title: A first-in-human phase I study of the oral Notch inhibitor, LY900009, in patients with advanced cancer.
abstract: BACKGROUND
  Notch signalling regulates stem cell development and survival and is deregulated in multiple malignancies. LY900009 is a small molecule inhibitor of Notch signalling via selective inhibition of the γ-secretase protein. We report the first-in-human phase I trial of LY900009.
  
  
  METHODS
  Dose escalation (Part A) was performed in cohorts of three advanced cancer patients using a modified continual reassessment method and dose confirmation (Part B) was performed in ovarian cancer patients. LY900009 was taken orally thrice weekly (every Monday, Wednesday, and Friday) during a 28-d cycle. The primary objective determined the maximum tolerated dose (MTD); secondary end-points included toxicity, pharmacokinetics, pharmacodynamics, and antitumour activity.
  
  
  RESULTS
  Thirty-five patients received LY900009 at dose levels ranging from 2-60 mg. Study drug-related adverse events were diarrhoea (46%), vomiting (34%), anorexia (31%), nausea (31%), and fatigue (23%). At 30 mg, a dose-limiting toxicity (grade III mucosal inflammation) was observed. LY900009 absorption was rapid, with median tmax at 1-4 h post-dose. LY900009 inhibited plasma levels of amyloid-β peptide in a dose-dependent manner with 80-90% inhibition observed in the 30- to 60-mg cohorts. No responses were seen, but five patients had stable disease. Two patients (5.7%) with leiomyosarcoma and ovarian cancer received four cycles of therapy. One patient (15 mg) showed markedly increased glandular mucin consistent with pharmacologic inhibition of the Notch pathway.
  
  
  CONCLUSIONS
  The recommended MTD schedule for future studies was 30 mg thrice weekly, which exceeds the target inhibition level observed in preclinical models to promote tumour regression in humans.
authors.affiliation: Stephenson Cancer Center University of Oklahoma, Oklahoma City, OK, USA; Sarah Cannon Research Institute, Nashville, TN, USA.
authors.forename: Shubham
authors.initials: S
authors.lastname: Pant
authors.affiliation: Sarah Cannon Research Institute, Nashville, TN, USA.
authors.forename: Suzanne F
authors.initials: SF
authors.lastname: Jones
authors.affiliation: Stephenson Cancer Center University of Oklahoma, Oklahoma City, OK, USA; Sarah Cannon Research Institute, Nashville, TN, USA.
authors.forename: Carla D
authors.initials: CD
authors.lastname: Kurkjian
authors.affiliation: Tennessee Oncology, Nashville, TN, USA; Sarah Cannon Research Institute, Nashville, TN, USA.
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Infante
authors.affiliation: Stephenson Cancer Center University of Oklahoma, Oklahoma City, OK, USA; Sarah Cannon Research Institute, Nashville, TN, USA.
authors.forename: Kathleen N
authors.initials: KN
authors.lastname: Moore
authors.affiliation: Tennessee Oncology, Nashville, TN, USA; Sarah Cannon Research Institute, Nashville, TN, USA.
authors.forename: Howard A
authors.initials: HA
authors.lastname: Burris
authors.affiliation: Stephenson Cancer Center University of Oklahoma, Oklahoma City, OK, USA; Sarah Cannon Research Institute, Nashville, TN, USA.
authors.forename: Donald S
authors.initials: DS
authors.lastname: McMeekin
authors.affiliation: Eli Lilly and Company, Indianapolis, IN, USA.
authors.forename: Karim A
authors.initials: KA
authors.lastname: Benhadji
authors.affiliation: Eli Lilly and Company, Indianapolis, IN, USA.
authors.forename: Bharvin K R
authors.initials: BKR
authors.lastname: Patel
authors.affiliation: Eli Lilly and Company, Indianapolis, IN, USA.
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Frenzel
authors.affiliation: Eli Lilly and Company, Indianapolis, IN, USA.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Kursar
authors.affiliation: Eli Lilly and Company, Indianapolis, IN, USA.
authors.forename: Maciej J
authors.initials: MJ
authors.lastname: Zamek-Gliszczynski
authors.affiliation: Eli Lilly and Company, Windlesham, Surrey, UK.
authors.forename: Eunice S M
authors.initials: ESM
authors.lastname: Yuen
authors.affiliation: Eli Lilly and Company, Indianapolis, IN, USA.
authors.forename: Edward M
authors.initials: EM
authors.lastname: Chan
authors.affiliation: Tennessee Oncology, Nashville, TN, USA; Sarah Cannon Research Institute, Nashville, TN, USA. Electronic address: jbendell@tnonc.com.
authors.forename: Johanna C
authors.initials: JC
authors.lastname: Bendell
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000409:Alanine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D003984:Dibenzazepines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D011480:Protease Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D051880:Receptors, Notch / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D016896:Treatment Outcome; D014481:United States; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D003984:Dibenzazepines; C000609015:LY900009; D011480:Protease Inhibitors; D051880:Receptors, Notch; D053829:Amyloid Precursor Protein Secretases; D000409:Alanine
keywords: Advanced cancer; Gamma secretase; LY900009; Notch