Nilotinib in TKI Resistant or Intolerant Patients With Metastatic Mucosal, Acral, or Chronically Sun Damaged Melanoma

A Phase II Study of Nilotinib (AMN107) In TKI Resistant or Intolerant Patients With Metastatic Mucosal, Acral or Chronically Sun Damaged Melanoma

Given the poor prognosis and limited treatment options available for patients with mucosal or acral/lentiginous melanomas who develop metastatic disease, genetic discoveries of KIT mutations in these cancers present the need to test multi-targeted kinase inhibitors with potent KIT inhibitory activity in this patient population. Imatinib and other tyrosine kinase inhibitors (TKIs) have the potential to be effective in this patient population, but patients may develop resistance to treatment. Therefore, in this study, we propose to test nilotinib in patients with metastatic mucosal, acral, or chronically sun-damaged melanoma following treatment with another TKI.

OBJECTIVES:

Primary

* To estimate the proportion of patients, with metastatic mucosal, acral, or chronically sun damaged melanomas, whose tumors have KIT aberrations, and who progressed or could not tolerate a KIT targeting tyrosine kinase inhibitor (TKI) (e.g. including but not limited to imatinib mesylate, sunitinib, or dasatanib), who are alive and without progression of disease four months after beginning treatment with nilotinib.

Secondary

• To determine early evidence of biologic and clinical activity by best overall response rate.
• To estimate time to progression of disease and overall survival.
• To determine the tolerability of nilotinib.
• To evaluate the use of FDG-PET scanning in determining early biologic response to therapy.
• To correlate c-kit mutational status and amplification status with response to therapy.
• To evaluate the feasibility of nilotinib.
• To evaluate the tolerability of nilotinib in patients with brain metastases.

Inclusion Criteria:

• 18 years of age or older
• Histologically documented diagnosis of mucosal melanoma or acral melanoma or chronically sun damaged melanoma as evidenced by solar elastosis on pathology
• Patient's tumor with evidence for KIT mutation or amplification. Patient tumors that already have documented mutations or amplification do not have to have tissue submitted again for analysis to confirm eligibility
• Have failed, progressed, or not been able to tolerate other tyrosine kinase inhibitors including but not limited to imatinib mesylate, sunitinib or dasatinib treatment.
• At least one measurable site of disease
• ECOG Performance Status 0, 1 or 2
• Adequate organ function as outlined in the protocol
• Negative pregnancy test for female patients of childbearing potential

Exclusion Criteria:

• Patient has received any other investigational agents within 28 days of first day of study drug dosing unless the disease is rapidly progressing
• Patient is < 5 years free of another primary malignancy except: if the other primary malignancy is not currently clinically significant nor requiring active intervention, or if other primary malignancy is a basal cell skin cancer or a cervical carcinoma in situ
• Female patients who are pregnant or breast-feeding
• Patient has a severe and/or uncontrolled medical disease
• Patient has a rare hereditary problem of galactose intolerance, severe lactase deficiency or of glucose-galactose malabsorption
• Patient with electrolyte abnormality unless the level can be corrected to normal levels prior to initiating study drug
• Known brain metastasis
• Known chronic liver disease
• Patient has received chemotherapy within 4 weeks prior to study entry, unless the disease is rapidly progressing (6 weeks for nitrosourea or mitomycin-C)
• Patient previously received radiotherapy to 25% or greater of the bone marrow
• Patient had a major surgery within 2 weeks prior to study entry
• Impaired cardiac function
• QTc > 450msec on screening ECG
• Myocardial infarction within one year prior to starting nilotinib
• Other clinically significant heart disease
• Patients who are currently receiving treatment with any of the medications that have the potential to prolong QT interval
• Patients who are currently receiving Warfarin > 1mg/day
• Patient with any significant history of non-compliance to medical regimens or with the inability to grant reliable informed consent
• Prior therapy with nilotinib