title: Phase I, dose-finding study of AZD8931, an inhibitor of EGFR (erbB1), HER2 (erbB2) and HER3 (erbB3) signaling, in patients with advanced solid tumors.
abstract: OBJECTIVE
  AZD8931 is an oral equipotent inhibitor of EGFR (erbB1), HER2 (erbB2) and HER3 (erbB3) signaling. This Phase I, open-label study evaluated the safety, tolerability, and pharmacokinetics of multiple ascending doses of AZD8931 in patients with advanced solid tumors (NCT00637039).
  
  
  METHODS
  Patients received AZD8931 as a single oral dose followed by 4 days of observation, then twice-daily dosing for 21 consecutive days. Using a standard 3 + 3 design, AZD8931 doses were escalated from 40 mg bid until the maximum tolerated dose (MTD) was established.
  
  
  RESULTS
  Twenty-eight patients received AZD8931 (n = 5, 40 mg bid; n = 8, 80 mg bid; n = 6, 160 mg bid; n = 6, 240 mg bid; n = 3, 300 mg bid). Ovary (n = 8) and breast (n = 5) were the most common primary tumor types. The most frequent adverse events were treatment-emergent cutaneous (n = 27) and diarrhea (n = 21). Dose-limiting toxicities (DLTs) were identified in one patient in the 240 mg bid cohort (Grade 3 rash) and two patients in the 300 mg bid cohort (Grade 3 and 4 diarrhea). The pharmacokinetic profile of AZD8931 supported twice-daily dosing. AZD8931 was rapidly absorbed (median tmax 1-3 h), was well distributed and had moderate to high clearance with an elimination half-life of approximately 11 h. Exposure appeared to increase approximately proportionally with dose up to 160 mg. Of 21 patients evaluable for response at day 21, 12 had stable disease and nine had disease progression.
  
  
  CONCLUSIONS
  The MTD of AZD8931 determined from the 21-day DLT period was 240 mg bid, although more long-term data are needed to confirm a dose of AZD8931 suitable for chronic treatment.
authors.affiliation: N. N. Blokhin Russian Cancer Research Centre of RAMS, Kashirskoe Shosse 24, 115478, Moscow, Russia, stjulandin@gmail.com.
authors.forename: S
authors.initials: S
authors.lastname: Tjulandin
authors.forename: V
authors.initials: V
authors.lastname: Moiseyenko
authors.forename: V
authors.initials: V
authors.lastname: Semiglazov
authors.forename: G
authors.initials: G
authors.lastname: Manikhas
authors.forename: M
authors.initials: M
authors.lastname: Learoyd
authors.forename: A
authors.initials: A
authors.lastname: Saunders
authors.forename: M
authors.initials: M
authors.lastname: Stuart
authors.forename: U
authors.initials: U
authors.lastname: Keilholz
mesh_terms: D000328:Adult; D000368:Aged; D003710:Demography; D004305:Dose-Response Relationship, Drug; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011799:Quinazolines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020893:Receptor, ErbB-3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction; D016896:Treatment Outcome; D047368:Tumor Burden
chemical_list: D066246:ErbB Receptors; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; C548875:AZD 8931