Originally published as JCO Early Release 10.1200/JCO.2006.09.7535 on July 2 2007

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Phase II Clinical Trial of Ixabepilone (BMS-247550), an Epothilone B Analog, As First-Line Therapy in Patients With Metastatic Breast Cancer Previously Treated With Anthracycline Chemotherapy

Henri Roché, Louise Yelle, Francesco Cognetti, Louis Mauriac, Craig Bunnell, Joseph Sparano, Pierre Kerbrat, Jean-Pierre Delord, Linda Vahdat, Ronald Peck, David Lebwohl, Rana Ezzeddine, Hervé Curé

From the Institut Claudius Regaud, Toulouse; Institut Bergonie, Bordeaux; Centre Eugene Marquis, Rennes; Centre Jean Perrin, Clermont-Ferrand, France; Centre Hospitalier de l'Université de Montréal–Hôpital Notre-Dame, Montreal, Quebec, Canada; Comitato Etico (Istituto di Ricovero e Cura a Carattere Scientifico) di Roma, IFO-Istituto Regina Elena, Rome, Italy; Dana-Farber Cancer Institute, Boston, MA; Albert Einstein Comprehensive Cancer Center, Montefiore Medical Center, Department of Oncology; Weill Medical College of Cornell University, New York, NY; and Bristol-Myers Squibb, Wallingford, CT

Address reprint requests to Henri Roché, MD, Institut Claudius Regaud, 20-24 rue du Saint Pierre, 31052 Toulouse Cedex, France; e-mail: roche.henri{at}claudiusregaud.fr

	ABSTRACT

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Purpose There is a need for new agents to treat metastatic breast cancer (MBC) in patients for whom anthracycline therapy has failed or is contraindicated. This study was conducted to assess the efficacy and safety of the novel antineoplastic, the epothilone B analog ixabepilone, in patients with MBC previously treated with an adjuvant anthracycline.

Patients and Methods Patients were age 18 years and had received a prior anthracycline-based regimen as adjuvant treatment. Ixabepilone as first-line metastatic chemotherapy was administered as a 40 mg/m² intravenous infusion during 3 hours every 3 weeks. The primary efficacy end point was objective response rate (ORR). Secondary efficacy end points included duration of response, time to response, time to progression, and survival.

Results All 65 patients were assessable for response. Their median age was 52 years (range, 33 to 80 years). ORR was 41.5% (95% CI, 29.4% to 54.4%), median duration of response was 8.2 months (95% CI, 5.7 to 10.2 months), and median time to response was 6 weeks (range, 5 to 17 weeks). Median survival was 22.0 months (95% CI, 15.6 to 27.0 months). Treatment-related adverse events were manageable and mostly grades 1/2: the most common of these (other than alopecia) was mild to moderate neuropathy, which was primarily sensory and mostly reversible in nature.

Conclusion Ixabepilone is efficacious and has a predictable and manageable safety profile in women with MBC previously treated with an adjuvant anthracycline.

	INTRODUCTION

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Although improvements have been achieved in the treatment of metastatic breast cancer (MBC) in recent years, the disease remains essentially incurable.¹ Anthracyclines and taxanes are considered the most active agents and are used both as single agents and in combination. With anthracyclines frequently used as the first class of chemotherapeutic agents in adjuvant therapy, there has been a subsequent increase in the number of patients with acquired resistance, discouraging anthracycline re-treatment. There is also a subset of patients with primary resistance to anthracyclines, often due to multidrug resistance through expression of P-glycoprotein. In addition, some patients cannot tolerate anthracyclines because of toxicity or they are not candidates for anthracycline treatment because of existing cardiac disease or previous exposure to the maximum cumulative dose. Therefore, there is a need for new agents that are effective in these patients.

The epothilones are a novel class of antineoplastic agents that target microtubules. Naturally occurring epothilones, including epothilones A to D, are macrolides originally isolated from the bacterium Sorangium cellulosum.^2,3 Owing to the promising antineoplastic activity of natural epothilones, numerous semisynthetic epothilone analogs have been synthesized.⁴ Epothilones promote cell death by stabilizing microtubules and inducing apoptosis.⁵ Ixabepilone is a semisynthetic analog of epothilone B, designed to optimize the antineoplastic characteristics of the natural product. It has shown encouraging efficacy in a range of tumor types in preclinical studies; of particular importance, ixabepilone has demonstrated efficacy in cell lines and xenografts with resistance to commonly used antineoplastic agents.⁶

On the basis of results of a phase I study, the recommended phase II dose for ixabepilone was 50 mg/m² administered during 1 hour every 3 weeks.⁷ The main toxicities at this dose were neutropenia, stomatitis/pharyngitis, myalgia, and arthralgia. Ixabepilone demonstrated antitumor activity in this study, with eight patients achieving durable objective responses across a variety of nonbreast tumor types.

This phase II study evaluated the clinical activity of first-line treatment with single-agent ixabepilone in patients with MBC previously treated with adjuvant anthracycline.

	PATIENTS AND METHODS

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Study Design and Treatment
At the beginning of this open-label phase II study, ixabepilone as first-line metastatic chemotherapy was administered as a 50 mg/m² intravenous (IV) infusion during 1 hour every 3 weeks. After treatment of 19 patients, the infusion time was increased from 1 hour to 3 hours because of an increased rate of grade 3/4 neuropathy. After an additional nine patients were treated with the 3-hour infusion, the ixabepilone dose was reduced from 50 to 40 mg/m² because of an increased rate of GI toxicities observed in a phase I study conducted in parallel with this study.⁷

Dosing continued for a maximum of 18 cycles until evidence of progressive disease (PD) and/or the patient met discontinuation criteria. Because the ixabepilone formulation contained Cremophor EL (BASF, Ludwigshafen, Germany), the protocol required premedication with H₁ and H₂ blockers (diphenhydramine and ranitidine, or cimetidine) with or without corticosteroids to prevent hypersensitivity reactions.

The study protocol was approved by the institutional review boards of participating institutions. All patients provided written informed consent. The study was conducted according to the Declaration of Helsinki and its amendments.

Patients and Eligibility Criteria
Eligible patients had to be age 18 years, have histologically or cytologically proven MBC, have at least one bidimensionally measurable lesion (bone lesions excluded), and have received a prior anthracycline-based adjuvant regimen (patients may have received a taxane as part of an adjuvant regimen, provided that 1 year had elapsed since completion of treatment). The following were also required: adequate hematologic, renal, and hepatic function; adequate recovery from recent surgery and/or radiation therapy; recovery from all prior treatment-related toxicities (to grade < 2 according to National Cancer Institute Common Toxicity Criteria, except alopecia); life expectancy of 12 weeks; and an Eastern Cooperative Oncology Group performance status score of 0 to 1. Women of child-bearing potential must have had a negative serum or urine pregnancy test within 72 hours before start of study medication.

Efficacy Assessment
The primary efficacy end point was objective response rate (ORR). Secondary efficacy end points included duration of response, time to response, time to progression (TTP), and overall survival (OS). Efficacy analyses were performed on response-assessable patients. Tumor evaluation according to the modified WHO criteria⁸ was performed every two cycles.

Safety Assessment
Safety was assessed on the basis of adverse event (AE) reporting and laboratory abnormalities, classified according to National Cancer Institute Common Toxicity Criteria (version 2.0). Serum biochemistry was evaluated before each treatment cycle, whereas hematology was assessed both weekly and before each cycle.

Statistical Design and Methodology
Estimates of the median duration of response, TTP, and survival, with 95% CIs, were calculated for each cohort using the Kaplan-Meier product-limit method. Duration of response, the time from start of treatment until documented progression or death was calculated for responding patients only. TTP was defined as the time from the first day of treatment until the first date of progression or death. Median time to response and minimum and maximum values were calculated. Descriptive statistics were used to summarize safety and laboratory observations.

A two-stage design⁹ was used to test whether the ORR was of strong clinical interest. In the first stage, 27 response-assessable patients were to be accrued. If there were no more than five responders at the end of the first stage, the study was to be terminated with the conclusion that the true response rate was likely to be 20%. If there were at least six responses, an additional 36 assessable patients were to be accrued in the second stage. With this design, there was less than 10% chance of stopping at the end of the first stage if the true ORR was 35%. A 10% inassessability rate was assumed for a total of approximately 70 patients to be enrolled in the cohort if accrual continued after the first stage. This design was applied at each dose level, restarted with each amendment, and completed only at the 40 mg/m² level.

	RESULTS

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Patient Characteristics
A total of 93 patients were enrolled at 12 study centers (United States, France, Italy, and Canada) from February 15, 2001, to July 22, 2003. The initial dose and schedule investigated in this study was 50 mg/m² as a 1-hour infusion (n = 19). This was amended subsequently to 50 mg/m² as a 3-hour infusion (n = 9) and then to 40 mg/m² IV infusion during 3 hours every 3 weeks in response to early safety findings. This report focuses on the 65 patients who received ixabepilone as a 40 mg/m² IV infusion during 3 hours every 3 weeks; summaries of results for the two 50 mg/m² cohorts are also provided.

The median patient age was 52 years, and the majority of women were white (94%) and premenopausal (65%; Table 1). Patients had extensive tumor burden at baseline; the majority had at least two involved disease sites (77%; n = 50) and/or visceral metastases (85%; n = 55). All patients had received at least one prior anthracycline-containing regimen; details of prior treatment are listed in Table 1. Five patients (8%) had experienced relapse 12 months after their last dose of an anthracycline-containing regimen, with three of these patients experiencing relapse after 6 months. Three patients had experienced progressive disease within 2 years of their last dose on a taxane regimen. Almost all patients had undergone surgery (98%; n = 64), and the majority had received prior radiation (89%; n = 58) or hormonal therapy (71%; n = 46).

Efficacy
All 65 treated patients were assessable for response. The ORR was 41.5% (95% CI, 29.4 to 54.4); 27 patients experienced a partial response (PR) and none had a complete response (Table 2). The median duration of response was 8.2 months (95% CI, 5.7 to 10.2). Of the 27 patients who responded, six were without PD for 12 months. The median time to response was 6 weeks (range, 5 to 17 weeks), with most responders achieving an objective PR at their first on-treatment tumor assessment at the end of cycle 2. Most responders had baseline visceral metastatic lesions involving the liver and lung.

Tolerability
Treatment-related AEs (Table 3) were manageable and mostly grades 1/2. The most common AE (other than alopecia) was neuropathy. Grades 1/2 sensory neuropathy occurred in 33 patients (51%), and grade 3 sensory neuropathy occurred in 13 patients (20%). Motor neuropathy was low grade and rare (grade 2 in one patient and grade 3 in three patients). No patient had grade 4 sensory or motor neuropathy. Eighteen patients (28%) discontinued treatment because of sensory neuropathy after a median of six cycles (range, three to 10 cycles). Although follow-up was often limited, all but two of these patients had sensory neuropathy that improved or resolved, most within 1 to 2 months of discontinuation. The two patients who did not show improvement in their neuropathy after discontinuation completed only one follow-up visit each.

Hematologic abnormalities (Table 3) were manageable; the most common grade 3 abnormality was neutropenia (grade 3 in 27% and grade 4 in 31% of patients). The median neutrophil nadir was 0.8 x 10³/L (range, 0.1 to 4.6 x 10³). Only three patients required growth factor support for neutropenia during treatment. Grade 4 treatment-related febrile neutropenia was reported in two patients; four patients with grade 3 treatment-related neutropenia developed infection, although these events did not lead to discontinuation. Anemia and thrombocytopenia were generally grade 1/2, with the exception of two patients with grade 3 anemia. There were no occurrences of grade 4 anemia or thrombocytopenia. Hematologic toxicities did not result in discontinuation or death; only seven patients required a dose delay, for a total of eight cycles (3%) with a dose delay.

No patients experienced a severe hypersensitivity reaction (HSR). Four patients (6%) had mild to moderate HSR. In two patients, the reaction occurred during ixabepilone infusion and resulted in temporary dose interruption. In the third patient, HSR occurred on the day of infusion but did not result in dose interruption. The fourth patient developed a grade 2 skin rash 1 day after receiving her second dose. The majority of liver function tests (ALT, AST, and alkaline phosphatase) and serum creatinine abnormalities were mild to moderate in intensity and did not lead to treatment discontinuation.

The majority of patients (52%) discontinued treatment because of PD. Twenty-two patients (34%) discontinued because of treatment-related AEs (most were because of sensory neuropathy [18 patients]). Fourteen of these 22 patients (64%) discontinued after receiving at least six cycles (range, one to 10 cycles). Five additional patients discontinued because of physician request, and one patient each discontinued because of administrative decision, clinical deterioration, no improvement, and patient request. One patient died within 30 days of the last treatment; the investigator judged the death to be related to disease progression.

Extent of Exposure
The 65 patients treated on the 40 mg/m² 3-hour regimen received a total of 350 cycles, and a median of six cycles (range, one to 14 cycles) of ixabepilone. A total of 34 (52%) patients received at least six cycles; 13 patients (20%) received at least eight cycles. Of the 350 cycles, most (82%) were administered at the patient's starting dose level of 40 mg/m². The median cumulative dose was 206.5 mg/m² (range, 40.1 to 466.1 mg/m²), reflecting a dose reduction that occurred in 18 patients (28%). The median dose-intensity, calculated as the cumulative dose divided by the intended treatment duration in weeks (duration from first study drug administration to start of last cycle plus 3 weeks) was 12.7 mg/m²/wk (range, 9.2 to 13.9 mg/m²/wk).

Ixabepilone 50 mg/m² 1- and 3-Hour Cohorts
This study also assessed efficacy and safety of ixabepilone administered as 1- and 3-hour infusions at a starting dose of 50 mg/m² every 3 weeks (19 and nine patients, respectively). Ixabepilone demonstrated clinical activity in these patients. ORR in the 1- and 3-hour cohorts were 58% and 22%, respectively (all PRs); median TTPs were 9.3 months (95% CI, 6.8 to 14.1 months) and 4.2 months (95% CI, 2.8 to 5.6 months), respectively (Table 4). Median duration of response for the 1-hour cohort was 9.3 months (95% CI, 6.8 to 11.7 months; n = 11) and 5.6 months (95% CI, not applicable; two responders only) for the 3-hour cohort.

	DISCUSSION

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Anthracyclines and taxanes are considered to be the most active antineoplastic agents in breast cancer, and are the mainstay of treatment in both the adjuvant and metastatic settings. However, some tumors demonstrate primary resistance to anthracyclines and taxanes. Furthermore, anthracycline usage is limited by its cardiotoxicity; it is recommended that cumulative lifetime doses of doxorubicin and epirubicin do not exceed 450 to 550 and 900 mg/m², respectively. Therefore, there is a need for new agents that demonstrate efficacy in patients in whom anthracycline therapy has failed or is contraindicated.

In previous clinical trials of the novel tubulin-targeting agent ixabepilone, antitumor activity against advanced breast cancer has been demonstrated in patients with triple-resistant (taxane, anthracycline, and capecitabine) metastatic disease (ORR, 18%; response duration, 5.3 months); taxane-resistant, anthracycline-pretreated metastatic disease (ORR, 12%; response duration, 10.4 months); and as monotherapy in the neoadjuvant setting (ORR, 61%; complete response, 17%; complete pathologic response in breast, 18%).^10-12

This phase II study demonstrated that ixabepilone 40 mg/m² during 3 hours is effective in women with MBC previously treated with an adjuvant anthracycline-based regimen. The ORR was 41.5%, responses were durable, and median survival was 22.0 months. Although the activity of ixabepilone 50 mg/m² administered every 3 weeks seemed to be greater, this regimen was associated with an unacceptable rate of toxicity. A comparison of grades 3/4 sensory neuropathy among the three treatment cohorts is summarized in Table 5. The greater than expected incidence of neuropathy observed at 50 mg/m² 1 hour compared with that in 22 patients treated in the phase I trial⁷ (5%) was likely due to longer duration of therapy experienced by patients in this trial.

Ixabepilone 40 mg/m² infused during 3 hours had a predictable and manageable safety profile; there were no treatment-related deaths. Myelosuppression was moderate, consisting primarily of neutropenia and leukopenia, but was manageable and not treatment limiting. Febrile neutropenia and infection with neutropenia were infrequent. Neuropathy was mainly sensory, generally mild to moderate, and largely reversible. Sensory neuropathy that was severe and/or resulted in treatment discontinuation was cumulative in most cases and characterized by paresthesia. Even among the 18 patients who discontinued therapy because of neuropathy, improvement or resolution occurred in 16 patients, most within 1 to 2 months. Although neurologic function tests may eventually prove useful in predicting risk for sensory neuropathy with ixabepilone,¹⁸ current methods are unreliable, and diagnosis of early-stage neuropathy can be complex in the presence of other AEs. It is important, therefore, to note that the onset of sensory neuropathy leading to discontinuation in this study was relatively late (median, six cycles). Given that most responders had achieved a PR at their first on-treatment tumor assessment at the end of cycle 2, sufficient ixabepilone was administered to achieve responses before sensory neuropathy became limiting. Despite the reversibility of neuropathy in our study, we recommend decreasing the dose of ixabepilone when grade 2 sensory neuropathy appears and stopping treatment if grade 3 sensory neuropathy occurs.

In conclusion, this phase II study demonstrated that single-agent ixabepilone 40 mg/m² administered as a 3-hour infusion every 3 weeks is effective, with a predictable and manageable safety profile in women with MBC previously treated with adjuvant anthracycline-based chemotherapy. After promising results from this and other phase II trials,^10-12,19-21 ixabepilone is being evaluated both as a single agent and in combination with capecitabine in phase II and III trials in MBC. Full results are also anticipated from a trial searching for gene expression profiles to predict complete pathologic response to ixabepilone as neoadjuvant therapy for early breast cancer,²² which could identify ixabepilone as suitable for use in earlier stages of breast cancer.

	AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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Although all authors completed the disclosure declaration, the following authors or their 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: Ronald Peck, Bristol-Myers Squibb; Rana Ezzeddine, Bristol-Myers Squibb Leadership: N/A Consultant: Henri Roché, Sanofi-aventis; Joseph Sparano, Bristol-Myers Squibb Stock: Ronald Peck, Bristol-Myers Squibb; David Lebwohl, Bristol-Myers Squibb Honoraria: Joseph Sparano, Bristol-Myers Squibb Research Funds: Louise Yelle, Bristol-Myers Squibb; Craig Bunnell, Bristol-Myers Squibb; Joseph Sparano, Bristol-Myers Squibb Testimony: N/A Other: N/A

	AUTHOR CONTRIBUTIONS

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Conception and design: Henri Roché, Louise Yelle, Francesco Cognetti, Ronald Peck, David Lebwohl

Financial support: Louise Yelle, Ronald Peck

Administrative support: Louise Yelle, Ronald Peck, David Lebwohl

Provision of study materials or patients: Henri Roché, Louise Yelle, Francesco Cognetti, Craig Bunnell, Joseph Sparano, Pierre Kerbrat, Jean-Pierre Delord, Linda Vahdat, Hervé Curé

Collection and assembly of data: Louise Yelle, Craig Bunnell, Joseph Sparano, Jean-Pierre Delord, David Lebwohl

Data analysis and interpretation: Henri Roché, Louise Yelle, Louis Mauriac, Linda Vahdat, Ronald Peck, David Lebwohl, Rana Ezzeddine

Manuscript writing: Henri Roché, Louise Yelle, Linda Vahdat, Ronald Peck, Rana Ezzeddine

Final approval of manuscript: Henri Roché, Louise Yelle, Francesco Cognetti, Louis Mauriac, Craig Bunnell, Joseph Sparano, Pierre Kerbrat, Jean-Pierre Delord, Linda Vahdat, Ronald Peck, David Lebwohl, Rana Ezzeddine, Hervé Curé

	ACKNOWLEDGMENTS

 
We thank Laura Whitaker, the protocol manager, for her role in the coordination and management of this trial, and Diana McCulloch, PhD, for her editorial assistance.

	NOTES

 
published online ahead of print at www.jco.org on July 31, 2006.

Supported by Bristol-Myers Squibb Co.

Presented in part at the 38th Annual Meeting of the American Society of Clinical Oncology, May 18-21, 2002, Orlando, FL; 39th Annual Meeting of the American Society of Clinical Oncology, May 31-June 3, 2003, Chicago, IL; International Union Against Cancer Meeting, 2006; and Roché H, Perez E, Llombart-Cussac A, et al: Ixabepilone, an epothilone analog, is effective in ER-, PR-, HER2-negative (triple-negative) patients: data from neoadjuvant and metastatic breast cancer trials. Ann Oncol 17:ix93-ix113, 2006 (abstr 256-P).

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

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11. Thomas E, Perez EA, Mukhopadhyay P, et al: Phase II trial of ixabepilone in patients with metastatic breast cancer (MBC) who are resistant to an anthracycline, a taxane and capecitabine. J Clin Oncol 24:42s, 2006 (suppl; abstr 660)[CrossRef]

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Submitted October 31, 2006; accepted April 2, 2007.

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