A phaseI study with tumor molecular pharmacodynamic (MPD)evaluation of dose ands... Page 1 of 1
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`Joumalof Clinical Oncology, 2005 ASCO Annual Meeting Proceedings.
`Vol 23, No 16S (June 1 Supplement), 2005: 3007
`© 2005 American Society of Clinical Oncology
`Abstract
`
`A phaseI study with tumor molecular pharmacodynamic
`(MPD)evaluation of dose and schedule of the oral mTOR-
`inhibitor Everolimus (RAD001)in patients (pts) with advanced
`solid tumors
`J. Tabernero, F. Rojo, H. Burris, E. Casado, T. Macarulla, S. Jones, S. Dimitrijevic, K.
`Hazell, N. Shand, J. Baselga study group
`
`Vall d'Hebron Univ Hosp, Barcelona, Spain; Sarah Cannon CancerCtr, Nashville, TN;
`Novartis Oncology, Basel, Switzerland
`3007
`
`Background: Everolimus (E), an oral derivative of rapamycin, inhibits mTOR,a protein
`kinase downstream of PI3K and Akt,involved in the regulation of cell growth,proliferation
`andsurvival. In preclinical models, the administration of E is associated with reduction of
`mTORdownstream phosphorylated(p}-S6 (p-S6) and p-4E-BP1, and occasionally with
`increase in upstream p-Akt. This study explores safety, PK and MPD changes in tumorat
`different doses and schedulesof E to define the recommendeddose forfurther
`development. Methods: Pts with advanced solid tumors were treated in successive cohorts
`of E: weekly 20, 50 and 70 mgordaily 5 and 10 mg. Dose escalation depended on dose
`limiting toxicity (DLT) rate during thefirst 4-week period. Pre- and on-treatment steady-
`state (24hr post-dose and, for the weekly schedule, 5 days post-dose) tumor biopsies were
`obtained from each pt. Tumortissue was evaluated by immunchistochemistry (IHC) for
`p-S6, p-4E-BP1 and p-Akt expression by a pathologistblinded for the biopsy sequence.
`Results: 33 pts have beentreated with 6-8 pts in each cohort. Grade 3 DLT occurred in 5
`pts comprising stomatitis (1 pt at 10 mg daily, 2 at 70 mg weekly), neutropenia and
`hyperglycemia (1 pt each at 70 mg weekly). There were onepartial response (colon
`cancer) and 2 stabilizations of >4 months (renal call and breast cancer). MPD studies (see
`table) demonstrated an almost completeinhibition of p-S6 at all doses and schedules
`(p=0.001). Preliminary results suggest a dose-related decrease in p-4E-BP1 andincrease
`in p-Akt expression with maximal effect at 10 mg daily and >50 mg weekly. Conclusions:
`This phase | study shows thatE, at the doses and schedules studied, results in intratumoral
`inhibition of mTORsignaling. Based onthe toxicity profile and the MPDfindings, a dosage
`of 10 mg daily can be recommendedfor further phaseII-III developmentwith E as a single
`agent.
`
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`AuthorDisclosure
`Other
`Expert
`Research
`Stock
`Employment Consultant or
`or Leadership Advisory Role Ownership Honoraria Funding Testimony Remuneration
`
`Novartis
`
`Merck KGaA,
`Novartis,
`Roche,sanofi-
`aventis
`
`Abstract presentation from the 2005 ASCO Annual Meeting
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