Study of the Anti-Angiogenesis Agent Axitinib in Patients With Stage III Malignant Melanoma

The American Cancer Society estimates that there will be about 68,720 new cases of melanoma
(29,900 in men and 25,200 in women) annually in the United States, and about 8,650 people
will die from this cancer. The systemic therapy of advanced disease remains palliative until
new agents are found that might improve the survival of patients with stage III melanoma.

Melanomas are often vascular, and a decrease in the number of blood vessels that supply the
tumor may starve it of needed nutrients. An approach to blocking the growth of blood vessels
that supply the tumor is to inhibit the vascular endothelial growth factor receptor tyrosine
kinase (VEGFR TK) signaling pathway. Axitinib (AG 013736) is a VEGFR TK inhibitor.

Because of the poor prognosis of patients with stage III melanoma and indications that
anti-angiogenesis compounds might have clinically meaningful activity in this disease, a
Phase 2 trial of the vascular endothelial growth factor receptor tyrosine kinase (VEGFR TK)
inhibitor Axitinib (AG 013736) is warranted.

Inclusion Criteria:

- Histologically documented melanoma with local lymph node stage III metastases.

- No prior systemic therapy. Prior adjuvant therapy with interferon does not count.

- No expectation of further effects of prior anticancer therapy.

- At least 1 target lesion, as defined by RECIST, that has not been irradiated. New
lesions that have developed in a previously irradiated field may be used as sites of
measurable disease assuming all other criteria are met. All target lesions must have a
unidimensional diameter of at least 1 cm for spiral CT scans if the reconstruction
algorithm is 0.5 cm), or an standard uptake value (SUV) value ≥ 2.5. Baseline
measurements/evaluations must be completed within 4 weeks prior to treatment.

- Adequate bone marrow, hepatic, and renal function documented within 14 days prior to
treatment as documented by:

- absolute neutrophil count (ANC, calculated as the absolute number of neutrophils
and bands) ≥1.5 x 10^9 cells/L

- platelets ≥100 x 10^9 cells /L

- aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 x upper
limit of normal (ULN), unless there are liver metastases in which case AST and
ALT ≤5.0 x ULN

- total bilirubin ≤1.5 x ULN

- serum creatinine ≤1.5 x ULN or calculated creatinine clearance ≥60 mL/min

- urinary protein <2+ by urine dipstick. If dipstick is ≥2+ then a 24-hour urine
collection can be done and the patient may enter only if urinary protein is <2 g
per 24 hours

- Age ≥18 years.

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

- No evidence of preexisting uncontrolled hypertension as documented by 2 baseline blood
pressure readings taken at least 1 hour apart. The baseline systolic blood pressure
readings must be ≤140, and the baseline diastolic blood pressure readings must be ≤90.
Patients whose hypertension is controlled by antihypertensive therapies are eligible.

- Women of childbearing potential must have a negative serum or urine pregnancy test
within 7 days prior to treatment.

- Written and voluntary informed consent

Exclusion Criteria:

- Stage IV disease

- History of hemoptysis

- Gastrointestinal abnormalities including:

- inability to take oral medication

- requirement for intravenous alimentation

- prior surgical procedures affecting absorption including gastric resection

- treatment for active peptic ulcer disease in the past 6 months

- active gastrointestinal bleeding, unrelated to cancer, as evidenced by
hematemesis, hematochezia or melena in the past 3 months without evidence of
resolution documented by endoscopy or colonoscopy.

- malabsorption syndromes.

- Previous treatment with anti-angiogenesis agents including thalidomide, or inhibitors
of epidermoid growth factor (EGF), platelet derived growth factor (PDGF), or
fibroblast growth factors (FGF) receptors.

- Current use or anticipated inability to avoid use of drugs that are known potent
cytochrome P450 3A4 (CYP3A4) inhibitors (ie, grapefruit juice, verapamil,
ketoconazole, miconazole, itraconazole, erythromycin, clarithromycin, ergot
derivatives, indinavir, saquinavir, ritonavir, nelfinavir, lopinavir, and
delavirdine).

- Current use or anticipated inability to avoid use of drugs that are known CYP3A4 or
Cytochrome P450 1A2 (CYP1A2) inducers (ie, carbamazepine, dexamethasone, felbamate,
omeprazole, phenobarbital, phenytoin, primidone, rifabutin, rifampin, and St. John's
wort).

- Active seizure disorder or evidence of brain metastases. (Appropriate imaging should
be done to rule out brain metastases.)

- A serious uncontrolled medical disorder or active infection that would impair their
ability to receive study treatment.

- History of a malignancy (other than melanoma) except those treated with curative
intent for skin cancer (other than melanoma) or in situ breast or cervical cancer or
those treated with curative intent for any other cancer with no evidence of disease
for 5 years.

- 10. Major surgical procedure or any radiation therapy within 4 weeks of treatment,
minimum rest period is 28 days post surgery; maximum rest period 56 days post surgery.

- Dementia or significantly altered mental status that would prohibit the understanding
or rendering of informed consent and compliance with the requirements of this
protocol.

- Patients (male and female) having procreative potential who are not using adequate
contraception or practicing abstinence.

- Women who are pregnant or breast-feeding.