Multi-Institutional Randomized Phase II Trial of the Epothilone B Analog Ixabepilone (BMS-247550) With or Without Estramustine Phosphate in Patients With Progressive Castrate Metastatic Prostate Cancer

Galsky, Matthew D.; Small, Eric J.; Oh, William K.; Chen, Isan; Smith, David C.; Colevas, A. Dimitrios; Martone, Lou; Curley, Tracy; Delacruz, A.; Scher, Howard I.; Kelly, Wm. Kevin

doi:10.1200/jco.2005.09.042

Cited by 182 publications

(103 citation statements)

References 22 publications

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“…68 Of these, ixabepilone (BMS247550) is the furthest along in terms of clinical development and has shown promising efficacy and a manageable safety profile in a range of tumor types, including multiresistant BC. [69][70][71][72][73][74][75] EPO-906 also has shown promising activity in a Phase II trial of gastric cancer, 76 and patients currently are being recruited for a Phase III trial in ovarian cancer (see www.clinicaltrials.gov; NCT00262990). In addition, epothilone D (KOS-862) is undergoing Phase II clinical evaluation in BC and lung cancer.…”

Section: Identifying New Agents For Neoadjuvant Therapy In Breast Cancermentioning

confidence: 99%

Preoperative chemotherapy treatment of breast cancer—A review

Buzdar

2007

Cancer

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Despite proven benefits of neoadjuvant chemotherapy in patients with locally advanced, invasive breast cancer, no regimen is recommended as the treatment of choice. Neoadjuvant chemotherapy regimens encompass single-agent and combination therapy and sequential treatment. For this report, the author reviewed the literature to determine which regimen, if any, was most beneficial.The results indicated that studies have yielded a wide range of response rates, but no single regimen has emerged as a clear leader. The literature is compounded further by lack of standardized criteria to determine pathologic complete response (which is predictive of survival benefits) and between-study variation in the stringency by which this endpoint is defined. Given the lack of a preferred treatment regimen in the neoadjuvant setting, identifying patients who are likely to respond to specific agents could inform treatment decisions, improve treatment outcomes, and aid in avoiding unnecessary exposure to potential toxicities. The development of novel agents for use alone or in combination with existing agents may improve response rates further in the neoadjuvant setting, especially because a significant proportion of breast tumors can be resistant to many current antineoplastic agents. Particularly noteworthy are the epothilones and their analogs because of their low susceptibility to common tumor-resistance mechanisms. Initial data have indicated that ixabepilone, which is an epothilone analog, has activity in the neoadjuvant setting, and predictive factors for response have been identified. The future of neoadjuvant therapy lies in tailoring treatment to individual patients by identifying response predictors and developing novel agents. This ultimately may lead to improved outcomes for women with breast cancer.

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Section: Identifying New Agents For Neoadjuvant Therapy In Breast Cancermentioning

confidence: 99%

Preoperative chemotherapy treatment of breast cancer—A review

Buzdar

2007

Cancer

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“…The dose-limiting toxicity (DLT) was fatigue with the weekly schedule, whereas neutropenia and mucositis were dose limiting with the 3-weekly dosing schedule; peripheral neuropathy was also a significant toxicity. Ixabepilone was evaluated in a series of early-phase studies in patients with CRPC (summarized in Table 1) [9,[43][44][45][46][47][48][49][50], with promising antitumor activity as monotherapy and in combination with mitoxantrone and prednisone in men who have progressed on docetaxel. Furthermore, antitumor activity with ixabepilone has been observed in the first-line and docetaxel-resistant settings.…”

Section: Clinical Experience With Epothilones In Crpc Ixabepilonementioning

confidence: 99%

“…That study was subsequently expanded into a phase II randomized clinical trial comparing i.v. ixabepilone at a dose of 35 mg/m 2 on day 2 of a 21-day cycle alone (n ϭ 45) with ixabepilone at the same dose in combination with oral estramustine at a dose of 280 mg three times daily on days 1-5 (n ϭ 47) [44]. Patients also received warfarin (2 mg/day) to prevent thromboembolism.…”

Section: Chemotherapy-naïve Crpc Patientsmentioning

confidence: 99%

“…The most common hematologic toxicity in the phase II study [44] was neutropenia, which was grade Ն3 in 10 of 45 (22%) patients treated with ixabepilone alone and in 13 of 47 (29%) patients treated with ixabepilone plus estramustine. However, neutropenic fever was rare in both groups, occurring in two of 47 (4%) patients treated with ixabepilone alone and in four of 45 (9%) patients treated with ixabepilone plus estramustine.…”

Section: Chemotherapy-naïve Crpc Patientsmentioning

confidence: 99%

“…Similar responses were reported with Figure 1. Efficacy of ixabepilone alone or in combination with estramustine in patients with CRPC [44].…”

Section: Docetaxel-resistant Crpcmentioning

confidence: 99%

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The Epothilones: New Therapeutic Agents for Castration-Resistant Prostate Cancer

Dorff

Gross

2011

The Oncologist

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The management of castration-resistant prostate cancer (CRPC) presents a clinical challenge because of limitations in efficacy and durability with currently available therapeutics. The epothilones represent a novel class of anticancer therapy that stabilizes microtubules, causing cell death and tumor regression in preclinical models. The structure of the tubulin-binding site for epothilones is distinct from that of the taxanes. Moreover, preclinical studies suggest nonoverlapping mechanisms of resistance between epothilones and taxanes. In early-phase studies in patients with CRPC, treatment with ixabepilone, a semisynthetic analog of epothilone B, induced objective responses and prostatespecific antigen declines in men previously progressing on docetaxel-based regimens. Clinical activity has been observed in nonrandomized trials for patients with CRPC using ixabepilone in the first-and second-line settings as a single agent and in combination with estramustine. Patupilone and sagopilone were also shown to have promising efficacy in phase II clinical trials of patients with CRPC. All three epothilones appear to be well tolerated, with modest rates of neutropenia and peripheral neuropathy. The lack of crossresistance between epothilones and taxanes may allow sequencing of these agents. Evaluating epothilones in phase III comparative trials would provide much-needed insight into their potential place in the management of patients with CRPC. The Oncologist 2011;16:1349 -1358

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