title: A phase I first-in-human pharmacokinetic and pharmacodynamic study of serdemetan in patients with advanced solid tumors.
abstract: OBJECTIVE
  Originally isolated on the basis of its ability to induce p53, serdemetan showed potent activity in various preclinical models, inducing S-phase arrest and apoptosis in TP53 wild-type and mutant tumors. This study evaluated the safety and tolerability of serdemetan, determined the pharmacokinetic and pharmacodynamic profiles, and identified a recommended phase II dose.
  
  
  METHODS
  Patients (71) with refractory solid tumors were allocated to dose-escalating cohorts (3+3 patients each) and received oral serdemetan once daily in 21-day cycles to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT). Plasma was collected for pharmacokinetic analyses. Paired baseline and on-treatment skin and tumor biopsies were done; blood samples were collected for pharmacodynamic analyses, including p53 and macrophage inhibitory cytokine-1 induction.
  
  
  RESULTS
  The MTD of serdemetan was determined to be 350 mg once daily. During this study, grade 3 QTc prolongation was the most common DLT and nausea (66.2%) was the most frequent treatment-emergent adverse event. Serdemetan was rapidly absorbed after oral administration and exhibited dose-proportional pharmacokinetics. At steady state, mean maximum plasma concentration (C(max)) was 2,330 ng/mL and mean area under plasma concentration curve (AUC(0-24h)) was 43.0 μg.h/mL, with serdemetan 300 mg/d. There was a dose- and exposure-dependent p53 induction. One patient with breast cancer showed a partial response; 22 (38.6%) patients had stable disease.
  
  
  CONCLUSIONS
  Serdemetan treatment was associated with p53 induction in both tumor and surrogate tissue pharmacodynamic studies and modest clinical activity. Although serdemetan was well tolerated with dose-proportional pharmacokinetics, exposure-related QTc liability was observed.
authors.affiliation: Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain. jtabernero@vhio.net
authors.forename: Josep
authors.initials: J
authors.lastname: Tabernero
authors.forename: Luc
authors.initials: L
authors.lastname: Dirix
authors.forename: Patrick
authors.initials: P
authors.lastname: Schöffski
authors.forename: Andrés
authors.initials: A
authors.lastname: Cervantes
authors.forename: Jose Antonio
authors.initials: JA
authors.lastname: Lopez-Martin
authors.forename: Jaume
authors.initials: J
authors.lastname: Capdevila
authors.forename: Ludy
authors.initials: L
authors.lastname: van Beijsterveldt
authors.forename: Suso
authors.initials: S
authors.lastname: Platero
authors.forename: Brett
authors.initials: B
authors.lastname: Hall
authors.forename: Zhilong
authors.initials: Z
authors.lastname: Yuan
authors.forename: Roland
authors.initials: R
authors.lastname: Knoblauch
authors.forename: Sen Hong
authors.initials: SH
authors.lastname: Zhuang
mesh_terms: D000284:Administration, Oral; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; 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*; D014363:Tryptamines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D014363:Tryptamines; C568210:JNJ 26854165