title: Phase I trial of afatinib plus vinorelbine in Japanese patients with advanced solid tumors, including breast cancer.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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/m(2) weekly.
  
  
  RESULTS
  Seventeen patients were enrolled. Dose level 2 (afatinib 40 mg and vinorelbine 25 mg/m(2)) 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/m(2) and dose level 3: afatinib 40 mg and vinorelbine 25 mg/m(2) 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.
  
  
  CONCLUSIONS
  Afatinib 40 mg QD plus vinorelbine 25 mg/m(2) 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.
authors.affiliation: Division of Oncology/Hematology, National Cancer Center Hospital East, Kashiwa, Japan. hrmukai@east.ncc.go.jp.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Mukai
authors.affiliation: Department of Surgery, Breast Oncology, Osaka National Hospital, Osaka, Japan.
authors.forename: Norikazu
authors.initials: N
authors.lastname: Masuda
authors.affiliation: Outpatient Oncology Unit, Kyoto University Hospital, Kyoto, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ishiguro
authors.affiliation: Department of Clinical Oncology and Chemotherapy, Nagoya University Hospital, Nagoya, Japan.
authors.forename: Ayako
authors.initials: A
authors.lastname: Mitsuma
authors.affiliation: Department of Clinical Oncology and Chemotherapy, Nagoya University Hospital, Nagoya, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Shibata
authors.affiliation: Department of Mammary Gland and Internal Secretion Surgery, Sakai City Hospital, Sakai, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Yamamura
authors.affiliation: Department of Breast Surgery, Kyoto University Hospital, Kyoto, Japan.
authors.forename: Masakazu
authors.initials: M
authors.lastname: Toi
authors.affiliation: Clinical Trial Management Department, Nippon Boehringer Ingelheim Co. Ltd., Tokyo, Japan.
authors.forename: Aiko
authors.initials: A
authors.lastname: Watabe
authors.affiliation: Clinical PK/PD Department, Nippon Boehringer Ingelheim Co. Ltd., Kobe, Hyogo, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Sarashina
authors.affiliation: TA Oncology, Boehringer Ingelheim Pharma GmbH and Co. KG, Biberach, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Uttenreuther-Fischer
authors.affiliation: Department of Clinical Oncology and Chemotherapy, Nagoya University Hospital, Nagoya, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Ando
mesh_terms: D000328:Adult; D000077716:Afatinib; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000097:blood / Q000188:drug therapy / Q000473:pathology; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D016903:Drug Monitoring; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D005260:Female; D006801:Humans; D007564:Japan; D007970:Leukopenia / Q000139:chemically induced; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D010352:Patient Dropouts; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use; D011799:Quinazolines / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use; D047368:Tumor Burden / Q000187:drug effects; D014747:Vinblastine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D000077235:Vinorelbine
chemical_list: D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000077716:Afatinib; D014747:Vinblastine; D066246:ErbB Receptors; D000077235:Vinorelbine
keywords: Afatinib; Dose escalation; Japanese; Phase I; Vinorelbine