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

A Phase I-II, Open-label Study of RAD001 in Combination With Glivec®/Gleevec™ (Imatinib) in Patients With Glivec/Gleevec-refractory/Resistant Gastrointestinal Stromal Tumors.

This trial was a Phase I/II, non-randomized, open label, multi-center study, following a sequential 2-part design.

The first part, Phase I, was designed to assess whether there is a pharmacokinetic interaction between Glivec/Gleevec (imatinib) and RAD001(everolimus) as well as to collect safety data when these two drugs are co-administered. The second part, (Phase II), was designed to assess the potential efficacy of the combination in imatinib-resistant GIST patients in two strata of patients:

• Patients resistant to imatinib as first-line drug therapy and in whom the maximum tolerated dose was at least 600 mg/d (Stratum 1, first-line resistant/refractory)
• Patients resistant to imatinib as well as to post-imatinib drug therapy (Stratum 2, post second-line therapy).

It was decided to discontinue the study and close to further enrollment based on alternative treatment options that became available. Phase 1 and Phase 2 Stratum 1 were ended early on 02-Nov-2006. Investigators were allowed to complete the enrollment in the Phase 2 Stratum 2.

Inclusion Criteria:

Phase l:

• Patients aged ≥ 18 years
• Patients with a histologically proven diagnosis of GIST and clinical evidence of resistance 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 despite uninterrupted therapy for 2 months at ≥800 mg/d for patients entering the Phase I cohort investigating the 800 mg/d dose)
• Patients were to have at least one measurable lesion (longest diameter ≥20 mm on conventional CT or MRI scan
• patients were to have ≥10 mm on spiral CT) and were to have a WHO Performance Status Score ≤ 2.
• Patients also were to have adequate bone marrow, liver and renal function on imatinib treatment, as specified in the protocol

Phase ll:

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

Exclusion Criteria:

• Women who are pregnant or breast-feeding
• Patients presenting with known or symptomatic CNS metastases or leptomeningeal involvement
• Patients with any concurrent major medical condition liable to compromise the patient's participation in the study (e.g. known HIV infection, uncontrolled diabetes, serious cardiac dysrhythmia or condition, New York Heart Association classification of III or IV, congestive cardiac failure, myocardial infarction with 6 months, unstable angina, chronic or acute renal or liver disease, uncontrolled infections including abscess 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 being performed), since these have been shown to inhibit p70s6 kinase1 activity.