A phase I study with tumor molecular pharmacodynamic (MPD) evaluation of dose and s...
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`Journal of Clinical Oncology, 2005 ASCO Annual Meeting Proceedings.
`Vol 23, No 16S (June 1 Supplement), 2005: 3007
`© 2005 American Society of Clinical Oncology
`
`Abstract
`A phase I 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 Cancer Ctr, 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
`and survival. In preclinical models, the administration of E is associated with reduction of
`mTOR downstream 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 tumor at
`different doses and schedules of E to define the recommended dose for further
`development. Methods: Pts with advanced solid tumors were treated in successive cohorts
`of E: weekly 20, 50 and 70 mg or daily 5 and 10 mg. Dose escalation depended on dose
`limiting toxicity (DLT) rate during the first 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. Tumor tissue was evaluated by immunohistochemistry (IHC) for
`p-S6, p-4E-BP1 and p-Akt expression by a pathologist blinded for the biopsy sequence.
`Results: 33 pts have been treated 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 one partial response (colon
`cancer) and 2 stabilizations of >4 months (renal cell and breast cancer). MPD studies (see
`table) demonstrated an almost complete inhibition of p-S6 at all doses and schedules
`(p=0.001). Preliminary results suggest a dose-related decrease in p-4E-BP1 and increase
`in p-Akt expression with maximal effect at 10 mg daily and 50 mg weekly. Conclusions:
`This phase I study shows that E, at the doses and schedules studied, results in intratumoral
`inhibition of mTOR signaling. Based on the toxicity profile and the MPD findings, a dosage
`of 10 mg daily can be recommended for further phase II-III development with E as a single
`agent.
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`Author Disclosure
`Employment
`Consultant or
`or Leadership
`Advisory Role
`
`Stock
`Ownership Honoraria
`
`Research
`Funding
`
`Expert
`Testimony
`
`Other
`Remuneration
`
`Merck KGaA,
`Novartis,
`Roche, sanofi-
`aventis
`
`Novartis
`
`Novartis
`
`Abstract presentation from the 2005 ASCO Annual Meeting
`
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`http://meeting.ascopubs.org/cgi/content/abstract/23/16_suppl/3007?sid=ee291936-2619-47...
`
`5/19/2015
`
`Par Pharm., Inc.
`Exhibit 1038
`Page 001
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