Everolimus in Combination With Imatinib in Patients With Glivec Refractory/Resistant Gastrointestinal Stromal Tumors

Inclusion Criteria: Phase l:

• Patients aged ≥ 18 years
• Patients with a histologically proven diagnosis of GIST and clinical evidence ofresistance to imatinib despite at least 4 months continuous treatment with imatinib
• Patients with at least 2 months at a dosage of ≥ 600 mg/day (progression despiteuninterrupted therapy for 2 months at ≥800 mg/d for patients entering the Phase Icohort investigating the 800 mg/d dose)
• Patients were to have at least one measurable lesion (longest diameter ≥20 mm onconventional CT or MRI scan
• patients were to have ≥10 mm on spiral CT) and were to have a WHO Performance StatusScore ≤ 2.
• Patients also were to have adequate bone marrow, liver and renal function on imatinibtreatment, as specified in the protocol Phase ll:

• For Phase II (Stratum 2) patients must have progression on other 2nd line drug therapiesfollowing prior progression on imatinib (Stratum 2)

Exclusion Criteria:

• Women who are pregnant or breast-feeding
• Patients presenting with known or symptomatic CNS metastases or leptomeningealinvolvement
• Patients with any concurrent major medical condition liable to compromise thepatient's participation in the study (e.g. known HIV infection, uncontrolled diabetes,serious cardiac dysrhythmia or condition, New York Heart Association classification ofIII or IV, congestive cardiac failure, myocardial infarction with 6 months, unstableangina, chronic or acute renal or liver disease, uncontrolled infections includingabscess or fistulae, etc.)
• Patients with a history of another malignancy within 5 years prior to study entry,except curatively treated non-melanotic skin cancer or in-situ cervical cancer
• Patients unwilling to or unable to comply with the protocol
• Patients who are receiving glucocorticoids (only if the p70s6 kinase1 assay is beingperformed), since these have been shown to inhibit p70s6 kinase1 activity.