior immunotherapy treatments. These can include dacarbazine and/or temozolomide but not carboplatin or paclitaxel.
• At least 2 weeks since the end of prior systemic treatment (4 weeks for bevacizumab-containing regimens), radiotherapy, or surgical procedure with resolution of all treatment-related toxicity to NCI CTCAE Version 4.0 grade ≤ 1 or back to baseline except for alopecia or hypothyroidism.
• No evidence of preexisting uncontrolled hypertension. The baseline systolic blood pressure readings must be ≤140 mm Hg, and the baseline diastolic blood pressure readings must be ≤90 mm Hg. Patients whose hypertension is controlled by antihypertensive therapies are eligible.
• Adequate organ function as defined by the following criteria:
• 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
• Total serum bilirubin ≤ 1.5 x ULN (Grade 0-1)
• Absolute neutrophil count (ANC) ≥ 1500 /ml
• Platelets ≥ 100,000/mL
• Hemoglobin ≥ 9.0 g/dL (may be transfused or erythropoietin treated)
• Serum calcium ≥12.0 mg/dL
• Serum creatinine ≤ 1.5 x ULN
• Patients with CNS (central nervous system) metastasis must have had either:
• Resected CNS metastasis without evidence of recurrence for > 12 weeks, OR
• Brain metastasis treated by stereotactic radiosurgery without evidence of recurrence or progression for 12 weeks, OR
• Multiple brain lesions treated with whole brain radiation therapy with stable disease off corticosteroids for at least 12 weeks prior to the start of therapy, AND
• Without any evidence of leptomeningeal disease, AND
• Patients must be neurologically intact.
• May have previous adjuvant therapy with interferon, vaccines, or therapy with IL-2 or GM-CSF.
• Measurable disease by RECIST criteria.
• ECOG performance status 0 or 1.

Exclusion Criteria

• Major surgery within 4 weeks of starting the study treatment.
• 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.
• NCI CTCAE version 4.0 grade 2 or greater hemorrhage within 4 weeks of starting study treatment.
• History of hemoptysis or bleeding from GI tract.
• History of abdominal fistulae or perforation within 6 months prior to starting study treatment.
• History of or known carcinomatous meningitis, or evidence of symptomatic leptomeningeal disease on screening CT or MRI scan.
• Any of the following within the 6 months prior to study drug administration: myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident or transient ischemic attack, or pulmonary embolism.
• Hypertension that cannot be controlled by medications.
• Current use or anticipated need for treatment with drugs that are known potent CYP3A inhibitors (grapefruit juice, verapamil, ketoconazole, miconazole, itraconazole, erythromycin, telithromycin, clarithromycin, indinavir, saquinavir, ritonavir, nelfinavir, lopinavir, atazanavir, amprenavir, fosamprenavir and delavirdine).
• Current use or anticipated need for treatment with drugs that are known potent CYP3A or CYP1A2 inducers (ie, carbamazepine, dexamethasone, felbamate, omeprazole, phenobarbital, phenytoin, amobarbital, nevirapine, primidone, rifabutin, rifampin, and St. John's wort).

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