Safety and pharmacokinetics of ramucirumab in combination with docetaxel in Japanese patients with locally advanced or metastatic breast cancer: a Phase Ib study.
OBJECTIVE
The primary objective of this study was to investigate the safety and tolerability and to confirm the recommended dose of the anti-vascular endothelial growth factor receptor 2 monoclonal antibody ramucirumab in combination with docetaxel in Japanese patients with metastatic/locally advanced breast cancer.


METHODS
In this multicenter, single-arm, Phase Ib trial, eligibility criteria included: 20 years or older, Eastern Cooperative Oncology Group performance status of 0/1 and confirmed diagnosis of human epidermal growth factor receptor 2-negative metastatic/locally recurrent inoperable breast adenocarcinoma. Patients received docetaxel (75 mg/m2) followed by ramucirumab (10 mg/kg) on Day 1 of 21-day cycles. Recommended dose was defined as <33% dose-limiting toxicities in dose-limiting toxicity-evaluable patients in Cycle 1. The safety, pharmacokinetics, immunogenicity and antitumor activity were examined.


RESULTS
Seven patients were treated. Most adverse events were mild to moderate. Two patients during Cycle 1 experienced a dose-limiting toxicity; one patient each experienced Grade 3 febrile neutropenia and Grade 3 gingivitis. Both dose-limiting toxicities subsequently resolved. No patients discontinued study therapies during Cycle 1. Four serious adverse events were possibly related to ramucirumab in combination with docetaxel. Anti-ramucirumab antibodies were not detected. Pharmacokinetic analysis revealed low total body clearance and long apparent terminal elimination half-life (~7-12 days). Partial response was reported in four patients.


CONCLUSIONS
The combination of ramucirumab and docetaxel was tolerable in female Japanese patients with breast cancer. Ramucirumab 10 mg/kg in combination with docetaxel (75 mg/m2) was confirmed as the recommended dose among Japanese patients, supporting its use in future studies.
Department of Surgery, Breast Oncology, National Hospital Organization, Osaka National Hospital, Osaka nmasuda@alpha.ocn.ne.jp.
Norikazu
N
Masuda
Department of Breast Oncology, Aichi Cancer Center Hospital, Nagoya.
Hiroji
H
Iwata
Department of Breast Oncology, National Hospital Organization, Shikoku Cancer Center, Ehime, Japan.
Kenjiro
K
Aogi
Lilly Research Laboratory, Eli Lilly and Company, Bridgewater, NJ, USA.
Yihuan
Y
Xu
Lilly Research Laboratory, Eli Lilly and Company, Bridgewater, NJ, USA.
Ayman
A
Ibrahim
Lilly Research Laboratory, Eli Lilly and Company, Bridgewater, NJ, USA.
Ling
L
Gao
Lilly Research Laboratory, Eli Lilly and Company, Bridgewater, NJ, USA.
Rita
R
Dalal
Medicines Development Unit-Japan, Eli Lilly Japan K.K., Kobe, Hyogo.
Reigetsu
R
Yoshikawa
Division of Medical Oncology, Department of Medicine, Saitama University International Medical Center, Saitama, Japan.
Yasutsuna
Y
Sasaki
D000368:Aged; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D044466:Asian People; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D000077143:Docetaxel; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005260:Female; D005891:Gingivitis / Q000209:etiology; D006207:Half-Life; D006801:Humans; D007564:Japan; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D009503:Neutropenia / Q000209:etiology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D043823:Taxoids / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016896:Treatment Outcome; D000096662:Ramucirumab
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D000077143:Docetaxel; D018719:Erb-b2 Receptor Tyrosine Kinases; D043823:Taxoids; D000096662:Ramucirumab; C508053:ERBB2 protein, human
angiogenesis; breast cancer; docetaxel; ramucirumab; vascular endothelial growth factor receptor 2