title: Safety, pharmacokinetics, and pharmacodynamic properties of oral DEBIO1143 (AT-406) in patients with advanced cancer: results of a first-in-man study.
abstract: OBJECTIVE
  To assess safety/tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity of DEBIO1143, an antagonist of inhibitor apoptosis proteins.
  
  
  METHODS
  This first-in-man study in patients with advanced cancer used an accelerated dose titration design. DEBIO1143 was given orally once daily on days 1-5 every 2 or 3 weeks until disease progressed or patients dropped out. The starting dose of 5 mg was escalated by 100% in single patients until related grade 2 toxicity occurred. This triggered expansion to cohorts of three and subsequently six patients and reduction in dose increments to 50%. Maximum tolerated dose (MTD) was exceeded when any two patients within the same cohort experienced dose-limiting toxicity (DLT). On days 1 and 5, PK and PD samples were taken.
  
  
  RESULTS
  Thirty-one patients received doses from 5 to 900 mg. Only one DLT was reported at 180 mg. No MTD was found. Most common adverse drug reactions were fatigue (26%), nausea (23%), and vomiting (13%). Average t max and T 1/2 was about 1 and 6 h, respectively. Exposure increased proportionally with doses from 80 to 900 mg, without accumulation over 5 days. Plasma CCL2 increased at 3-6 h postdose and epithelial apoptosis marker M30 on day 5; cIAP-1 levels in PBMCs decreased at all doses >80 mg. Five patients (17%) had stable disease as the best treatment response.
  
  
  CONCLUSIONS
  DEBIO1143 was well tolerated at doses up to 900 mg and elicited PD effects at doses greater 80 mg. Limited antitumor activity may suggest development rather as adjunct treatment.
authors.affiliation: Department of Medicine, Duke University School of Medicine, DUMC 3052, Durham, NC, 27710, USA, herbert.hurwitz@duke.edu.
authors.forename: Herbert I
authors.initials: HI
authors.lastname: Hurwitz
authors.forename: David C
authors.initials: DC
authors.lastname: Smith
authors.forename: Henry C
authors.initials: HC
authors.lastname: Pitot
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Brill
authors.forename: Rashmi
authors.initials: R
authors.lastname: Chugh
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Rouits
authors.forename: Joseph
authors.initials: J
authors.lastname: Rubin
authors.forename: John
authors.initials: J
authors.lastname: Strickler
authors.forename: Gregoire
authors.initials: G
authors.lastname: Vuagniaux
authors.forename: J Mel
authors.initials: JM
authors.lastname: Sorensen
authors.forename: Claudio
authors.initials: C
authors.lastname: Zanna
mesh_terms: D000284:Administration, Oral; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001392:Azocines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001559:Benzhydryl Compounds / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D018932:Chemokine CCL2 / Q000097:blood; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000097:blood; D008297:Male; D020714:Maximum Tolerated Dose; D009369:Neoplasms / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D001392:Azocines; D001559:Benzhydryl Compounds; C111835:CCL2 protein, human; D018932:Chemokine CCL2; D051034:Inhibitor of Apoptosis Proteins; C559144:N-benzhydryl-5-(2-(methylamino)propanamido)-3-(3-methylbutanoyl)-6-oxodecahydropyrrolo(1,2-a)(1,5)diazocine-8-carboxamide