Affiliation:
1. Ian Krop and Patrick Y. Wen, Dana-Farber Cancer Institute, Boston, MA; Tim Demuth, Samuel Blackman, James Watters, Andrey Loboda, Alexei Podtelezhnikov, Jared Lunceford, Cong Chen, Maxine Giannotti, Jeremy Hing, and Robert Beckman, Merck Research Laboratories, North Wales, PA; Tina Guthrie and Patricia LoRusso, Karmanos Cancer Center, Wayne State University, Detroit, MI; Warren P. Mason, Princess Margaret Hospital, Toronto, Ontario, Canada; Prakash Chinnaiyan, H. Lee Moffitt Cancer Center, Tampa, FL;...
Abstract
PurposeAberrant Notch signaling has been implicated in the pathogenesis of many human cancers. MK-0752 is a potent, oral inhibitor of γ-secretase, an enzyme required for Notch pathway activation. Safety, maximum-tolerated dose, pharmacokinetics (PKs), pharmacodynamics, and preliminary antitumor efficacy were assessed in a phase I study of MK-0752.Patients and MethodsMK-0752 was administered in three different schedules to patients with advanced solid tumors. Hair follicles were collected at higher dose levels to assess a gene signature of Notch inhibition.ResultsOf 103 patients who received MK-0752, 21 patients received a continuous once-daily dosing at 450 and 600 mg; 17 were dosed on an intermittent schedule of 3 of 7 days at 450 and 600 mg; and 65 were dosed once per week at 600, 900, 1,200, 1,500, 1,800, 2,400, 3,200, and 4,200 mg. The most common drug-related toxicities were diarrhea, nausea, vomiting, and fatigue. PKs (area under the concentration-time curve and maximum measured plasma concentration) increased in a less than dose proportional manner, with a half-life of approximately 15 hours. Significant inhibition of Notch signaling was observed with the 1,800- to 4,200-mg weekly dose levels, confirming target engagement at those doses. One objective complete response and an additional 10 patients with stable disease longer than 4 months were observed among patients with high-grade gliomas.ConclusionMK-0752 toxicity was schedule dependent. Weekly dosing was generally well tolerated and resulted in strong modulation of a Notch gene signature. Clinical benefit was observed, and rational combination trials are currently ongoing to maximize clinical benefit with this novel agent.
Publisher
American Society of Clinical Oncology (ASCO)
Cited by
274 articles.
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