Trial of Tasigna (Nilotinib) 400 mg Twice Daily Alone or With Gleevec (Imatinib Mesylate) 400 mg Daily for Patients With Advanced Gastrointestinal Stromal Tumor (GIST)

Resistance to imatinib does develop and represents a major clinical challenge. Mechanisms
implicated in imatinib resistance include: target resistance due to new KIT or PDGFRA
mutations or over expression of the KIT protein; target modulation due to activation of an
alternate receptor tyrosine kinase protein with loss of KIT oncoprotein expression;
functional resistance due to KIT or PDGFRA activation without a secondary mutation; and
alterations in imatinib uptake by P-glycoprotein.

This study seeks to test nilotinib alone and nilotinib in combination with imatinib in
patients that have progressed on imatinib.

Nilotinib is a new synthetic second-generation inhibitor of the BCR-ABL tyrosine kinase that
competes for the ATP-bindings sites of BCR-ABL. A completed phase I trial assessed the
activity of nilotinib alone and in combination with imatinib in patients that have
progressed on imatinib in a population of patients with imatinib refractory and intolerant
patients. There were rare responses, but stable disease was observed in grater than 50% of
patients.

This study is aiming to treat patients with advanced or metastatic GIST who have disease
progression on imatinib dose escalated up to 600 mg or greater. The rationale for
exploring Nilotinib in this setting is to determine if it has therapeutic efficacy, with
potentially less toxicity than the current standard of care for second line therapy. In
addition, since it is not uncommon to see progression of some metastatic GIST lesions on
imatinib, while others remain controlled, adding nilotinib may treat the progressing lesions
while imatinib continues to control the areas without disease progression.