Dasatinib in Treating Patients With Stage III Melanoma That Cannot Be Removed By Surgery or Stage IV Melanoma

PRIMARY OBJECTIVES:

I. Determine the objective response rate in patients with stage III unresectable or stage IV melanoma treated with dasatinib.

II. Determine the progression-free survival of patients treated with this drug.

SECONDARY OBJECTIVES:

I. To assess the expression of targets of Dasatinib prior to treatment by obtaining pre-treatment biopsies or examining paraffin-embedded tissues from previous tumor resections.

II. In selected patients (approximately 5-10) where tumor tissue is available pre-treatment and can be obtained post-treatment with Dasatinib (21 days after initiation of therapy), to determine if Dasatinib induces changes in expression of selected targets and downstream mediators, including MEK, ERK and RSK-1.

III. To assess toxicity.

OUTLINE:

Patients receive oral dasatinib twice daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 4 weeks.

Inclusion criteria

• Histologically confirmed stage III unresectable or stage IV melanoma
• Measurable disease
• Must have evidence of tumor growth or new lesions within the past 6 months
• No large pleural effusions
• No known brain metastases or leptomeningeal metastases

• Previously treated brain metastases allowed provided there is no requirement for steroids AND no evidence of progression for ≥ 8 weeks after treatment
• ECOG performance status (PS) 0-1 OR Karnofsky PS 70-100%
• Life expectancy > 3 months
• WBC ≥ 3,000/mm³
• Absolute neutrophil count ≥ 1,500/mm³
• Platelet count ≥ 100,000/mm³
• Hemoglobin ≥ 9.0 g/dL (transfusions allowed)
• Bilirubin ≤ 1.5 mg/mL
• AST and ALT ≤ 2.5 times upper limit of normal (ULN)
• PT/INR and PTT normal
• Creatinine ≤ 1.5 times ULN OR creatinine clearance ≥ 60 mL/min
• No medical condition that may affect the ability to swallow and retain dasatinib tablets, including any of the following:

• Gastrointestinal tract disease resulting in an inability to take oral medication
• Requirement for IV alimentation
• Prior surgical procedures affecting absorption
• Active peptic ulcer disease
• No clinically significant cardiovascular disease, including any of the following:

• Myocardial infarction or ventricular tachyarrhythmia within the past 6 months
• Prolonged QTc > 480 msec
• Major conduction abnormality (unless a cardiac pacemaker is present)
• No uncontrolled intercurrent illness including, but not limited to, any of the following:

• Ongoing or active infection
• History of significant congenital or acquired bleeding disorder, including any of the following:

• Von Willebrand's disease
• Antifactor VIII antibodies
• Dyspnea at rest or with minimal exertion
• Uncontrolled seizure disorder
• Psychiatric illness or social situations that would preclude study compliance
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• No other active malignancy within the past 3 years except curatively treated stage I malignancies or resected skin carcinomas
• Recovered from prior therapy
• Prior adjuvant therapy for stage II or III melanoma allowed
• No prior cytotoxic therapy for metastatic melanoma
• No prior dasatinib or other inhibitors of src, bcr-abl, c-Kit, EPHA2, and PDGFRβ
• No more than 2 prior immunomodulator therapies for metastatic melanoma
• At least 1 week since prior and no concurrent warfarin or other anticoagulants or medications that inhibit platelet function (including acetylsalicylic acid)
• At least 1 week since prior and no concurrent steroids or other immunosuppressive agents

• Concurrent steroids to treat induced pleural effusions allowed
• At least 3 weeks since prior immunomodulators including, but not limited to, any of the following:

• Aldesleukin
• Cancer vaccines
• T-cell-activating monoclonal antibodies
• At least 4 weeks since prior radiotherapy

• Prior palliative radiotherapy to a single site of disease allowed (tumor is not considered evaluable for response unless there is tumor progression at the site of radiation)
• More than 7 days since prior and no concurrent CYP3A4 inhibitors
• At least 7 days since prior and no concurrent agents with proarrhythmic potential
• No other concurrent investigational agents
• No other concurrent anticancer agents or therapies
• No concurrent enzyme-inducing anticonvulsant agents
• No concurrent grapefruit or grapefruit juice
• No concurrent combination antiretroviral therapy for HIV-positive patients
• No concurrent CYP3A4 inducers