A phase I dose-escalation study of eribulin and S-1 for metastatic breast cancer

• Published in: British journal of cancer Vol. 112; no. 5; pp. 819 - 824
• Main Authors: Sakiyama, T, Tsurutani, J, Iwasa, T, Kawakami, H, Nonagase, Y, Yoshida, T, Tanaka, K, Fujisaka, Y, Kurata, T, Komoike, Y, Nishio, K, Nakagawa, K
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 03-03-2015; Nature Publishing Group
• Subjects: 631/154/436/108; 692/699/67/1347; 692/700/565/1436/1437; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols - administration & dosage; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Biomedical and Life Sciences; Biomedicine; Breast Neoplasms - drug therapy; Cancer Research; Clinical Study; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Combinations; Drug Resistance; Epidemiology; Female; Furans - administration & dosage; Furans - pharmacokinetics; Furans - therapeutic use; Humans; Ketones - administration & dosage; Ketones - pharmacokinetics; Ketones - therapeutic use; Maximum Tolerated Dose; Middle Aged; Molecular Medicine; Neoplasm Metastasis - drug therapy; Oncology; Oxonic Acid - administration & dosage; Oxonic Acid - pharmacokinetics; Oxonic Acid - therapeutic use; Tegafur - administration & dosage; Tegafur - pharmacokinetics; Tegafur - therapeutic use; Young Adult; triple negative; breast cancer; combination therapy
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/bjc.2015.10

Background:
We evaluated the safety, maximum-tolerated dose (MTD), pharmacokinetics, recommended dose for phase II (P2RD), and preliminary anticancer activity of a combination eribulin and S-1 therapeutic in metastatic breast cancer patients pretreated with anthracycline and taxane.
Method:
Patients aged 20–74 years were recruited. In level 1, patients received S-1 (65 mg m
−2
) from day 1 to 14, and eribulin (1.1 mg m
−2
) on day 1 and 8 in a 21-day cycle. In level 2, eribulin was increased to 1.4 mg m
−2
. In level 3, S-1 was increased to 80 mg m
−2
.
Results:
Twelve patients were enrolled into three cohorts. Planned dose escalation was completed, with one case exhibiting dose-limiting toxicity (grade 3 hypokalaemia) at level 3, without reaching the MTD. The P2RD was determined to be level 2 (eribulin 1.4 mg m
−2
and S-1 65 mg m
−2
). The most common grade 3 or 4 toxicity was neutropenia (83.3%), followed by febrile neutropenia (25.0%). Five of eleven patients (41.7%) with measurable disease had a partial response. Pharmacokinetics were characterised by dose-dependent elimination and nonlinear exposure.
Conclusion:
Dose level 3 was not tolerated owing to febrile neutropenia development. Thus, intermediate dose level 2 was recommended for further evaluation. Preliminary antitumour activity warrants further investigation in this setting.