title: Phase I study of RO4929097, a gamma secretase inhibitor of Notch signaling, in patients with refractory metastatic or locally advanced solid tumors.
abstract: OBJECTIVE
  To determine the maximum-tolerated dose (MTD) and assess safety, pharmacokinetics, pharmacodynamics, and evidence of antitumor activity of RO4929097, a gamma secretase inhibitor of Notch signaling in patients with advanced solid malignancies.
  
  
  METHODS
  Patients received escalating doses of RO4929097 orally on two schedules: (A) 3 consecutive days per week for 2 weeks every 3 weeks; (B) 7 consecutive days every 3 weeks. To assess reversible CYP3A4 autoinduction, the expanded part of the study tested three dosing schedules: (B) as above; modified A, 3 consecutive d/wk for 3 weeks; and (C) continuous daily dosing. Positron emission tomography scans with [(18)F]fluorodeoxyglucose (FDG-PET) were used to assess tumor metabolic effects.
  
  
  RESULTS
  Patients on schedule A (n = 58), B (n = 47), and C (n = 5; expanded cohort) received 302 cycles of RO4929097. Common grade 1 to 2 toxicities were fatigue, thrombocytopenia, fever, rash, chills, and anorexia. Transient grade 3 hypophosphatemia (dose-limiting toxicity, one patient) and grade 3 pruritus (two patients) were observed at 27 mg and 60 mg, respectively; transient grade 3 asthenia was observed on schedule A at 80 mg (one patient). Tumor responses included one partial response in a patient with colorectal adenocarcinoma with neuroendocrine features, one mixed response (stable disease) in a patient with sarcoma, and one nearly complete FDG-PET response in a patient with melanoma. Effect on CYP3A4 induction was observed.
  
  
  CONCLUSIONS
  RO4929097 was well tolerated at 270 mg on schedule A and at 135 mg on schedule B; the safety of schedule C has not been fully evaluated. Further studies are warranted on the basis of a favorable safety profile and preliminary evidence of clinical antitumor activity.
authors.affiliation: South Texas Accelerated Research Therapeutics, 4383 Medical Dr, 4th Floor, San Antonio, TX 78229, USA. atolcher@start.stoh.com
authors.forename: Anthony W
authors.initials: AW
authors.lastname: Tolcher
authors.forename: Wells A
authors.initials: WA
authors.lastname: Messersmith
authors.forename: Stanislaw M
authors.initials: SM
authors.lastname: Mikulski
authors.forename: Kyriakos P
authors.initials: KP
authors.lastname: Papadopoulos
authors.forename: Eunice L
authors.initials: EL
authors.lastname: Kwak
authors.forename: Darlene G
authors.initials: DG
authors.lastname: Gibbon
authors.forename: Amita
authors.initials: A
authors.lastname: Patnaik
authors.forename: Gerald S
authors.initials: GS
authors.lastname: Falchook
authors.forename: Arvind
authors.initials: A
authors.lastname: Dasari
authors.forename: Geoffrey I
authors.initials: GI
authors.lastname: Shapiro
authors.forename: John F
authors.initials: JF
authors.lastname: Boylan
authors.forename: Zhi-Xin
authors.initials: ZX
authors.lastname: Xu
authors.forename: Ka
authors.initials: K
authors.lastname: Wang
authors.forename: Astrid
authors.initials: A
authors.lastname: Koehler
authors.forename: James
authors.initials: J
authors.lastname: Song
authors.forename: Steven A
authors.initials: SA
authors.lastname: Middleton
authors.forename: Jonathan
authors.initials: J
authors.lastname: Deutsch
authors.forename: Mark
authors.initials: M
authors.lastname: Demario
authors.forename: Razelle
authors.initials: R
authors.lastname: Kurzrock
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Wheler
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D001552:Benzazepines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D051880:Receptors, Notch / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D005466:Fluorocarbons
chemical_list: D053829:Amyloid Precursor Protein Secretases; D001552:Benzazepines; D051880:Receptors, Notch; C545185:2,2-dimethyl-N-(6-oxo-6,7-dihydro-5H-dibenzo(b,d)azepin-7-yl)-N'-(2,2,3,3,3-pentafluoropropyl)malonamide; D005466:Fluorocarbons