Inclusion Criteria:

1. Histologically confirmed diagnosis of Kit-expressing advanced GIST. Advanced GIST is defined by patients who have disease that is unresectable . This includes patients with metastatic disease or primary tumors that cannot be safely removed by a sarcoma surgical oncologist.
2. A pre-imatinib paraffin block of tumor or 20 unstained slides will be requested for correlative studies.
3. All patients must have either "limited" progression on imatinib (arm 1, some but not all tumor foci progressing and are not amenable to local therapy) or "generalized" progression (widespread progression of all tumor foci) after adequate therapy with imatinib mesylate (> or = 400 mg/day for at least 6 weeks).
4. Measurable disease by CT. Tests used to assess disease must be done within 28 days prior to registration. If a targeted lesion has been previously embolized or irradiated, or if the patient has received imatinib, there must be objective evidence of progression to be considered for response assessment.
5. ECOG performance status 0-2.
6. Patients must be at least 18 years of age or older.
7. At least 4 weeks and recovery from effects of prior therapy(i.e.radiation, biotherapy, chemotherapy other than imatinib mesylate, or embolization.) Recovery from the effects of prior therapy such that they are less than or equal to grade 1 in severity for non-hematological toxicities excluding nausea and vomiting controlled with standard anti-emetic regimens, alopecia, fatigue, and peripheral edema. Hematologic recovery is specified in section 5.1.8.
8. Adequate organ function that has been determined within 2 weeks prior to registration, defined as: absolute neutrophil count (ANC) >/= 1000/mm3, platelets >/= 100,000/mm3, serum creatinine </= 1.5 x ULN, serum bilirubin </= 1.5 x ULN, serum SGOT or SGPT </= 2.5 x ULN if no liver metastases or </= 5 x ULN if liver metastases are present, PT and PTT </= 1.5 x ULN.
9. Understand and sign written informed consent in accordance with institutional and federal guidelines.
10. All patients must have progressive disease defined as 1) an increase in unidimensional tumor size of > or = 10% AND did not meet criteria for PR by CT density, 2) any new lesions, including new tumor nodules in a previous cystic tumor (Choi et al, ASCO 2003
11. Patients with widespread metastatic and progressive disease will be eligible for this protocol.
12. Patients without widespread metastases will be evaluated by a sarcoma surgical oncologist to determine the benefit of and risk of surgical resection. If surgical resection is not recommended, the patient will be eligible for therapy with the study drug.
13. Pregnancy or lactation. Women or men of reproductive potential must agree to use an effective barrier contraceptive method during treatment and for three months after the last dose of drug. Women of reproductive potential must have a negative serum pregnancy test within 7 days prior to registration. Post-menopausal women must be amenorrheic for at least 12 months to be considered of non-child bearing potential. .

Exclusion Criteria:

1. Significant concurrent medical disease other than cancer including: New York Heart Association class III or IV cardiac problems (e.g., congestive heart failure, acute myocardial infarction within 2 months of study); uncontrolled chronic renal or liver disease; uncontrolled diabetes; uncontrolled seizure disorder; active uncontrolled infection, e.g., HIV; organ allografts.
2. History of second cancer, except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or other cancer for which the patient has been disease-free for five or more years.