Originally published as JCO Early Release 10.1200/JCO.2006.08.1646 on December 18 2006

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Dofequidar Fumarate (MS-209) in Combination With Cyclophosphamide, Doxorubicin, and Fluorouracil for Patients With Advanced or Recurrent Breast Cancer

Toshiaki Saeki, Tadashi Nomizu, Masakazu Toi, Yoshinori Ito, Shinzaburo Noguchi, Tadashi Kobayashi, Taro Asaga, Hironobu Minami, Naohito Yamamoto, Kenjiro Aogi, Tadashi Ikeda, Yasuo Ohashi, Wakao Sato, Takashi Tsuruo

From the National Shikoku Cancer Center, Matsuyama; Hoshi General Hospital, Koriyama; Japanese Foundation for Cancer Research, Tokyo; School of Medicine, Osaka University, Osaka; Nihon Schering K.K., Osaka; Kanagawa Cancer Center, Yokohama; National Cancer Center Hospital East, Kashiwa; Chiba Cancer Center, Chiba; Tokyo Metropolitan Komagome Hospital; The Jikei University School of Medicine; School of Medicine, Keio University; Biostatistics/Epidemiology and Preventive Health Sciences, University of Tokyo; Institute of Molecular and Cellular Biosciences, University of Tokyo; and Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan

Address reprint requests to Toshiaki Saeki, MD, PhD, Saitama Medical School Hospital, 38 Morohongo, Moroyama, Iruma-gun, Saitama 350-0495, Japan; e-mail: tsaeki{at}saitama-med.ac.jp

Purpose To evaluate the efficacy and tolerability of dofequidar plus cyclophosphamide, doxorubicin, and fluorouracil (CAF) therapy in comparison with CAF alone, in patients with advanced or recurrent breast cancer. Dofequidar is a novel, orally active quinoline derivative that reverses multidrug resistance.

Patients and Methods In this randomized, double-blind, placebo-controlled trial, patients were treated with six cycles of CAF therapy: 28 days/cycle, with doxorubicin (25 mg/m²) and fluorouracil (500 mg/m²) administered on days 1 and 8 and cyclophosphamide (100 mg orally [PO]) administered on day 1 through 14. Patients received dofequidar (900 mg PO) 30 minutes before each dose of doxorubicin. Primary end point was overall response rate (ORR; partial or complete response). In total, 221 patients were assessable.

Results ORR was 42.6% for CAF compared with 53.1% for dofequidar + CAF, a 24.6% relative improvement and 10.5% absolute increase (P = .077). There was a trend for prolonged progression-free survival (PFS; median 241 days for CAF v 366 days for dofequidar + CAF; P = .145). In retrospectively defined subgroups, significant improvement in PFS in favor of dofequidar was observed in patients who were premenopausal, had no prior therapy, and were stage IV at diagnosis with an intact primary tumor. Except for neutropenia and leukopenia, there was no statistically significant excess of grade 3/4 adverse events compared with CAF. Treatment with dofequidar did not affect the plasma concentration of doxorubicin.

Conclusion Dofequidar + CAF was well tolerated and is suggested to have efficacy in patients who had not received prior therapy.

published online ahead of print at www.jco.org on December 18, 2006.

Supported by Schering AG, Berlin, Germany.

Presented in part at the 29th European Society for Medical Oncology Congress, Vienna, Austria, October 29–November 2, 2004, and the 27th San Antonio Breast Cancer Conference, San Antonio, TX, December 8-11, 2004.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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