Combination of Temozolomide and Sunitinib in Treatment of Patients With Metastatic and Unresectable Malignant Melanoma

The therapy with a combination of a chemotherapeutic agent with a known activity against
melanoma (temozolomide) and a new small molecule that inhibits angiogenesis (sunitinib
malate) will be tested in this clinical trial. Both agents have been approved for use in
humans with different types of malignancies, and the tolerated doses of each medication have
been established,but they have never been studied in combination. Therefore, this trial will
start as a phase-1 trial that will allow us to establish the maximum tolerated dose of both
medications, and then we will proceed with the phase-2 trial. Temozolomide has been widely
used in patients with melanoma, and protracted dosing of the drug has been shown to be safe;
sunitinib malate has not been studied in melanoma. We will use temozolomide at a dose of
75mg/m2 daily, and only the dose of sunitinib malate will be escalated. The patient will be
started on 12.5 mg of sunitinib malate daily. Both drugs will be given daily for 6 weeks out
of an 8-week cycle. If no dose limiting toxicities are noted, the dose of sunitinib malate
will be increased to 25 mg daily, and then to 37.5 mg daily.

Inclusion Criteria:

- Patients with histologically confirmed, surgically incurable or unresectable stage
IIIc or IV melanoma, including ocular melanoma.

- Patients must not have received prior chemotherapy for melanoma, excluding
chemotherapy given during isolated limb perfusion for stage IIIc melanoma. Patients
who received adjuvant immunotherapy and/or immunotherapy for metastatic disease are
eligible for the trial.

- ECOG of 0-2.

- Age >= 18 years.

- Adequate laboratory values performed within 28 days prior to initiation of dosing.

- Absolute neutrophil count (ANC) >=1500/uL

- Platelet count >=100,000/uL

- Hemoglobin >=10.0 g/dL

- Serum creatinine ≤ 2 times ULN

- Total serum bilirubin <= 2 times ULN

- LDH <= 5 times ULN

- AST/SGOT or ALT/SGPT <= 2.5 times ULN, and <= 5 times ULN in cases of liver
metastasis

- Patients must have recovered from effects of major surgery or other prior therapy,
which should have been completed at least 28 days before starting experimental
therapy.

- Women of childbearing potential should be using an effective method of contraception.
Women of childbearing potential must have a negative urine or serum pregnancy test up
to 28 days prior to commencement of dosing and be practicing medically approved
contraceptive precautions for at least 6 months after completion of treatment as
directed by their physician.

- Men should use an effective method of contraception during treatment and for at least
6 months after completion of treatment as directed by their physician.

Exclusion Criteria:

- Major surgery, radiation therapy or immunotherapy within 4 weeks of starting the
study treatment.

- Evidence of active brain metastases.

- Any of the following within the 12 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.

- Ongoing cardiac dysrhythmias of NCI CTCAE Version 3.0 grade >= 2.

- Prolonged QTc interval on baseline EKG.

- Left ventricular ejection fraction less than 50% on screening echocardiogram

- Uncontrolled hypertension (>150/100 mm Hg despite optimal medical therapy).

- Pre-existing thyroid abnormality with thyroid function that cannot be maintained in
the normal range with medication.

- Treatment with drugs with dysrhythmic potential

- Treatment with potent CYP3A4 inhibitors and inducers

- Known clinically uncontrolled infectious disease including HIV positivity or
AIDS-related illness.

- Pregnant or nursing.