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Investigational New Drugs

, Volume 32, Issue 5, pp 946–954 | Cite as

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

  • Takayasu KurataEmail author
  • Junji Tsurutani
  • Yasuhito Fujisaka
  • Wataru Okamoto
  • Hidetoshi Hayashi
  • Hisato Kawakami
  • Eisei Shin
  • Nobuya Hayashi
  • Kazuhiko Nakagawa
PHASE I STUDIES

Summary

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/m2 (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. Conclusion 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.

Keywords

AZD8931 Paclitaxel HER Advanced solid tumors Breast cancer 

Notes

Acknowledgments

This study was sponsored by AstraZeneca. Andrew Jones, PhD, from Mudskipper Business Ltd provided medical writing support, funded by AstraZeneca.

Ethical standards

All patients provided written informed consent. The study was approved by the Institutional Review Board of Kinki University, Osakasayama, Japan, and was conducted in accordance with the Declaration of Helsinki, Good Clinical Practice and the AstraZeneca policy on bioethics [22]. The experiments comply with the current laws of the country in which they were performed.

Conflict of interest

Takayasu Kurata has received lecturer’s fees from AstraZeneca. Yasuhito Fujisaka has received research fees for clinical studies from AstraZeneca. Kazuhiko Nakagawa has received lecturer’s fees and research fees for clinical studies from AstraZeneca. Eisei Shin and Nobuya Hayashi are employees of AstraZeneca. Junji Tsurutani, Wataru Okamoto, Hidetoshi Hayashi and Hisato Kawakami have no conflicts of interest to disclose.

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Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Takayasu Kurata
    • 1
    • 3
    Email author
  • Junji Tsurutani
    • 1
  • Yasuhito Fujisaka
    • 1
    • 4
  • Wataru Okamoto
    • 1
  • Hidetoshi Hayashi
    • 1
    • 5
  • Hisato Kawakami
    • 1
  • Eisei Shin
    • 2
  • Nobuya Hayashi
    • 2
  • Kazuhiko Nakagawa
    • 1
  1. 1.Department of Medical OncologyKinki University School of MedicineOsakaJapan
  2. 2.AstraZeneca K.K.Ohyodo-nakaJapan
  3. 3.Department of Thoracic OncologyKansai Medical University Hirakata HospitalHirakataJapan
  4. 4.Clinical Trial CenterOsaka Medical College HospitalTakatsukiJapan
  5. 5.Department of Medical OncologyKishiwada Municipal HospitalKishiwadaJapan

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