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Originally published as JCO Early Release 10.1200/JCO.2006.10.0784 on July 2 2007 © 2007 American Society of Clinical Oncology. Phase II Trial of Ixabepilone, an Epothilone B Analog, in Patients With Metastatic Breast Cancer Previously Untreated With Taxanes
From the Breast Cancer Section, Medical Oncology Branch and Biostatistics and Data Management Section, Office of the Clinical Director, Center for Cancer Research; Cancer Therapy Evaluation Program, Division of Cancer Treatment and Diagnosis; Diagnostic Radiology Department, Warrant G. Magnuson Clinical Center; National Clinical Target Validation Laboratory, Division of Cancer Treatment and Diagnosis, Bethesda, MD; Washington Cancer Institute, Washington Hospital Center, Washington, DC; and Yale Cancer Center, Yale University School of Medicine, New Haven, CT Address reprint requests to Sandra M. Swain, MD, Washington Cancer Institute, Washington Hospital Center, 110 Irving St NW, Washington, DC 20010; e-mail: sandra.m.swain{at}medstar.net
Purpose Ixabepilone is an epothilone B analog that binds to microtubules and results in microtubule stabilization and mitotic arrest. Ixabepilone was evaluated for efficacy and safety in a phase II clinical trial for women with metastatic breast cancer.
Patients and Methods Patients were eligible if they had not previously received treatment with a taxane and had measurable metastatic breast cancer. Ixabepilone was administered at 6 mg/m2/d intravenously days 1 through 5 every 3 weeks until unacceptable toxicity or disease progression. Patients underwent pretreatment and post-treatment tumor biopsies, and tissues were analyzed for acetylated
Results Twenty-three patients received 210 cycles with a median of eight cycles (range, two to 22 cycles) per patient. Thirteen patients (57%; exact 95% CI, 34.5% to 76.8%) had partial responses, six patients (26%) had stable disease, and four patients (17%) had progressive disease. Median time to progression and duration of response were 5.5 and 5.6 months, respectively. Four patients required dose reductions for neutropenia, neuropathy, or fatigue. Grade 3 or 4 toxicities included neutropenia (22%), fatigue (13%), anorexia (9%), and motor neuropathy (4%). Thirty-nine percent of patients experienced grade 1, 13% experienced grade 2, and none experienced grade 3/4 sensory neuropathy. The six patients with paired biopsies all had increases in tumor Conclusion Women with metastatic breast cancer previously untreated with taxanes have a meaningful durable response to single-agent ixabepilone therapy. Minimal hematologic toxicity and no grade 3 sensory neuropathy were noted.
Breast cancer is estimated to account for more than 40,910 deaths in 2007 in the United States.1 Taxanes, potent microtubule stabilizers, have remained the mainstay of cytotoxic therapy for patients with metastatic breast cancer during the last decade. Adjuvant therapy with taxanes is the standard of care for patients with node-positive breast cancer.2-4 Although taxanes are efficacious, routine steroid premedication use, neuropathy, and bone marrow suppression continue to be problematic. In addition, increasing use of taxanes in the adjuvant setting has led to development of resistance and decreased response rates with single-agent use in the metastatic setting.5 This highlights the need for development of novel agents with greater or equal efficacy and improved adverse effect profiles.
Microtubules are comprised of Promising preclinical data prompted evaluation of ixabepilone in multiple phase I studies. A phase I study completed at the National Cancer Institute established that ixabepilone administered at 6 mg/m2/d for 5 days every 3 weeks was the maximum tolerated dose.11 The dose-limiting toxicity was neutropenia in heavily pretreated patients. Objective responses were noted in patients with breast cancer. Neurotoxicity was noted, but seemed to be decreased on this administration schedule compared with schedules in other phase I trials. This trial also established that corticosteroid premedication is not required with ixabepilone, in contrast to treatment with paclitaxel or docetaxel.11
Because of encouraging results and tolerable toxicity profiles in phase I studies, a phase II trial with two cohorts was initiated at our institution to evaluate efficacy of ixabepilone in the metastatic breast cancer population. The cohort of patients previously treated with taxanes before ixabepilone treatment has been published.12 We present the clinical efficacy, safety, and correlative studies in the cohort of patients that did not receive taxanes in the adjuvant or metastatic setting. Although microtubule function and mechanisms of microtubule-stabilizing agents are well understood, biomarkers of tumor response or tumor resistance to microtubule-stabilizing agents are yet to be fully elucidated. In tumor biopsies obtained before and during treatment with ixabepilone, we evaluated p53, tau-1 expression, and
Eligibility Eligible patients had a diagnosis of metastatic breast adenocarcinoma that was confirmed pathologically; an Eastern Cooperative Oncology Group performance status of 0, 1, or 2; and measurable disease by Response Criteria in Solid Tumors criteria.13 Patients could not have received a taxane in either the adjuvant or metastatic setting, but there were no other limits for prior therapy. Laboratory values required a total bilirubin  1.5x institutional upper limit of normal, ALT and AST 2.5x institutional upper limit of normal, creatinine within normal institutional limits, an absolute neutrophil count of  1.5 x 109/L, and platelet count of 100 x 109/L. Because of possible interference of cytochrome P450 3A4 activity by ixabepilone, patients were excluded from receiving the following medications at enrollment and while enrolled onto the study: amiodarone, clarithromycin, erythromycin, fluconazole, itraconazole, ketoconazole, indinavir, nelfinavir, ritonavir, and saquinavir. Patients with grade 2 or greater neuropathy at baseline were excluded.
Study Design and Treatment Modifications Toxicities were assessed using NCI Common Toxicity Criteria version 2.0 at baseline and at the conclusion of each cycle of treatment.14 Dose reductions to 5 mg/m2/d and then to 4 mg/m2/d were implemented for patients experiencing grade 3 and 4 nonhematologic toxicities during the prior cycle, or for grade 1 or 2 toxicities requiring treatment delays. Toxicities required resolution to grade 1 or baseline before the next cycle of treatment. Granulocyte colony-stimulating factors were not administered at cycle 1, but could be added subsequently. Treatment intervals could be extended up to 5 weeks between cycles for patients with optimal responses who completed six cycles of treatment.
Response Assessment
Statistical Considerations Progression-free survival probabilities as a function of time were calculated using the Kaplan-Meier method with censoring at last follow-up (without progression), or removal from study for toxicity. Duration of response was calculated actuarially for 13 patients who had confirmed partial responses, and was calculated from the day of first radiologic partial response until the date of progression. An exact Wilcoxon rank sum test was performed to compare continuous parameters between responders (partial response) and nonresponders (stable and progressive disease). P values are two tailed, and are presented without adjustment for multiple comparisons.
Correlative Studies
Immunohistochemistry on tissue sections of formalin-fixed paraffin-embedded samples was performed using a standard avidin-biotin-peroxidase complex indirect immunoperoxidase procedure. Mouse monoclonal antibodies to p53 (Vector Laboratories Inc, Burlingame, CA), acetylated
Patients Twenty-three patients were enrolled between June 2002 and September 2005, two of whom were enrolled due to a registration error. The baseline characteristics and patients' prior therapy for breast cancer are summarized in Table 1. Sixteen of 23 patients received prior chemotherapy, and 11 of 18 patients with hormone receptor–positive breast cancer were treated with prior hormonal therapy. Twelve patients received prior anthracycline therapy. Patients received a median of eight cycles (range, two to 22 cycles). Of 23 patients enrolled, 17 patients were removed from study because of disease progression, four patients were removed because of toxicity, and two patients remain on study (with treatment times of 9 and 10 months each).
Efficacy The objective response rate was 57% (95% CI, 34.5% to 76.8%), with 13 partial responses. Stable disease for at least 6 weeks was the best response for 26% (six patients) of patients. The median time to progression for all patients was 5.5 months (Fig 1). For 13 patients who achieved a partial response, median duration of response from date of first documentation of response was 5.6 months. The best response in each patient's target tumor measurements from baseline are presented in Figure 2. Measurable responses were observed in visceral sites such as lung and liver, soft tissue masses, and lymph nodes. Improvements were also seen in nontarget lesions, including breast, skin, and bone. Of five patients who received ixabepilone as initial therapy for their metastatic breast cancer, three had partial responses and one patient each had stable disease and progressive disease. Of 12 patients who had prior anthracycline therapy, seven patients (58%) had partial responses, four patients (33%) had stable disease, and one patient (8%) had progressive disease. Of the 18 patients with hormone receptor–positive disease, 12 (67%) had partial responses, four patients (22%) had stable disease, and two patients (11%) had progressive disease. One of five patients with hormone receptor–negative disease achieved a partial response.
Toxicities A total of 210 cycles of therapy were administered. Toxicity information was collected for all patients. The worst toxicity grades are summarized in Table 2. No patients experienced febrile neutropenia. Only one patient required filgrastim. The most notable and frequent nonhematologic toxicities were fatigue, neuropathy, and nail changes. Four patients were removed from the study because of toxicity. Reasons for removal from the study included the following: one patient because of grade 3 weight loss, one patient with grade 3 motor neuropathy, one patient because of prolonged autonomic neuropathy, and one patient because of grade 2 fatigue. Four patients required dose reductions while on study, and two of these four patients required two dose reductions. The dose was reduced due to prolonged neutropenia in one patient, neuropathy in three patients, and fatigue in two patients. The patient with prolonged neutropenia received filgrastim for subsequent cycles. Eight patients required antinausea medication for one cycle, and two patients required antinausea medication for two cycles.
Neuropathy Five of 23 patients had grade 1 baseline neuropathy before treatment with ixabepilone. Three of five patients with baseline grade 1 sensory neuropathy developed worsening neuropathy: two patients had grade 2 sensory neuropathy, and one patient had grade 2 motor neuropathy. Of 18 patients with no baseline neuropathy, nine patients developed grade 1, and two patients developed grade 2 sensory neuropathy. One of 18 patients developed grade 3 motor neuropathy. In total, three patients developed at least grade 2 sensory neuropathy, one patient developed grade 2 motor neuropathy, and one patient developed grade 3 motor neuropathy. The patient who developed grade 3 motor neuropathy had severe rheumatoid arthritis and did not regain function of her fingers due to both ixabepilone and worsening rheumatoid arthritis.
Correlative Studies
Our data demonstrate that ixabepilone administered daily for 5 days every 3 weeks is an efficacious agent in metastatic breast cancer. The high partial response rate of 57% and 5.6-month duration of response in a taxane-naïve patient population are encouraging. Of 12 patients who received prior anthracyclines on our study, seven (58%) achieved a partial response. A trial evaluating ixabepilone 40 mg/m2 as a single dose every 3 weeks in a taxane-naïve metastatic breast cancer population that was treated with anthracyclines reported a response rate of 34%.16 Patient populations treated with ixabepilone exposed to prior taxanes achieved response rates between 11.5% and 31%.12,17-19 Our response rate compares favorably to response rates (25% to 68%) in studies that evaluated docetaxel or paclitaxel in patient populations that did not previously receive taxanes.20-26 In a trial in which 21% of patients received adjuvant chemotherapy, the response rate was 29% and the median time to progression was 5.3 months after paclitaxel therapy.27 Patients treated with docetaxel after anthracycline therapy achieved a 30% response rate and a 4.25-month time to progression.24 Patients treated with ABI-007 (American BioScience, Santa Monica, CA), a taxane that does not require corticosteroid premedication, experienced a 33% response rate and a 5.75-month time to progression.28 The median time to progression of 5.5 months on our trial is similar to that of these agents. Bone marrow suppression, an issue with taxanes and other schedules of ixabepilone, was not predominant in our patients.20,26,27,29 Only one patient had neutropenia requiring growth factor support and delay in ixabepilone therapy. Our rates of neuropathy with this schedule were less frequent than in other trials using ixabepilone during shorter administration schedules or taxanes including ABI-007.16,21,22,25,30 Relatively low rates of grade 2 and 3 neuropathy (13% grade 2 sensory neuropathy, 0% grade 3 sensory neuropathy, 4% grade 2 motor neuropathy, 4% grade 3 motor neuropathy) on our trial as well as other trials evaluating this dosing schedule of ixabepilone may be due to daily administration with lower peak doses.11,12,31 Increased duration of peak concentrations of microtubule-stabilizing agents may contribute to increased neurotoxicity.32 There is also a report that genetic polymorphisms in P-glycoprotein may increase the risk of developing neuropathy after treatment with paclitaxel, and similar studies should be performed with ixabepilone.33 Neurologic function tests such as the Jebsen Test of Hand Function may predict grade 2 or higher peripheral neuropathy with ixabepilone.34
Biomarkers of tumor response to microtubule-stabilizing agents are not yet established. A recently completed pharmacogenomic study using ixabepilone in the neoadjuvant setting showed that low concentration or lack of estrogen receptor was the best single-gene predictor of tumor response to ixabepilone.35 From six paired tumor biopsies available on our study, we observed increased levels of acetylated Our data did not show any association with p53 expression and response to ixabepilone treatment. Nine patients with tissue available had p53 levels in tumor consistent with wild-type p53. Six of these patients achieved partial responses, and three patients achieved stable disease. Two patients on our study with inflammatory breast cancer had increased expression of p53 in the tumor samples, suggesting a mutated p53 phenotype.36 One of these patients achieved a partial response; the other patient had progressive disease. These results are consistent with prior evidence that tumor response to microtubule-stabilizing agents is indifferent to intact p53 status.37 tau-1 is a microtubule-associated protein that promotes tubulin stabilization.7 There is no consensus whether tau-1 expression inhibits or enhances cytotoxicity to microtubule-stabilizing agents. Our data did not show association between tau-1 expression and clinical response to ixabepilone. Similarly, tau-1 expression did not correlate with pathologic complete response to ixabepilone in a pharmacogenomic study.35 However, low tumor tau-1 expression did correlate with response to paclitaxel.38-40 An absence of significant trends in the biomarkers in our study may be due to small numbers of patients with available biopsies and few patients with progressive disease. Another possible reason we were unable to detect significant trends is that we assessed each biomarker using immunohistochemistry. Immunohistochemistry shows an effect in target tissue, but the degree of expression is not necessarily quantitative and may not be an ideal method to predict response to cytotoxic therapy. Future studies to validate predictive markers of response to ixabepilone may be more fruitful with microarray analyses.35,39 In conclusion, our study establishes that ixabepilone has efficacy in patients previously untreated with taxanes similar to response rates seen with docetaxel or paclitaxel in the first- or second-line metastatic setting.21,23-26,29 Most patients tolerated ixabepilone well, with low hematologic toxicity and minimal nausea, vomiting, and diarrhea. Unlike paclitaxel and docetaxel, ixabepilone does not require corticosteroid premedication. Neurotoxicity, a major concern for microtubule-stabilizing drugs, was relatively mild on this schedule. Continued evaluation of potential predictors of response to ixabepilone should be pursued. The favorable efficacy and tolerability seen in our trial and other trials discussed must be confirmed. We await data from two phase III trials examining capecitabine and ixabepilone compared with capecitabine alone in approximately 2,000 patients who have been treated previously with anthracyclines and taxanes. If these trials are positive, additional evaluation of ixabepilone in randomized phase III studies in the first-line metastatic and adjuvant settings would be warranted.
The author(s) indicated no potential conflicts of interest.
Conception and design: Neelima Denduluri, Jennifer A. Low, James J. Lee, Seth M. Steinberg, Sandra M. Swain Administrative support: Neelima Denduluri, Jennifer A. Low, Arlene W. Berman Provision of study materials or patients: Neelima Denduluri, Jennifer A. Low, James J. Lee, Arlene W. Berman, Janice M. Walshe, Catherine K. Chow, Sherry X. Yang, Sandra M. Swain Collection and assembly of data: Neelima Denduluri, Jennifer A. Low, James J. Lee, Arlene W. Berman, Janice M. Walshe, Ujala Vatas, Sherry X. Yang, Sandra M. Swain Data analysis and interpretation: Neelima Denduluri, Jennifer A. Low, James J. Lee, Ujala Vatas, Seth M. Steinberg, Sherry X. Yang, Sandra M. Swain Manuscript writing: Neelima Denduluri, Jennifer A. Low, James J. Lee, Seth M. Steinberg, Sherry X. Yang, Sandra M. Swain Final approval of manuscript: Neelima Denduluri, Jennifer A. Low, James J. Lee, Sandra M. Swain Other: Catherine K. Chow [radiologist who evaluates responses by Response Evaluation Criteria in Solid Tumors Group]
We thank Diana Nguyen, MD, for technical support and A. Tito Fojo, MD, PhD, for helpful discussion.
published online ahead of print at www.jco.org on July 2, 2007. Supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health. Presented in part at the 41st and 42nd Annual Meetings of the America Society of Clinical Oncology, May 13-17, 2005, Orlando, FL, and June 2-6, 2006, Atlanta, GA, respectively. 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
-tubulin, tau-1, and p53 expression when possible. 
