Phase III randomized trial of second-line ixabepilone versus paclitaxel or doxorubicin in women with advanced endometrial cancer

https://doi.org/10.1016/j.ygyno.2015.04.026Get rights and content

Highlights

  • An interim analysis of futility for overall survival (OS) favored the control arm.

  • The study was discontinued based on the OS results of the interim analysis.

  • Safety results were consistent with the known safety profile of ixabepilone/control.

Abstract

Objective

The purpose of this multicenter, open label, randomized phase III study was to determine whether ixabepilone resulted in improved overall survival (OS) compared with commonly used single-agent chemotherapy (doxorubicin or paclitaxel) in women with locally advanced, recurrent, or metastatic endometrial cancer with at least one failed prior platinum-based chemotherapeutic regimen.

Methods

Patients were randomized 1:1 to ixabepilone (40 mg/m2), or either paclitaxel (175 mg/m2) or doxorubicin (60 mg/m2), every 21 days. Patients that had previously received an anthracycline were randomized to ixabepilone or paclitaxel; all other patients were randomized to ixabepilone or doxorubicin. An interim analysis of futility for OS was planned.

Results

At the time of database lock, 496 patients were randomized to receive ixabepilone (n = 248) or control (n = 248); nine patients in the control arm were not treated. The interim analysis of futility for OS (219 events) favored the control chemotherapy arm (hazard ratio = 1.3 [95% confidence interval: 1.0–1.7], stratified log rank test P = 0.0397), indicating that the study would not meet its primary objective. The study was discontinued based on the interim OS results. The frequency of adverse events was comparable between the treatment arms.

Conclusions

The study did not meet its primary objective of improving OS in the ixabepilone arm compared to the control chemotherapy arm. A favorable risk/benefit ratio was not observed for ixabepilone versus control at the time of the interim analysis. The safety results were consistent with the known safety profiles of ixabepilone and control.

Introduction

Endometrial cancer is the fourth most common cancer in women in the United States after breast, lung, and colon cancers [1]. In 2015, 54,870 new cases (7% of total cancer cases) and 10,170 deaths (4% of total cancer deaths) were estimated [1]. The majority of patients with endometrial cancer (~ 75%) present at an early stage, and are treated surgically with or without adjuvant radiotherapy [2], [3]. However, there is uncertainty over what constitutes optimal adjuvant therapy for localized disease. While endometrial cancer is radiosensitive, a combination of radiotherapy plus chemotherapy has been shown to be superior to radiotherapy alone in the adjuvant setting [4].

For patients with advanced disease, standard first-line therapy consists of carboplatin plus paclitaxel, or cisplatin and doxorubicin ± paclitaxel combinations [5], [6], [7], [8]. Recent data from the Gynecologic Oncology Group (GOG) phase III trial of first-line chemotherapy for metastatic or recurrent endometrial carcinoma showed that the combination of carboplatin and paclitaxel had equivalent efficacy and substantially less toxicity than the three-drug combination of cisplatin, paclitaxel, and doxorubicin [8]. However, patients who progress following initial chemotherapy have limited treatment options, and the prognosis remains poor.

Treatment guidelines from the National Comprehensive Cancer Network in the United States list the following options for the systemic treatment of advanced, recurrent or metastatic endometrial cancer: progestational agents (e.g. megestrol acetate), selective estrogen receptor modulators (e.g. tamoxifen) or aromatase inhibitors; single-agent chemotherapy (e.g. cisplatin, carboplatin, doxorubicin, paclitaxel, docetaxel), and combination chemotherapy (e.g. cisplatin/doxorubicin/paclitaxel, carboplatin/paclitaxel) [9]. However, the guidelines do not provide guidance on first- or second-line regimens. In a recent Cochrane review of 14 randomized controlled trials comparing chemotherapy versus another intervention (including different chemotherapy) in advanced, recurrent or metastatic endometrial cancer, no conclusions could be made as to which single-agent or combination chemotherapy gave the greatest benefit [10]. The review suggested that more intense cytotoxic chemotherapy regimens administered in the first-line setting, including agents such as cisplatin, carboplatin, doxorubicin and taxanes, may improve overall survival (OS) and progression-free survival (PFS), but at the expense of increased toxicity.

Given the lack of definitive treatment recommendations, it is no surprise that there is a lack of consensus on the most appropriate therapies in the second- and/or third-line setting. In addition to the risk of toxicity, activity with second-line chemotherapeutic agents is modest and the limited data suggest that patients may be resistant to standard agents, such as docetaxel [11]. In a single-center retrospective analysis of 723 patients diagnosed with endometrial cancer and treated with first-line paclitaxel/carboplatin with or without epirubicin, there were no significant differences in response rates, PFS and OS between the various chemotherapeutic agents used [12]. This study also showed that patients who relapse within 6 months of first-line chemotherapy were likely not to respond to second-line treatment, which is similar to the platinum-resistant nature observed with ovarian cancer [13]. Thus, an important unmet medical need remains in patients with advanced endometrial cancer.

Ixabepilone, a semi-synthetic analog of epothilone B, exerts antitumor activity by promoting microtubule stability in a similar but distinct manner to the taxane class of drugs, and has low susceptibility to multiple drug resistance mechanisms [14]. In combination with capecitabine, ixabepilone is indicated for the treatment of metastatic or locally advanced breast cancer in patients after failure of an anthracycline and a taxane, or as monotherapy for the treatment of metastatic or locally advanced breast cancer in patients after failure of an anthracycline, a taxane, and capecitabine [15]. In a phase II GOG study, ixabepilone demonstrated modest activity as second-line chemotherapy in women with advanced endometrial cancer who had previously received chemotherapy [16]. The purpose of this study was to determine whether ixabepilone, administered to women with locally advanced, recurrent, or metastatic endometrial cancer who had experienced treatment failure on prior chemotherapy that included a platinum agent, resulted in improved OS compared with commonly used single-agent chemotherapy (doxorubicin or paclitaxel).

Section snippets

Patients

Eligible patients included women ≥ 18 years of age with histologic or cytologic diagnosis of advanced, recurrent or metastatic endometrial carcinoma, not curable by local measures, and a Karnofsky Performance Status ≥ 70. Measurable or non-measurable disease progression was required since the last treatment, along with one failed prior platinum-based chemotherapeutic regimen for endometrial cancer, regardless of setting or disease stage. Patients may have received up to two prior cytotoxic

Patients

Over a 29.6 month period, between August 17, 2009, and February 7, 2012, a total of 496 patients across 90 sites from 19 countries (North America, Europe, Latin America, Australia, and Asia/Japan) were randomized to receive ixabepilone (n = 248) or control (n = 248) (Fig. 1). Of the 248 patients randomized to the control arm, 171 received doxorubicin and 68 received paclitaxel; nine patients were not treated (Fig. 1). Baseline demographics were similar for randomized patients in the ixabepilone and

Discussion

Women with advanced, recurrent and/or metastatic endometrial cancer that relapse after first-line treatment have limited treatment options. Phase II studies of various agents have demonstrated modest if any activity, and therefore, a second-line regimen for patients previously treated with platinum-based chemotherapy has yet to be established. Similar to observations in ovarian cancer, there is evidence to suggest that time to recurrence following first-line treatment is predictive of survival

Acknowledgments

The authors take full responsibility for the content of this publication and confirm that it reflects their viewpoint and scientific expertise. They wish to acknowledge Clair Thomas of StemScientific, funded by Bristol-Myers Squibb, for providing writing and editorial support.

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