Cancer Chemotherapy and Pharmacology

, Volume 76, Issue 4, pp 739–750 | Cite as

Phase I trial of afatinib plus vinorelbine in Japanese patients with advanced solid tumors, including breast cancer

  • Hirofumi MukaiEmail author
  • Norikazu Masuda
  • Hiroshi Ishiguro
  • Ayako Mitsuma
  • Takashi Shibata
  • Jun Yamamura
  • Masakazu Toi
  • Aiko Watabe
  • Akiko Sarashina
  • Martina Uttenreuther-Fischer
  • Yuichi Ando
Original Article



This phase I trial assessed afatinib, an irreversible ErbB family blocker, plus vinorelbine in Japanese patients with advanced solid tumors not amenable to standard treatment.


Primary objectives were evaluation of safety and the maximum tolerated dose (MTD) of once-daily (QD) afatinib plus weekly intravenous vinorelbine. Secondary objectives included pharmacokinetic assessments and preliminary efficacy. Dose finding utilized a 3 + 3 design, with a starting dose of afatinib 20 mg QD plus vinorelbine 25 mg/m2 weekly.


Seventeen patients were enrolled. Dose level 2 (afatinib 40 mg and vinorelbine 25 mg/m2) exceeded the MTD; dose-limiting toxicities (DLTs) were considered vinorelbine-related. Dose finding continued with modified dose levels; dose level 2a: afatinib 40 mg and a reduced dose of vinorelbine 20 mg/m2 and dose level 3: afatinib 40 mg and vinorelbine 25 mg/m2 allowing omission of vinorelbine for grade ≥2 neutropenia/thrombocytopenia and afatinib dose modification for adverse events (AEs). At dose level 3, 1/6 patients had a DLT (upper abdominal pain requiring afatinib dose reduction). Overall, the most frequent treatment-related AEs (any/grade 3 and 4) were: neutropenia (100/71 %), leukopenia (100/59 %), diarrhea (94/0 %), anemia (71/12 %) and stomatitis (65/0 %). Two patients with breast cancer achieved a partial response; eight patients (various cancer indications) had stable disease. Pharmacokinetic analyses suggested no relevant drug–drug interactions.


Afatinib 40 mg QD plus vinorelbine 25 mg/m2 weekly was tolerated in Japanese patients when dose modifications for known AEs for either compound were allowed. Tumor shrinkage was also observed. This dose schedule was recommended for phase II/III trials in Japanese patients.


Afatinib Dose escalation Phase I Japanese Vinorelbine 



The authors would like to acknowledge the support of all trial investigators, clinical trial support staff and participating patients and their families. This study was supported by Nippon Boehringer Ingelheim Co. Ltd. The authors were fully responsible for all content and editorial decisions, and were involved at all stages of manuscript development and have approved the final version. Medical writing assistance, supported financially by Boehringer Ingelheim, was provided by Christine Arris and Caroline Allinson of GeoMed, an Ashfield Company, part of UDG Healthcare plc, during the preparation of this article.

Compliance with ethical standards

Conflict of interest

Hirofumi Mukai has received funding from Boehringer Ingelheim. Akiko Sarashina, Martina Uttenreuther-Fischer and Aiko Watabe are employees of Boehringer Ingelheim. Yuichi Ando has received remuneration from Kyowa Hakko Kirin, Nippon Kayaku and Boehringer Ingelheim; has held a consultant/advisory role with Boehringer Ingelheim; and has received funding from Kyowa Hakko Kirin and Nippon Kayaku. All other authors declare no potential conflicts of interest.

Supplementary material

280_2015_2826_MOESM1_ESM.docx (648 kb)
Supplementary material 1 (DOCX 648 kb)


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Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Hirofumi Mukai
    • 1
    Email author
  • Norikazu Masuda
    • 2
  • Hiroshi Ishiguro
    • 3
  • Ayako Mitsuma
    • 4
  • Takashi Shibata
    • 4
  • Jun Yamamura
    • 5
  • Masakazu Toi
    • 6
  • Aiko Watabe
    • 7
  • Akiko Sarashina
    • 8
  • Martina Uttenreuther-Fischer
    • 9
  • Yuichi Ando
    • 4
  1. 1.Division of Oncology/HematologyNational Cancer Center Hospital EastKashiwaJapan
  2. 2.Department of Surgery, Breast OncologyOsaka National HospitalOsakaJapan
  3. 3.Outpatient Oncology UnitKyoto University HospitalKyotoJapan
  4. 4.Department of Clinical Oncology and ChemotherapyNagoya University HospitalNagoyaJapan
  5. 5.Department of Mammary Gland and Internal Secretion SurgerySakai City HospitalSakaiJapan
  6. 6.Department of Breast SurgeryKyoto University HospitalKyotoJapan
  7. 7.Clinical Trial Management DepartmentNippon Boehringer Ingelheim Co. Ltd.TokyoJapan
  8. 8.Clinical PK/PD DepartmentNippon Boehringer Ingelheim Co. Ltd.KobeJapan
  9. 9.TA OncologyBoehringer Ingelheim Pharma GmbH and Co. KGBiberachGermany

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