Peller, Patrick J.

Abstract Background: The mammalian target of rapamycin (mTOR) functions within the PI3K/Akt signaling pathway as a critical modulator of cell survival. We previously demonstrated significant synergy of the mTOR inhibitor sirolimus with RT in glioma xenografts. This Phase I study evaluated the safety and tolerability of combined therapy with the mTOR inhibitor RAD001, RT and TMZ. Methods: All patients received weekly oral RAD001, starting 1 week prior to RT/TMZ and continuing until progression, with a break from therapy between RT/TMZ and adjuvant TMZ. RAD001 was dose escalated in cohorts of 6 patients. In addition to RAD001, all pts received standard treatment with RT (60 Gy)/TMZ (75 mg/m2 daily) and adjuvant TMZ (200 mg/m2 daily × 5 every 28 days). DLTs were defined during therapy with RAD001 combined with TMZ/RT. Results: A total of 18 patients were enrolled. Combined RAD001/RT/TMZ was well tolerated at all dose levels with 1 of 6 patients with a DLT at each dose level. DLTs were Grade 3 fatigue (RAD001 25 mg/week), Grade 4 hematologic toxicity (RAD001 50 mg/week), and Grade 4 liver function elevation (RAD001 70 mg/week). With adverse event information available for all 18 patients, no grade 5 events were seen. Nine grade 4 events (thrombosis, fatigue, anemia, neutropenia, thrombocytopenia, leukopenia, SGPT (ALT), SGOT (AST), bilirubin elevation) were seen in 3 patients. On the basis of these results, the recommended Phase II dose currently being tested is RAD001 70 mg/week in combination with standard RT/TMZ and adjuvant TMZ. FDG PET scans were also obtained prior to the first dose of RAD001 and within 24 hours of the second dose of RAD001, prior to starting RT or TMZ, and changes in maximum standard uptake values (SUV) were compared between scans for each patient. Two patients at 25 mg RAD001/week had a 21% and 24% change in SUV, and 2 patients receiving 70 mg/week had a change in SUV uptake of −33% and −16%. Additional follow-up will be required to evaluate whether these SUV changes are associated with outcome. Conclusions: RAD001 in combination with RT/TMZ and adjuvant TMZ was well tolerated, and the imaging results support continued evaluation of PET imaging as an early predictor of response to therapy. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C56.