title: Phase I pharmacologic and pharmacodynamic study of the gamma secretase (Notch) inhibitor MK-0752 in adult patients with advanced solid tumors.
abstract: OBJECTIVE
  Aberrant 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.
  
  
  METHODS
  MK-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.
  
  
  RESULTS
  Of 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.
  
  
  CONCLUSIONS
  MK-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.
authors.affiliation: Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: Ian
authors.initials: I
authors.lastname: Krop
authors.forename: Tim
authors.initials: T
authors.lastname: Demuth
authors.forename: Tina
authors.initials: T
authors.lastname: Guthrie
authors.forename: Patrick Y
authors.initials: PY
authors.lastname: Wen
authors.forename: Warren P
authors.initials: WP
authors.lastname: Mason
authors.forename: Prakash
authors.initials: P
authors.lastname: Chinnaiyan
authors.forename: Nicholas
authors.initials: N
authors.lastname: Butowski
authors.forename: Morris D
authors.initials: MD
authors.lastname: Groves
authors.forename: Santosh
authors.initials: S
authors.lastname: Kesari
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Freedman
authors.forename: Samuel
authors.initials: S
authors.lastname: Blackman
authors.forename: James
authors.initials: J
authors.lastname: Watters
authors.forename: Andrey
authors.initials: A
authors.lastname: Loboda
authors.forename: Alexei
authors.initials: A
authors.lastname: Podtelezhnikov
authors.forename: Jared
authors.initials: J
authors.lastname: Lunceford
authors.forename: Cong
authors.initials: C
authors.lastname: Chen
authors.forename: Maxine
authors.initials: M
authors.lastname: Giannotti
authors.forename: Jeremy
authors.initials: J
authors.lastname: Hing
authors.forename: Robert
authors.initials: R
authors.lastname: Beckman
authors.forename: Patricia
authors.initials: P
authors.lastname: Lorusso
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D001555:Benzene Derivatives; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D011422:Propionates / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology*; D013450:Sulfones / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology*; D016896:Treatment Outcome
chemical_list: C554093:3-(4-((4-chlorophenyl)sulfonyl)-4-(2,5-difluorophenyl)cyclohexyl)propanoic acid; D001555:Benzene Derivatives; D011422:Propionates; D013450:Sulfones; D053829:Amyloid Precursor Protein Secretases