PMID- 26254023
OWN - NLM
STAT- MEDLINE
DCOM- 20151217
LR  - 20181202
IS  - 1432-0843 (Electronic)
IS  - 0344-5704 (Linking)
VI  - 76
IP  - 4
DP  - 2015 Oct
TI  - Phase I trial of afatinib plus vinorelbine in Japanese patients with advanced 
      solid tumors, including breast cancer.
PG  - 739-50
LID - 10.1007/s00280-015-2826-4 [doi]
AB  - PURPOSE: 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.
FAU - Mukai, Hirofumi
AU  - Mukai H
AD  - Division of Oncology/Hematology, National Cancer Center Hospital East, Kashiwa, 
      Japan. hrmukai@east.ncc.go.jp.
FAU - Masuda, Norikazu
AU  - Masuda N
AD  - Department of Surgery, Breast Oncology, Osaka National Hospital, Osaka, Japan.
FAU - Ishiguro, Hiroshi
AU  - Ishiguro H
AD  - Outpatient Oncology Unit, Kyoto University Hospital, Kyoto, Japan.
FAU - Mitsuma, Ayako
AU  - Mitsuma A
AD  - Department of Clinical Oncology and Chemotherapy, Nagoya University Hospital, 
      Nagoya, Japan.
FAU - Shibata, Takashi
AU  - Shibata T
AD  - Department of Clinical Oncology and Chemotherapy, Nagoya University Hospital, 
      Nagoya, Japan.
FAU - Yamamura, Jun
AU  - Yamamura J
AD  - Department of Mammary Gland and Internal Secretion Surgery, Sakai City Hospital, 
      Sakai, Japan.
FAU - Toi, Masakazu
AU  - Toi M
AD  - Department of Breast Surgery, Kyoto University Hospital, Kyoto, Japan.
FAU - Watabe, Aiko
AU  - Watabe A
AD  - Clinical Trial Management Department, Nippon Boehringer Ingelheim Co. Ltd., 
      Tokyo, Japan.
FAU - Sarashina, Akiko
AU  - Sarashina A
AD  - Clinical PK/PD Department, Nippon Boehringer Ingelheim Co. Ltd., Kobe, Hyogo, 
      Japan.
FAU - Uttenreuther-Fischer, Martina
AU  - Uttenreuther-Fischer M
AD  - TA Oncology, Boehringer Ingelheim Pharma GmbH and Co. KG, Biberach, Germany.
FAU - Ando, Yuichi
AU  - Ando Y
AD  - Department of Clinical Oncology and Chemotherapy, Nagoya University Hospital, 
      Nagoya, Japan.
LA  - eng
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Multicenter Study
PT  - Research Support, Non-U.S. Gov't
DEP - 20150808
PL  - Germany
TA  - Cancer Chemother Pharmacol
JT  - Cancer chemotherapy and pharmacology
JID - 7806519
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Antineoplastic Agents, Phytogenic)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Quinazolines)
RN  - 41UD74L59M (Afatinib)
RN  - 5V9KLZ54CY (Vinblastine)
RN  - EC 2.7.10.1 (ErbB Receptors)
RN  - Q6C979R91Y (Vinorelbine)
SB  - IM
MH  - Adult
MH  - Afatinib
MH  - Aged
MH  - Antineoplastic Agents/administration & dosage/adverse 
      effects/pharmacokinetics/therapeutic use
MH  - Antineoplastic Agents, Phytogenic/administration & dosage/adverse 
      effects/pharmacokinetics/therapeutic use
MH  - Antineoplastic Combined Chemotherapy Protocols/administration & dosage/*adverse 
      effects/pharmacokinetics/therapeutic use
MH  - Breast Neoplasms/blood/drug therapy/pathology
MH  - Cohort Studies
MH  - Dose-Response Relationship, Drug
MH  - Drug Monitoring
MH  - ErbB Receptors/*antagonists & inhibitors
MH  - Female
MH  - Humans
MH  - Japan
MH  - Leukopenia/chemically induced
MH  - Male
MH  - Middle Aged
MH  - Neoplasms/blood/*drug therapy/pathology
MH  - Patient Dropouts
MH  - Protein Kinase Inhibitors/administration & dosage/*adverse 
      effects/pharmacokinetics/therapeutic use
MH  - Quinazolines/administration & dosage/*adverse 
      effects/pharmacokinetics/therapeutic use
MH  - Tumor Burden/drug effects
MH  - Vinblastine/administration & dosage/adverse effects/*analogs & 
      derivatives/pharmacokinetics/therapeutic use
MH  - Vinorelbine
OTO - NOTNLM
OT  - Afatinib
OT  - Dose escalation
OT  - Japanese
OT  - Phase I
OT  - Vinorelbine
EDAT- 2015/08/09 06:00
MHDA- 2015/12/19 06:00
CRDT- 2015/08/09 06:00
PHST- 2015/06/22 00:00 [received]
PHST- 2015/07/09 00:00 [accepted]
PHST- 2015/08/09 06:00 [entrez]
PHST- 2015/08/09 06:00 [pubmed]
PHST- 2015/12/19 06:00 [medline]
AID - 10.1007/s00280-015-2826-4 [pii]
AID - 10.1007/s00280-015-2826-4 [doi]
PST - ppublish
SO  - Cancer Chemother Pharmacol. 2015 Oct;76(4):739-50. doi: 
      10.1007/s00280-015-2826-4. Epub 2015 Aug 8.