Efficacy and Safety of Ixabepilone (BMS-247550) in a Phase II Study of Patients With Advanced Breast Cancer Resistant to an Anthracycline, a Taxane, and Capecitabine

Perez, Edith A.; Lerzo, Guillermo; Pivot, Xavier; Thomas, Edward L.; Vahdat, Linda T.; Bosserman, Linda D.; Viens, Patrice; Cai, Can; Mullaney, Brian P.; Peck, Ronald; Hortobágyi, Gabriel N.

doi:10.1200/jco.2006.09.3849

Cited by 365 publications

(270 citation statements)

References 19 publications

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“…A phase 2 trial in patients with MBC resistant to an anthracycline, a taxane, and capecitabine showed a response rate of 12% with stabilization of disease in an additional 50% of patients (54). Ixabepilone treatment led to durable responses in this highly chemo-resistant patient population, even in patients who had not responded to multiple previous therapies (54). Consistent with these results, a 12% response rate was reported in a phase 2 trial in patients with taxaneresistant MBC (55).…”

Section: Epothilone B Analog Ixabepilonesupporting

confidence: 71%

“…Clinical activity of ixabepilone has also been reported in other tumor types including prostate, renal, NSCLC, and pancreatic cancers (38). A phase 2 trial in patients with MBC resistant to an anthracycline, a taxane, and capecitabine showed a response rate of 12% with stabilization of disease in an additional 50% of patients (54). Ixabepilone treatment led to durable responses in this highly chemo-resistant patient population, even in patients who had not responded to multiple previous therapies (54).…”

Section: Epothilone B Analog Ixabepilonementioning

confidence: 99%

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Microtubule inhibitors: Differentiating tubulin-inhibiting agents based on mechanisms of action, clinical activity, and resistance

Perez

2009

Molecular Cancer Therapeutics

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Microtubules are important cellular targets for anticancer therapy because of their key role in mitosis. Microtubule inhibitors (MTI) such as taxanes, vinca alkaloids, and epothilones stabilize or destabilize microtubules, thereby suppressing microtubule dynamics required for proper mitotic function, effectively blocking cell cycle progression and resulting in apoptosis. In spite of their antitumor activity, innate or acquired drug resistance to MTIs such as the taxanes is common, limiting their overall clinical efficacy. Further insight into the mechanisms of action of microtubule-targeting drugs has lead to the discovery of novel agents that may provide higher efficacy with limited toxicity and help overcome resistance to conventional MTIs. This review will focus on the different mechanisms of action of MTIs, potential factors related to resistance and tolerability, and will discuss the recent approval as well as the development of new antineoplastic agents.

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Section: Epothilone B Analog Ixabepilonesupporting

confidence: 71%

Section: Epothilone B Analog Ixabepilonementioning

confidence: 99%

Microtubule inhibitors: Differentiating tubulin-inhibiting agents based on mechanisms of action, clinical activity, and resistance

Perez

2009

Molecular Cancer Therapeutics

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“…This may have selected a patient population less likely to experience neuropathy. Nevertheless, neuropathy was comparable to that seen in breast cancer studies [9][10][11][12][13] in which 12% to 20% of patients develop grade 3 neurotoxicity.…”

Section: Discussionsupporting

confidence: 76%

Ixabepilone, mitoxantrone, and prednisone for metastatic castration‐resistant prostate cancer after docetaxel‐based therapy

Harzstark

Rosenberg

Weinberg

et al. 2010

Cancer

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BACKGROUND: Mitoxantrone plus prednisone and ixabepilone each have modest activity as monotherapy for second-line chemotherapy in patients with docetaxel-refractory castration-resistant prostate cancer. Clinical noncrossresistance was previously observed. Phase 1 testing determined the maximum tolerated dose and dose-limiting toxicities with the combination regimen; a phase 2 study was conducted to evaluate the activity of the combination. METHODS: Patients with metastatic progressive castration-resistant prostate cancer during or after 3 or more cycles of taxane-based chemotherapy enrolled in a phase 2 multicenter study of ixabepilone 35 mg/m 2 and mitoxantrone 12 mg/m 2 administered on Day 1 every 21 days with pegfilgrastim support, along with prednisone 5 mg twice daily. Patients were evaluated for disease response and toxicity. RESULTS: Results are reported for the 56 evaluable patients. Twenty-five (45%; 95% confidence interval [CI], 31%-59%) experienced confirmed !50% prostate-specific antigen (PSA) declines, 33 (59%; 95% CI, 45%-72%) experienced confirmed !30% PSA declines, and 8 of 36 patients (22%; 95% CI, 10%-39%) with measurable disease experienced objective responses. Median time to PSA or objective progression was 4.4 months (95% CI, 3.5-5.6), and median progression-free survival was also 4.4 months (95% CI, 3.0-6.0). Median overall survival was 12.5 months (95% CI, 10.2-15.9). Thirty-two percent of patients experienced grade 3 of 4 neutropenia, and 11% experienced grade 3 or higher neutropenic infections, including 1 treatment-related death. Grade 2 and 3 neuropathy occurred in 11% and 12.5% of patients, respectively. CONCLUSIONS: These results suggest that the combination of ixabepilone and mitoxantrone is both feasible and active in castration-resistant prostate cancer and requires dosing with pegfilgrastim. Cancer 2011;117:2419-25.

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“…Accelerated approval is granted based on the surrogate end points that are less well established but reasonably likely to predict a longer or a better life. During the past decade, new agents that have been approved include the selective estrogen receptor downregulator fulvestrant for HR-positive disease [110,111] and cytotoxic agents such as nab-paclitaxel [112], gemcitabine combined with paclitaxel for the first-line therapy [113], capecitabine for anthracycline and taxane-resistant disease [114,115], and ixabepilone alone [116] or plus capecitabine for anthracycline and taxane-resistant disease (Table 3) [117]. Biologic agents that have been approved include trastuzumab combined with paclitaxel or used alone for HER2-positive disease [67,118], lapatinib, a tyrosine kinase inhibitor, combined with capecitabine for trastuzumab-refractory HER2-positive disease [73], and bevacizumab plus paclitaxel for the first-line therapy of Her2/neu negative disease [76].…”

Section: Regulatory Approval Of New Agentsmentioning

confidence: 99%

Recommendations for research priorities in breast cancer by the Coalition of Cancer Cooperative Groups Scientific Leadership Council: systemic therapy and therapeutic individualization

Sparano

Hortobágyi

Gralow

et al. 2009

Breast Cancer Res Treat

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Over 9,000 women with breast cancer are enrolled annually on clinical trials sponsored by the National Cancer Institute (NCI), accounting for about one-third of all patients enrolled on NCI-sponsored trials. Thousands are also enrolled on pharmaceutical-sponsored studies. Although breast cancer mortality rates have recently declined for the first time in part due to systemic therapeutic advances, coordinated efforts will be necessary to maintain this trend. The Coalition of Cancer Cooperative Groups convened the Scientific Leadership Council in breast cancer (BC), an expert panel, to identify priorities for future research and current trials with greatest practice-changing potential. Panelists formed a consensus on research priorities for chemoprevention, development and application of molecular markers for predicting therapeutic benefit and toxicity, intermediate markers predictive of therapeutic effect, pathogenesisbased therapeutic approaches, utilization of adaptive designs requiring fewer patients to achieve objectives, special and minority populations, and effects of BC and treatment on patients and families. Panelists identified 13 ongoing studies as High Priority and identified gaps in the current trial portfolio. We propose priorities for current and future clinical breast cancer research evaluating systemic therapies that may serve to improve the efficiency of clinical trials, identify individuals most likely to derive therapeutic benefit, and prioritize therapeutic strategies.

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Efficacy and Safety of Ixabepilone (BMS-247550) in a Phase II Study of Patients With Advanced Breast Cancer Resistant to an Anthracycline, a Taxane, and Capecitabine

Abstract: Ixabepilone demonstrated clear activity and a manageable safety profile in patients with MBC resistant to anthracycline, taxane, and capecitabine. Responses were durable and notable in patients who had not previously responded to multiple prior therapies.

Cited by 365 publications

References 19 publications

Microtubule inhibitors: Differentiating tubulin-inhibiting agents based on mechanisms of action, clinical activity, and resistance

Microtubule inhibitors: Differentiating tubulin-inhibiting agents based on mechanisms of action, clinical activity, and resistance

Ixabepilone, mitoxantrone, and prednisone for metastatic castration‐resistant prostate cancer after docetaxel‐based therapy

Recommendations for research priorities in breast cancer by the Coalition of Cancer Cooperative Groups Scientific Leadership Council: systemic therapy and therapeutic individualization

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