title: Inhibition of EGFR, HER2 and HER3 signaling with AZD8931 alone and in combination with paclitaxel: phase i study in Japanese patients with advanced solid malignancies and advanced breast cancer.
abstract: BACKGROUND
  AZD8931 is an equipotent, reversible inhibitor of signaling by epidermal growth factor receptor (EGFR), human EGFR 2 (HER2) and HER3. This two-part Japanese study (NCT01003158) assessed the safety/tolerability of AZD8931 monotherapy in patients with advanced solid tumors and in combination with paclitaxel in female patients with advanced breast cancer.
  
  
  METHODS
  Monotherapy part: ascending doses of AZD8931 (40/60/80 mg twice daily [bid]) for 21 consecutive days. Combination part: AZD8931 40 mg bid and paclitaxel 90 mg/m(2) (on days 1, 8 and 15 of a 28-day cycle).
  
  
  RESULTS
  Seventeen patients received AZD8931: 11 received AZD8931 monotherapy (40/60/80 mg [n = 3/4/4]) and six AZD8931 40 mg bid plus paclitaxel. No dose-limiting toxicities were observed for AZD8931 alone or combined with paclitaxel. The most frequent adverse events (AEs) were diarrhea, paronychia, pustular rash and dry skin (each n = 8) with AZD8931 monotherapy and diarrhea, stomatitis, rash, alopecia, epistaxis and neutropenia (each n = 4) with combination therapy. Grade ≥3 AEs were reported for one, two and four patients in the 40 mg, 60 mg and combination groups, respectively. AZD8931 was rapidly absorbed with a half-life of 12 h. There was no evidence of pharmacokinetic interaction between AZD8931 and paclitaxel. Two patients (one in each part) had unconfirmed and confirmed partial responses, with a duration of 42 and 172 days, respectively.
  
  
  CONCLUSIONS
  Although maximum tolerated dose was not confirmed for AZD8931, based on overall incidence of rash and diarrhea AEs in the 80 mg group, doses up to 60 mg bid as monotherapy and 40 mg bid combined with paclitaxel are the feasible AZD8931 doses in Japanese patients.
authors.affiliation: Department of Medical Oncology, Kinki University School of Medicine, 589-8511, 377-2 Ohno-Higashi, Osakasayama, Osaka, Japan, kuratat@hirakata.kmu.ac.jp.
authors.forename: Takayasu
authors.initials: T
authors.lastname: Kurata
authors.forename: Junji
authors.initials: J
authors.lastname: Tsurutani
authors.forename: Yasuhito
authors.initials: Y
authors.lastname: Fujisaka
authors.forename: Wataru
authors.initials: W
authors.lastname: Okamoto
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Hayashi
authors.forename: Hisato
authors.initials: H
authors.lastname: Kawakami
authors.forename: Eisei
authors.initials: E
authors.lastname: Shin
authors.forename: Nobuya
authors.initials: N
authors.lastname: Hayashi
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Nakagawa
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D044466:Asian People; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy*; D017239:Paclitaxel / Q000008:administration & dosage / Q000009:adverse effects; D011799:Quinazolines / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors*; D020893:Receptor, ErbB-3 / Q000037:antagonists & inhibitors*
chemical_list: D066246:ErbB Receptors; D017239:Paclitaxel; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; C548875:AZD 8931; C508053:ERBB2 protein, human; C581292:ERBB3 protein, human