title: A multicenter phase 1 study of γ -secretase inhibitor RO4929097 in combination with capecitabine in refractory solid tumors.
abstract: BACKGROUND
  RO4929097 is an oral inhibitor of γ -secretase that results in Notch signaling inhibition. Prior work has demonstrated that Notch signaling inhibition enhances chemotherapy sensitivity of cancer cells. This phase I study was conducted to determine maximum tolerated dose (MTD), toxicities and efficacy of RO4929097 and capecitabine in advanced solid tumors.
  
  
  METHODS
  Patients with refractory solid tumors received capecitabine at a fixed dose of 1,000 mg/m(2) twice daily with escalating doses of RO4929097 on a 21-day cycle in a 3 + 3 design. Capecitabine was administered for 14 days and the RO49029097 once daily, 3 days per week, both for a 21 day cycle.
  
  
  RESULTS
  Thirty patients were treated on six dose levels (20 to 150 mg). The maximally tolerated dose was not reached. One dose limiting toxicity was observed at each level 3 through 6 (hypophosphatemia, fatigue, and nausea/vomiting). Three confirmed partial responses were observed: two patients with fluoropyrimide-refractory colon cancer and one patient with cervical cancer. Autoinduction of RO4929097 was demonstrated with increasing dose levels and duration.
  
  
  CONCLUSIONS
  The recommended phase 2 dose is capecitabine 1,000 mg/m(2) orally twice daily on days 1 through 14 with RO4929097 20 mg orally once daily on days 1-3, 8-10 and 15-17 with a 21 day cycle. Clinical benefit was observed in cervical and colon cancer. Autoinduction of RO4929097 was seen both with increasing cycle number and increasing dose. Plasma concentrations of RO4929097 were above those needed for Notch inhibition.
authors.affiliation: University of Wisconsin Carbone Cancer Center, 600 Highland Ave, CSC K4/548, Madison, WI, 53792, USA, ns3@medicine.wisc.edu.
authors.forename: Noelle K
authors.initials: NK
authors.lastname: LoConte
authors.forename: Albiruni R A
authors.initials: AR
authors.lastname: Razak
authors.forename: Percy
authors.initials: P
authors.lastname: Ivy
authors.forename: Amye
authors.initials: A
authors.lastname: Tevaarwerk
authors.forename: Rachael
authors.initials: R
authors.lastname: Leverence
authors.forename: Jill
authors.initials: J
authors.lastname: Kolesar
authors.forename: Lillian
authors.initials: L
authors.lastname: Siu
authors.forename: Sam J
authors.initials: SJ
authors.lastname: Lubner
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Mulkerin
authors.forename: William R
authors.initials: WR
authors.lastname: Schelman
authors.forename: Dustin A
authors.initials: DA
authors.lastname: Deming
authors.forename: Kyle D
authors.initials: KD
authors.lastname: Holen
authors.forename: Lakeesha
authors.initials: L
authors.lastname: Carmichael
authors.forename: Jens
authors.initials: J
authors.lastname: Eickhoff
authors.forename: Glenn
authors.initials: G
authors.lastname: Liu
mesh_terms: D000368:Aged; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001552:Benzazepines / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D000069287:Capecitabine; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D011355:Prodrugs / Q000008:administration & dosage / Q000009:adverse effects; D005466:Fluorocarbons
chemical_list: D053829:Amyloid Precursor Protein Secretases; D001552:Benzazepines; D000069287:Capecitabine; D003841:Deoxycytidine; D005472:Fluorouracil; D011355:Prodrugs; 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