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Originally published as JCO Early Release 10.1200/JCO.2006.08.1646 on December 18 2006 © 2007 American Society of Clinical Oncology. Dofequidar Fumarate (MS-209) in Combination With Cyclophosphamide, Doxorubicin, and Fluorouracil for Patients With Advanced or Recurrent Breast Cancer
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.
Despite the advances in chemotherapeutic intervention, many cancers are either inherently resistant or develop resistance to chemotherapy.1,2 Consequently, multidrug resistance (MDR) remains a major obstacle to the successful treatment of cancer.1,3,4 One mechanism by which MDR operates is via the increased cellular efflux of cytotoxic compounds due to increased expression of membrane transport proteins such as P-glycoprotein (P-gp) and MDR-associated protein (MRP).1,4,5 MDR affects many structurally and functionally unrelated agents including cytotoxic drugs that are hydrophobic, natural products, such as taxanes, vinca alkaloids, anthracyclines, epipodophyllotoxins, topotecan, dactinomycin, and mitomycin.1,6,7 These represent some of the most commonly used chemotherapeutic agents. In tumors with low levels of P-gp expression at baseline or diagnosis, P-gp expression increases after exposure to chemotherapy agents, thus leading to the development of MDR. In breast cancer patients who had received prior chemotherapy, P-gp expression has been shown to increase from 11% in untreated patients to 30% after chemotherapy.8 Furthermore, compared with P-gp–negative tumors, a significant increase in resistance to paclitaxel and doxorubicin was reported in P-gp positive breast cancer tissue, irrespective of prior therapy. The degree of P-gp expression also strongly correlated with the degree of drug resistance observed.8 Chemotherapy remains the treatment of choice for women with hormone receptor–negative and hormone-refractory breast cancer disease.9-11 However, many tumors that are initially responsive to chemotherapy frequently relapse and develop resistance to the broad spectrum of cytotoxic drugs currently employed.8,12,13 Consequently, MDR remains a major reason for treatment failure in patients with metastatic breast cancer and highlights the urgent need for MDR modifiers in breast cancer chemotherapy. Since the discovery of verapamil as an MDR-reversing agent,14 many compounds have been investigated as MDR inhibitors.14-16 Dofequidar fumarate (Fig 1), is a novel, orally active, quinoline-derived inhibitor of MDR.17 In preclinical studies, dofequidar reversed MDR in P-gp–and MRP-1–expressing cancer cells in vitro (1 to 3 µmol/L), as well as enhancing the antitumor effects of doxorubicin in MDR tumor–bearing mice.17-19 A phase I trial in healthy volunteers showed dofequidar to be well tolerated (10 to 1,200 mg) with no dose-limiting toxicities and an effective plasma concentration was maintained for 8 hours at 900 mg (data on file, Schering AG, Berlin, Germany). In a phase II combination trial in patients with recurrent breast cancer, dofequidar potentiated the antitumor effects of CAF (cyclophosphamide, doxorubicin, and fluorouracil) therapy; patients who had not responded to treatment with three cycles of CAF responded to subsequent treatment with dofequidar plus CAF. The numbers of patients with an objective response were two of seven at 600 mg and two of six at 900 mg dofequidar, though dose escalation was stopped at 1,200 mg due to increased hematologic toxicity (data on file, Schering AG). On the basis of this result, this phase III study was conducted to compare the efficacy and safety of dofequidar plus CAF with placebo plus CAF in patients with advanced or recurrent breast cancer.
Study Design This was a randomized, multicenter, double-blind, placebo-controlled trial conducted at 46 centers across Japan, comparing the efficacy and safety of dofequidar plus CAF with placebo plus CAF. Female patients (age 20 to 70 years) with advanced (stage IV at diagnosis with an intact primary tumor) or recurrent breast cancer were enrolled onto the study. Other inclusion criteria included a histologically defined, measurable or assessable primary lesion; two or fewer regimens of prior chemotherapy in both neo/adjuvant and metastatic settings, (excluding prior endocrine or single-agent fluorouracil therapy); 180 mg/m2 anthracyclines (doxorubicin equivalent) or less previously; a performance status of 0 to 2; and adequate bone marrow, renal, hepatic and cardiac functions. Patients who progressed or had a recurrence in less than 6 months with anthracycline-containing chemotherapy, and those who had a history of major cardiac disease, uncontrolled hypertension, symptomatic brain metastasis, or simultaneous malignancy were excluded. The trial was approved by the institutional review board and was conducted in accordance with the Declaration of Helsinki (1996). All patients provided written informed consent before study entry.
Dosing and Dose Modification for Toxicity
Treatment Assignment
Efficacy Subgroup analyses were conducted to assess PFS within specific patient subpopulations, including premenopausal women, patients who had no prior therapy, and patients who had advanced primary breast cancer.
Safety and Tolerability
Pharmacokinetics
Statistical Analyses
Patient Characteristics A total of 227 patients were recruited onto the study (Fig A1, online only), of which 225 patients were included in the safety analysis (n = 113 for the dofequidar group; n = 112 for the placebo group); two patients did not receive the study treatment and were thus excluded. Four patients did not meet the inclusion/exclusion criteria; therefore, the FAS consisted of 221 patients (n = 113 for the dofequidar group; n = 108 for the placebo group). The PPS consisted of 199 patients (n = 100 for the dofequidar group; n = 99 for the placebo group). There were 22 patients excluded from the PPS analysis due to protocol deviations. Baseline patient characteristics were well balanced between the two treatment arms (Table 1). Most patients had predominantly recurrent disease and had received prior chemotherapy plus endocrine therapy. Also, many patients who had advanced primary breast cancer had received no prior therapy.
Efficacy The ORR, rated as CR or partial response rate, was 42.6% for CAF plus placebo versus 53.1% for dofequidar plus CAF (Table 2). Although this represents a 24.6% relative improvement and a 10.5% absolute increase in response rate for patients receiving dofequidar plus CAF compared with those receiving CAF plus placebo, this response was not statistically significant (P = .077). A higher value was observed in the dofequidar treatment group for all secondary end points compared with placebo, though these results were not statistically significant. Among them, Figure 2 shows a trend for prolonged PFS (median, 241 days for CAF plus placebo v 366 days for dofequidar plus CAF; P = .145).
Dofequidar plus CAF significantly improved PFS in several patient subgroups, including patients who were premenopausal (P = .046; Fig 3A), patients who had not received prior therapy (P = .0007; Fig 3B), and patients who had advanced primary breast cancer (P = .017; Fig 3C). An extended follow-up showed that dofequidar plus CAF also significantly improved overall survival (P = .0034; Fig 3D) in patients who had no prior therapy.
Safety and Tolerability A similar number of patients completed six treatment cycles in both groups (n = 53 for the dofequidar group; n = 51 for the placebo group). The mean number of treatment cycles was 4.5 in the dofequidar group and 4.3 in the placebo group. More than half of patients in both groups included in each cycle from cycle 2 onward had a delay in treatment, mostly due to prolonged hematologic toxicities. Dofequidar plus CAF was well tolerated throughout the study. No statistically significant excess of grade 3/4 AEs, except for neutropenia (P = .006) and leukopenia (P = .005), was found in the dofequidar group compared with placebo (Table A1, online only). Importantly, there was no marked difference in the incidence of neutropenia-related morbidity, such as febrile neutropenia or infection, between the two treatment groups. No significant differences in the incidence of cardiac AEs were found between the two treatment groups. In addition, dose intensities of chemotherapeutic agents were similar in both treatment arms. No significant difference in the incidence of serious AEs (SAEs) was observed between either group. However, there was a trend for a higher incidence of SAEs from leukopenia in the dofequidar group than in the placebo group (P = .060; Fisher's exact test); five leukopenia cases were reported for dofequidar, whereas no such case was reported for placebo. A total of 124 patients discontinued the study (n = 61 for the dofequidar group; n = 63 for the placebo group). The major reasons for discontinuation were progressive disease (n = 23 for the dofequidar group; n = 28 for the placebo group), grade 4 hematologic toxicity (n = 20 for the dofequidar group; n = 6 for the placebo group), failure to meet treatment continuation criteria (n = 6 for the dofequidar group; n = 8 for the placebo group), and consent withdrawal (n = 6 for the dofequidar group; n = 12 for the placebo group). Of the 225 patients who received treatment in the study, 14 patients died during the treatment period (n = 3), the follow-up period (n = 2), or the follow-up period after study termination (n = 9). There were 49 other serious AEs in 32 patients during the study and follow-up period.
Pharmacokinetics
Chemotherapy remains the preferred adjuvant treatment for patients with hormone receptor–negative disease and for patients with more aggressive, hormone receptor–positive tumors.11,20 However, despite the use of conventional adjuvant chemotherapy regimens, a significant proportion of patients with breast cancer still experience disease recurrence because of inherent or acquired drug resistance.12 In this randomized phase III trial, the efficacy and safety of the multidrug resistance inhibitor dofequidar plus CAF was compared with CAF plus placebo in patients with recurrent or advanced breast cancer. Although, there was an observed relative improvement and absolute increase in response rate for patients who received dofequidar plus CAF, these results did not reach statistical significance. This improvement in response rate may have been reflected in the observation that there was a trend for prolonged PFS, which favored patients in the dofequidar plus CAF group. To date, only two randomized trials have examined the efficacy of a P-gp inhibitor in combination with chemotherapy in breast cancer patients. Wishart et al21 examined quinidine combined with epirubicin in patients with advanced breast cancer, but failed to show any significant difference in overall survival or PFS compared with placebo. In a more recent prospective study of patients with anthracycline-resistant metastatic breast cancer (n = 99), verapamil combined with vindesine and fluorouracil resulted in a significantly longer overall survival and a higher response rate compared with patients who did not receive the P-gp inhibitor (median survival, 323 v 209 days; P = .036, respectively; ORR, 27% v 11%; P = .04, respectively).22 In the subgroup analyses, dofequidar in combination with CAF displayed a significantly increased PFS in patients who had not received prior therapy, who had advanced primary breast cancer or who were premenopausal. In addition, dofequidar also significantly improved overall survival in the patient group who had no prior therapy. Although the patient numbers in these analyses were small, the results remain important within these clinically significant patient populations. Both preclinical and clinical data have indicated that newer-generation MDR modulators can prevent the development of resistance.23,24 A phase I/II trial in patients with acute myeloid leukemia showed that dosing with cyclosporine before and in combination with daunorubicin prevented chemotherapy resistance, while also resulting in a decrease in MDR-1 RNA expression.24 Our results may highlight one potential treatment approach to MDR tumors that has not yet been fully exploited in the clinical environment, specifically the prevention of the emergence of resistance through the early use of P-gp inhibitors.1-3 It seems reasonable that agents such as dofequidar may be useful in the adjuvant or even neoadjuvant setting with the goal of preventing or delaying the induction of MDR associated with chemotherapy. The potential clinical significance of P-gp and MRP expression in breast cancer is supported by the results from a number of studies. For example in a study of primary breast cancer patients (n = 259), MRP expression was associated with an increased risk of treatment failure in patients with small tumors (T1) and node-positive patients who received adjuvant cyclophosphamide, methotrexate, and fluorouracil (CMF) chemotherapy but not in node-negative patients.25 Burger et al12 reported that the expression of MDR1 mRNA in primary breast tumors was inversely correlated with the efficacy of first-line chemotherapy. Additionally, the high level of MDR1 expression was suggested to be a significant predictor of poor prognosis in patients with advanced disease.12 Significantly increased expression of P-gp and MRP-1 has also been reported in an immunohistochemical study of patients treated with preoperative chemotherapy, whereas pretreatment expression of MRP-1 was associated with significantly shorter PFS in patients.26 In a more recent study, MRP-1 expression was shown to be an independent predictor for shorter relapse-free survival and overall survival, after adjuvant CMF treatment, in premenopausal, hormone receptor–positive patients.27 However, MRP-1 expression did not affect patients' response to adjuvant tamoxifen plus goserelin treatment.27 These findings and our results support the view of Leonard et al,3 who indicate that future patients will need to be carefully selected for the identification and development of effective drug-resistance modulators. Patient populations who may derive maximal benefit from MDR inhibition, for example, the no-prior-therapy, advanced-disease, or premenopausal patient group in the present study, could quite easily be overlooked or lost within a large, heterogeneous trial population.3 Furthermore, by refining future clinical trials to incorporate specific disease and patient characteristics, a clearer picture of drug resistance in cancer will be obtained and the most effective MDR inhibitor/chemotherapeutic agent(s) selected. Many MDR inhibitors have required high serum concentrations for MDR reversal, which resulted in unacceptable toxicity, thereby limiting their clinical impact.7,28-32 Although more recent agents have shown improved tolerability profiles, this has been countered by unpredictable pharmacokinetic interactions with other transporter molecules (eg, cytochrome P450–mediated drug metabolism and excretion, necessitating dose reductions in chemotherapy agents and leading to inconsistent chemotherapy dosing among patients).1,5 Similarly, the addition of the MDR-modulating agent valspodar (PSC 833) to chemotherapy agents did not improve treatment outcome.33,34 Toxicity was increased in the valspodar-treated group compared with chemotherapy agents alone, despite the reduction of chemotherapy doses in the valspodar-containing regimen. In our study, dofequidar was well tolerated, with no indication of the unacceptable toxicity associated with early MDR inhibitors. Importantly, dofequidar did not affect the plasma concentrations of doxorubicin in patients during the study and displayed an acceptable pharmacokinetic profile. In conclusion, this study suggests that treatment with dofequidar resulted in possible clinical benefit for patients who had not received prior therapy, who were premenopausal, or who were stage IV at diagnosis with an intact primary tumor. Dofequidar was also well tolerated in the clinical setting and had no impact on doxorubicin pharmacokinetics. Further studies are merited to assess the effect of dofequidar in specific patient populations with breast cancer.
Although all authors completed the disclosure declaration, the following author or immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment: N/A Leadership: N/A Consultant: Toshiaki Saeki, Nihon Schering; Takashi Tsuruo, Nihon Schering Stock: N/A Honoraria: N/A Research Funds: N/A Testimony: N/A Other: N/A
Conception and design: Toshiaki Saeki, Masakazu Toi, Yoshinori Ito, Shinzaburo Noguchi, Tadashi Kobayashi, Hironobu Minami, Tadashi Ikeda, Yasuo Ohashi, Wakao Sato, Takashi Tsuruo Financial support: Wakao Sato Administrative support: Toshiaki Saeki, Tadashi Ikeda Provision of study materials or patients: Toshiaki Saeki, Tadashi Nomizu, Masakazu Toi, Yoshinori Ito, Shinzaburo Noguchi, Tadashi Kobayashi, Taro Asaga, Hironobu Minami, Naohito Yamamoto, Kenjiro Aogi, Tadashi Ikeda Collection and assembly of data: Toshiaki Saeki, Tadashi Nomizu, Masakazu Toi, Yoshinori Ito, Shinzaburo Noguchi, Tadashi Kobayashi, Taro Asaga, Hironobu Minami, Naohito Yamamoto, Kenjiro Aogi Data analysis and interpretation: Toshiaki Saeki, Masakazu Toi, Yoshinori Ito, Shinzaburo Noguchi, Tadashi Kobayashi, Hironobu Minami, Tadashi Ikeda, Yasuo Ohashi, Wakao Sato Manuscript writing: Toshiaki Saeki, Wakao Sato Final approval of manuscript: 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
The participating institutions and principal investigators of the MS-209 Study Group included the following: Motoshi Tamura (Sapporo National Hospital), Tosei Ohmura (Sapporo Medical University), Seiichi Takenoshita (Fukushima Medical University), Hamaichi Ueki (Mito National Hospital), Morihiko Kimura (Gunma Prefectural Cancer Center), Toshio Tabei (Saitama Cancer Centre), Junichi Koh (Saitama Social Insurance Hospital), Tsuyoshi Saito (Omiya Red Cross Hospital), Masato Suzuki (Chiba University Hospital), Noriyuki Katsumata (National Cancer Center Central Hospital), Kenji Ogawa (Tokyo Women's Medical University Second Affiliate Hospital), Kiyoshi Nishiyama (Yokohama National Hospital), Mamoru Fukuda (St Marianna University School of Medicine Affiliate Hospital), Kazuo Ishida (Kitasatao University Hospital), Tomoki Kitaya (Atami National Hospital), Kazushige Toyama (Shizuoka Prefectural General Hospital), Keigo Goto (Hamamatsu Western Medical Center), Tomio Kashizuka (Gifu Municipal Hospital), Takae Kataoka (Nagoya Memorial Foundation Hospital), Kiichi Maeda (Toyama Prefectural Central Hospital), Yutaka Tanikawa (Fukui Medical Center for Adults), Eisei Shin (Osaka National Hospital), Hideo Inaji (Osaka Medical Center for Cancer and Cardiovascular Diseases), Norio Kohno (Hyogo Medical Center for Adults), Masahiro Watatani (Kinki University Hospital), Yoshikazu Masai (Kobe City General Hospital), Yuichi Takatsuka (Kansai Rosai Hospital), Hiroshi Sonoo (Kawasaki Medical School Hospital), Ryungsa Kim, (Hiroshima University Hospital), Masato Koseki (Kure National Hospital), Hideya Tashiro (Matsuyama Red Cross General Hospital), Kansei Komaki (Tokushima University Hospital), Shoshu Mitsuyama (Kitakyushu Municipal Medical Center), Fumie Matsuo (Fukuoka University Hospital), Teruhiko Fujii (Kurume University Hospital), Ikuo Takahashi (Oita Prefectural Hospital), and Reiki Nishimura (Kumamoto Municipal Hospital).
We thank the investigators (physicians and staff) at the participating institutions; Shunzo Kobayashi, Tomoo Tajima, and Chikuma Hamada (Independent Monitoring Committee); Shigeto Miura, Morihiko Kimura, Hideo Inaji, Izo Kimijima, and Hirokazu Watanabe (Efficacy Evaluation Committeee); and Nihon Schering K.K. for their help.
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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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
grade 3)
