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Breast Cancer

Targeting the Microtubules in Breast Cancer Beyond Taxanes: The Epothilones

Department of Oncology, Vall d'Hebron University Hospital, Barcelona, Spain

Key Words. Epothilones • Review • Breast cancer

Correspondence: Javier Cortes, M.D., Department of Oncology, Vall d'Hebron University Hospital, Barcelona, Spain. Telephone: 0034-948-296696; Fax: 0034-948-255500; e-mail: jacortes{at}vhebron.net

Received September 28, 2006; accepted for publication January 10, 2007.

	LEARNING OBJECTIVES

Top Learning Objectives Abstract Introduction Epothilones: Mechanisms of... Epothilones: Clinical Activity... Conclusion Disclosure of Potential... References

 
After completing this course, the reader will be able to:

1. Describe the mechanism of action of epothilones and the different epothilone analogs in clinical development.
   
2. Discuss the current status and the results of phase II trials with epothilone analogs in metastatic breast cancer.
   
3. Explain why epothilone may have utility in combination with other cytotoxic chemotherapeutic agents for treating metastatic breast cancer.
   

	ABSTRACT

Top Learning Objectives Abstract Introduction Epothilones: Mechanisms of... Epothilones: Clinical Activity... Conclusion Disclosure of Potential... References

 
Microtubule-targeting agents such as the taxanes are highly active against breast cancer and have become a cornerstone in the treatment of patients with early and advanced breast cancer. The natural epothilones and their analogs are a novel class of microtubule-stabilizing agents that bind tubulin and result in apoptotic cell death. Among this family of compounds, patupilone, ixabepilone, BMS-310705, ZK-EPO, and KOS-862 are in clinical development. Extensive preclinical studies have shown that epothilones are working through partially nonoverlapping mechanisms of action with taxanes. In the clinic, epothilones have been found in a series of phase I and phase II studies to be active even in patients who had recently progressed to taxanes. The toxicity profile of these agents consists mostly of sensory neuropathy, sometimes reversible. Neoadjuvant studies with epothilones have been conducted and a number of phase III studies in advanced breast cancer are either under way or have been recently completed. The results of these studies are eagerly awaited and it is anticipated that epothilones may become an important treatment option in patients with breast cancer.

Disclosure of potential conflicts of interest is found at the end of this article.

	INTRODUCTION

Top Learning Objectives Abstract Introduction Epothilones: Mechanisms of... Epothilones: Clinical Activity... Conclusion Disclosure of Potential... References

 
Breast cancer represents the most common cancer and the second cause of cancer death in women in the Western world [1]. However, over the last few years, breast cancer mortality has been steadily decreasing due to a variety of reasons, including the availability of newer cytotoxic agents. Among the most active newer agents, the taxanes, which target the microtubules, have emerged as a new cornerstone in the treatment of advanced breast cancer and, increasingly, of early disease as well.

The validation of the microtubules as a cancer target has led to the development of newer agents that target the microtubules. Microtubules play a fundamental role in diverse cellular functions such as cell division, growth, and motility, the development and maintenance of cell shape, and the trafficking of vesicles, organelles, and proteins. Microtubules are filaments formed with the polymerization of heterodimeric /ß tubulin subunits. A very complex dynamic process of polymerization and depolymerization is critical for microtubule homeostasis, which finally leads to the formation and functioning of the mitotic spindle. The taxanes and vinca alkaloids are two families of chemotherapeutic agents that interact with the tubulin units, resulting in alterations in the polymerization and depolymerization process. If this function is disrupted, a cell cycle arrest at the G₂/M phase occurs, which in turn results in apoptosis.

Among the taxane family, paclitaxel and docetaxel are the two most widely used agents and have shown important clinical benefits in the adjuvant and in the metastatic setting, with objective response rates of 32%–68% when used as single agents [2]. However, this clinical success has been accompanied by significant side effects and primary as well as acquired (secondary) resistance. The mechanisms of resistance to taxanes are not fully understood and, as with many other agents, are likely to be multifactorial, including the overexpression of P-glycoprotein, the presence of beta-tubulin mutations, and high microtubule-associated protein tau expression.

The results obtained with taxanes in breast cancer, and against other tumor types [3], have validated the role of microtubules as a promising therapeutic target in cancer. Therefore, new microtubule-stabilizing compounds are being intensively studied as new anticancer agents. Among them, the epothilones (isolated from the myxobacterium Sorangium cellulosum) are the furthest along in clinical development. Other microtubule-targeting agents include the discodermolides (isolated from the Caribbean sponge Discodermia dissoluta) and their close analogs dictyostatin, indanocine, sarcodictyns, eleutherobins (isolated from the soft coral Eleutherobia sp.), dolastatins, cryptophycins, halicondrin B, laulimalides (isolated from the marine sponge Cacospongia mycofijiensis), and peluroside A.

While an excellent summary of the mechanisms of action and the biologic activity of epothilones has been recently published [4], we review here the preclinical and early clinical studies with epothilones in patients with breast cancer.

	EPOTHILONES: MECHANISMS OF ACTION, EPOTHILONE ANALOGS, AND PRECLINICAL STUDIES

Top Learning Objectives Abstract Introduction Epothilones: Mechanisms of... Epothilones: Clinical Activity... Conclusion Disclosure of Potential... References

 
The epothilones, discovered in 1993 by Hofle and coworkers, are a novel class of nontaxane microtubule-stabilizing agents obtained from the fermentation of the cellulose degrading myxobacterium S. cellulosum. Although they were first described as natural product fungicidal macrolides, their interest as anticancer agents arose when they were identified in an in vitro screen for agents that induced microtubule polymerization at submicromolar concentrations [5]. In a similar fashion as taxanes, epothilones induce microtubule bundling, formation of multipolar spindles, and mitotic arrest [5]. Epothilones and paclitaxel compete for the same binding pocket on ß-tubulin, together with other microtubule stabilizers such as the endogenous neuronal tau protein [6]. This has led to the proposal that epothilones and taxanes possess a common pharmacophore for microtubule binding [5]. However, there is growing evidence supporting that their binding to tubulin is not identical. Studies combining nuclear magnetic resonance spectroscopy, electron crystallography, and molecular modeling have derived a structural model of the binding mode and conformation of epothilone A (see below) in complex with the ß-tubulin subunit in zinc-stabilized tubulin sheets [7]. That structure demonstrated that, whereas epothilone A and paclitaxel overlap in their occupation of a rather expansive common binding site on tubulin, the expectation of a common pharmacophore was unmet, because each ligand exploits the binding pocket in a unique and qualitatively independent manner. This could explain the unexpected differences in promoting the assembly and stabilization of yeast microtubules by epothilones and paclitaxel [8]. However, whether or not this is the reason why some point mutations in the ß-tubulin subunit do not necessarily confer resistance to the epothilones is unclear at the present time.

Five epothilones are currently in clinical trials: patupilone (epothilone B, EPO906), ixabepilone (aza-epothilone B, BMS-247550), BMS-310705 (a water-soluble semisynthetic analog of epothilone B), KOS-862 (epothilone D), and ZK-EPO. The natural products epothilones A and B show high in vitro antitumor activity, including in taxane-resistant cell lines [5]. Nevertheless, they show only modest in vivo activity, a fact that has been attributed to their metabolic instability, unfavorable pharmacokinetics (PK), and narrow therapeutic window [9]. Analogs to improve the in vivo activity of this chemical class have been pursued, and over 350 semisynthetic analogs have been made and tested. The natural epothilone B is similar to epothilone A with the addition of a methyl group at position C12, which yields a molecule that is much more potent than epothilone A or paclitaxel in inducing tubulin polymerization in vitro [10, 11]. These findings suggest that modifications of epothilones at or near the C12–C13 epoxide can affect microtubule activity [12]. However, epothilone D, which lacks the C12–C13 epoxide, is more potent than the other two epothilones, suggesting that the presence of an epoxide at C12–C13 is not required for microtubule binding. Replacement of the lactone oxygen of epothilone B with a lactam results in aza-epothilone B, also known as BMS-247550. Structures of these epothilones are detailed in Figure 1.

View larger version (27K): [in this window] [in a new window]   Figure 1. Structures of the epothilones that are furthest along in clinical development.

Ixabepilone has a broad spectrum of activity against a panel of tumor cell lines in vitro. Of 21 cell lines tested, 18 had IC₅₀ values between 1.4 and 6 nM [13]. In addition, it has activity in cell lines that are taxane resistant, as exemplified with cell line Pat-7, obtained from a patient with advanced ovarian cancer who was initially responsive to paclitaxel treatment but ultimately developed resistance. Ixabepilone has induced cures in a Pat-ovarian xenograft model [13]. Importantly, ixabepilone may be given orally and retains its high activity when administered orally. This suggests that, in addition to being orally bioavailable, its absorption is not prevented despite the high level of expression of P-glycoprotein in the intestine [14].

Also, epothilone B has shown significant activity in human tumor xenograft models, as demonstrated in the paclitaxel-resistant KB-8511 or in the MX-1 breast cancer xenograft models [9, 15]. Tanabe et al. [16] examined the interactions of patupilone with seven multidrug transporters in vitro: MDR1-type P-glycoprotein (ABCB1), the breast cancer resistance protein BCRP (ABCG2), and the multidrug resistance–associated proteins 1 through 5 (ABCC1–5), and it was not found to be a significant substrate of any of the transporters, or to alter their activity for test substrates. ZK-EPO is a derivative of epothilone B. It has been demonstrated that ZK-EPO is active against bone metastasis in a breast cancer metastasis model in nude mice [17].

Similarly, KOS-862 is very active against some multidrug-resistant xenografts, such as a doxorubicin-resistant MCF-7 breast cancer xenograft and a vinblastine-resistant CCRF-CEM leukemia cell xenograft [9, 18]. KOS-1584 is a novel and potent analog of KOS-862 that has recently entered phase I trials after showing antitumor activity in an MV522 xenograft model in mice and an HCT-116 xenograft model in rats with excellent PK properties [19].

	EPOTHILONES: CLINICAL ACTIVITY IN BREAST CANCER

Top Learning Objectives Abstract Introduction Epothilones: Mechanisms of... Epothilones: Clinical Activity... Conclusion Disclosure of Potential... References

 
Five epothilone analogs are currently in clinical development: patupilone, ixabepilone, BMS-310705, KOS-862, and ZK-EPO.

Phase I and II trials of single-agent epothilones are summarized in Tables 1 and 2.

Patupilone has been combined with other agents in phase I trials. The combination of Patupilone and carboplatin has been studied with two different schedules [22, 23]. In the first, patupilone was given weekly for 3 of 4 weeks (with weekly carboplatin), and the second one explored the administration of patupilone and carboplatin given once every 3 weeks. Diarrhea was the DLT with both schedules. Patupilone has also been studied in combination with capecitabine (1,250 mg/m² orally twice daily for 2 of every 3 weeks). Twenty-four patients with advanced cancers were treated and 10 achieved stable disease (SD). DLTs included diarrhea, nausea, anorexia, and small bowel obstruction [24]. As expected, diarrhea was one of the most common adverse events. It should be taken into account that the most important toxicity observed if capecitabine is combined with docetaxel is neutropenia and neutropenic fever [25]. In a combination study with gemcitabine [26], patupilone was administered followed by gemcitabine, 800 mg/m², for 3 weeks followed by a 1-week rest. In total, 24 patients were enrolled in five cohorts. DLTs were observed in the 2.5-mg/m² cohort and included diarrhea, nausea, and dizziness, so the MTD was established at 2.0 mg/m². One patient with laryngeal cancer achieved a PR and SD was observed in seven patients. Patupilone has been also combined with weekly oral estramustine, 280 mg on days 1–3 [27]. Diarrhea, asthenia, and vomiting were DLTs. Fourteen patients, predominantly with prostate and breast cancer, were enrolled in this study, and one PR and eight cases of SD were reported (three patients for 4 months and five patients for 2 months).

Several phase II studies are being developed in patients with breast, lung, ovarian, colorectal, and renal cell carcinomas. One unpublished study has been conducted in patients with breast cancer after failing prior therapy containing a taxane and/or anthracycline. Patupilone was administered at a dose of 2.5 mg/m² weekly for 3 weeks followed by a 1-week rest.

Ixabepilone
Ixabepilone has been extensively studied. A variety of i.v. infusion schedules were evaluated in the phase I setting, including a single dose every 3 weeks, a daily dose for 3 days every 3 weeks, a weekly schedule, and a daily dose for five consecutive days every 21 days. Several studies have assessed the once every 21 days schedule [28–30]. In total, sixty-three patients were treated with ixabepilone with the every 21 days schedule at several dose levels in the range of 7.4–65 mg/m². Oral H₁/H₂ blockers were administered in all three studies after observing a hypersensitivity reaction [28] in one patient on the 30-mg/m² dose. Responses were observed in patients with melanoma, non-small cell lung cancer (post-docetaxel), ovarian cancer (post-paclitaxel), and breast cancers (taxane naïve and refractory). The recommended dose for phase II trial development of ixabepilone was established at 40 mg/m² in one trial [30] and at 50 mg/m² in another [28]. DLTs included prolonged grade 4 neutropenia, peripheral neuropathy, gastrointestinal discomfort, fatigue, and emesis. One patient died with grade 4 neutropenia and pneumococcal sepsis. This schedule has also been explored in Japanese patients [31]. Thirteen patients were treated with a 3-hour infusion of 15–50 mg/m² every 3 weeks. Grade 4 neutropenia was the DLT. The recommended dose for phase II trials was 40 mg/m². Although 67% of patients had SD, no objective responses were observed.

Phase I studies have also been designed to establish the MTD for ixabepilone administered as a 1-hour infusion on five consecutive days every 3 weeks. The initial dose was 1.5 mg /m² per day (total dose, 7.5 mg/m²). At 8.0 mg/m², three of three patients experienced grade 4 neutropenia. Peripheral neuropathy was mild, even after multiple cycles of therapy, and it was not dose limiting. The recommended dose for phase II trials on this schedule is 6 mg/m² per day. Responses were observed in breast, cervical, and basal cell cancer [32]. This schedule was also evaluated in children with refractory solid tumors [33]. DLTs, consisting of neutropenia and fatigue, were observed at a dose of 10 mg/m². Twenty-six patients were enrolled in a phase I trial in which ixabepilone was administered as a 1-hour infusion on three consecutive days every 3 weeks [34]. Dose levels were 6, 8, 10, 12, 14, 16, and 18 mg/m² per day for 3 days. The DLT was, once again, grade 4 neutropenia and, interestingly, there was no grade 3 or 4 peripheral neuropathy. The recommended dose of ixabepilone administered daily for three consecutive days every 21 days is 8 mg/m² per day with escalation to 10 mg/m² per day on subsequent cycles if tolerated.

Ixabepilone was also evaluated on a weekly schedule [35–37]. Grade 4 neutropenia and grade 3 fatigue at the 30-mg/m² dose and cumulative sensory neuropathy at the 25-mg/m² dose were the DLTs. Two cases of grade 3–4 hypersensitivity reactions were observed, and premedication with diphenhydramine and ranitidine was mandatory with doses above 10 mg/m²; no further cases of hypersensitivity reactions have been observed. Antitumor activity was reported in patients with colon, ovarian, and head and neck carcinomas. In one study [37], the schedule was amended to explore a 1-hour infusion given weekly for 3 weeks followed by a 1-week break, in order to reduce the neuropathy. Toxicity was similar to that with the 30-minute infusion schedule, except that more patients were able to continue on therapy for >4 months.

Phase I trials to demonstrate the feasibility of combining ixabepilone with other cytotoxic agents have also been performed. In one study, ixabepilone (30 mg/m² and 40 mg/m²), administered i.v. in 1 hour every 3 weeks, was combined with carboplatin (to an area under the concentration–time curve [AUC] of 5 and 6), given i.v. in 30 minutes [38]. Two confirmed PRs were documented in patients with breast and neuroendocrine carcinomas. The hematological toxicity was unexpectedly high using this combination so the schedule was amended to ixabepilone 40 mg/m² plus carboplatin AUC 5. Ixabepilone at 40 mg/m² plus capecitabine 2,000 mg/m² per day for 14 days with a 1-week rest every 21 days was the recommended dose for further studies established in a phase I trial [39]. In that study, patients with metastatic breast cancer previously treated with a taxane and an anthracycline were offered treatment with ixabepilone in combination with capecitabine. No unexpected toxicities have been reported and discontinuations as a result of study therapy have been uncommon. Grade 3–4 toxicities included neutropenia, fatigue, hand–foot syndrome, diarrhea, myalgia, stomatitis, and sensory neuropathy. Interestingly, although in the O'Shaughnessy et al. study [25], fewer patients presented grade 3 and 4 neutropenia, the percentage of patients who presented grade 3 and 4 febrile neutropenia was 16%, much higher than in the ixabepilone and capecitabine phase I study (2%). Eleven of 40 patients showed PRs. Ixabepilone has also been evaluated in combination with gemcitabine [40]. Ixabepilone was administered over 3 hours on day 8 and gemcitabine was infused over 30 minutes on days 1 and 8 of a 21-day cycle. At the second dose level (ixabepilone/gemcitabine 30/900), two of three patients experienced grade 4 neutropenia; one of them also had grade 3 alanine aminotransferase elevation after cycle 1. For this reason, ixabepilone at a dose of 20 mg/m² and gemcitabine at a dose of 900 mg/m² were considered the recommended doses.

Several phase II trials of ixabepilone have also been conducted. In this review, we focus on those trials conducted in patients with breast cancer. In the first trial, ixabepilone was administered at 6 mg/m² per day i.v. on days 1–5 every 3 weeks to 37 patients with advanced breast cancer with measurable disease who had received at least one prior regimen that contained paclitaxel or docetaxel [41]. One patient achieved a complete response (3%) and 7 patients had PRs (19%), for an overall response rate of 21%. Interestingly, one patient with inflammatory breast cancer who had SD with neoadjuvant docetaxel and doxorubicin was switched to, and responded to, ixabepilone as neoadjuvant therapy. Grade 3 and 4 toxicities included neutropenia (35%), febrile neutropenia (14%), fatigue (14%), diarrhea (11%), nausea/vomiting (5%), myalgia/arthralgia (3%), and sensory neuropathy (3%). A second study [42] was conducted to determine the efficacy and safety of ixabepilone in patients with taxane-refractory or taxane-naïve metastatic breast cancer. Nine patients were treated because of an increased rate of myelosuppression and mucositis in this and other studies. All patients were premedicated with oral H₁ and H₂ blockers to prevent hypersensitivity reactions.

In total, 49 patients that received the 40 mg/m² dose level were evaluable for response. All patients had received prior chemotherapy, with the majority of patients (86%) receiving at least two prior chemotherapy regimens. All patients had received at least one prior taxane-containing regimen, with 31% receiving two or more. Ninety-eight percent of patients had had their most recent taxane-containing regimen in the metastatic setting and 73% of patients had progressed within 1 month of their last dose. The objective tumor response rate (ORR) was 12% (95% confidence interval [CI], 4.7%–26.5%), with all of the responders achieving PRs. The six patients achieving PRs had a median duration of response of 10.4 months. Each of the responders had extensive tumor metastases at baseline and had failed multiple prior therapies. Five of these patients entered the study after progressing within 1 month of their last dose on their most recent taxane-containing regimen, while only one had responded to the most recent taxane therapy. In the eight patients treated with ixabepilone at a dose of 50 mg/m² over 1 hour, two (25%) achieved PRs. In the nine patients receiving ixabepilone at a dose of 50 mg/m² over 3 hours, no patient achieved a PR, and four patients (44%) had SD. The median time to progression for all patients in this cohort was 1.4 months (95% CI, 1.2–3.8 months). Among patients on the 40 mg/m² over 3 hours regimen, the most frequent treatment-related grade 3 adverse events were fatigue (27%), sensory neuropathy (12%), myalgia (10%), nausea (6%), and vomiting (6%). Treatment-related neuropathy was mostly sensory, mild to moderate in severity (grade 1 or 2), cumulative, and reversible. Sensory neuropathy was managed mainly with dose reductions (12 of 49 patients had their dose reduced because of neuropathy). Treatment-limiting or severe neuropathy generally resolved or lessened in intensity within 1–2 months after therapy discontinuation. In terms of hematological toxicities, only six patients (12%) required growth factor support for neutropenia during their treatment. Treatment-related febrile neutropenia was reported in three patients (6%) (two patients reported febrile neutropenia; one patient reported infection with neutropenia) [42]. Taken together, the results of this study indicate the potential for lack of cross-resistance between ixabepilone and the taxanes. In the current study, the taxane had to have been the most recent therapy given with proven progression while on therapy or within 4 months of the last dose. Thus, the patient population consisted of those with tumors highly resistant to a microtubule-stabilizing agent. In this setting, we feel that the response rate observed in this trial, albeit small, represents a formal demonstration of the lack of cross-resistance between ixabepilone and taxanes.

Ixabepilone has also been evaluated in the neoadjuvant setting [43]. That study was designed to determine the pathological response obtained with ixabepilone as neoadjuvant therapy for breast cancer and to obtain tumor samples for analysis of gene expression and identification of potential predictors of response to ixabepilone. One hundred sixty-four women with invasive stage IIA–IIIB breast cancer with tumors 3 cm diameter received 40 mg/m² ixabepilone as a 3-hour infusion on day 1 for up to four 21-day cycles, followed by surgery within 3–4 weeks of completion of chemotherapy. Biopsies for the analysis of mRNA expression were obtained both pre- and post-therapy. Adjuvant chemotherapy with an anthracycline combination regimen followed by radiotherapy and hormonal therapy were administered as indicated. Pathological response was assessed using the Sataloff criteria. Pathological complete response in the breast was obtained in 19% of patients. Grade 3 and 4 neutropenia occurred in 14% and 5% of patients, respectively, and grade 3 toxicities for arthralgia/myalgia, neuropathy, and mucositis were 2%, 1%, and 3%, respectively. Based on the genomic study, patients with hormone receptor–negative disease were more likely to respond to ixabepilone [44].

Two studies of ixabepilone and trastuzumab in patients with HER-2–positive metastatic breast cancer have been recently completed [45, 46].

There are two randomized phase III studies examining capecitabine with or without ixabepilone. In the first completed trial (NCT00082433) [47], patients with metastatic breast cancer previously treated with an anthracycline and a taxane were randomized to receive either capecitabine with ixabepilone or capecitabine alone. Patients had to have received no more than two prior chemotherapy regimens, and patients who had not received treatment for metastatic disease had to have relapsed within 1 year from the completion of adjuvant chemotherapy. The expected total enrollment is 1,200 patients, and the primary objective is overall survival. In a second, recently completed, randomized trial (NCT00080301) [48], patients with metastatic breast cancer were also randomized to capecitabine with or without ixabepilone. In that study, patients also had been previously treated with an anthracycline and a taxane, but in contrast to the prior study, all patients had to be taxane resistant. The primary aim of the study was time to disease progression.

BMS-310705
BMS-310705 is a water-soluble, semisynthetic analog of epothilone B that does not require formulation in Cremophor®-EL. It has been evaluated in phase I trials with two different schedules. In one study [49], BMS-310705 was administered once every 3 weeks as a 15-minute infusion at doses of 0.6–70 mg/m². No premedications were used and no hypersensitivity reactions (HSRs) were reported. Two patients developed DLTs, consisting of grade 4 neutropenia and grade 4 hyponatremia. There were no DLTs at the 40-mg/m² dose level. However, sensory neuropathy at higher doses was the toxicity that led to a recommendation of 40 mg/m² as the recommended dose for phase II trials. PRs were reported in one patient with ovarian cancer and one patient with bladder cancer. Interestingly, one patient with non-small cell lung cancer achieved a complete response.

Another phase I trial has been conducted to define the MTD and the recommended phase II dose of BMS-310705 given weekly for three consecutive weeks every 28 days [50]. The starting dose was 5 mg /m² per day. At the 30-mg/m² dose level, the two treated patients had grade 3 diarrhea. At 20 mg/m², one patient had an HSR recurring under steroid prophylaxis, and two of three patients had severe sensory neuropathy requiring dose reduction. Responses were observed in patients with stomach and breast cancers. The investigators suggested further exploration of the 15-mg/m² per day dose and additional expansion to a modified 2-weekly every 21 days regimen.

KOS-862
The epothilone D analog KOS-862, which has demonstrated at least equivalent potency to and less toxicity than the taxanes and epothilone B in preclinical studies, is also in early clinical development. Three phase I single-agent studies investigated the safety, efficacy, PK, and pharmacodynamics of KOS-862. In the first study [51], KOS-862 was administered to patients with advanced solid tumors, according to the two following schedules: as a single dose every 3 weeks (dose levels, 9–185 mg/m²) or as doses over three consecutive days (dose levels, 20, 40, and 50 mg /m² per day). Comparison of the two schedules showed no difference in PK, including systemic exposure. However, the 150-mg /m² single dose (185 mg/m² was not tolerable) produced more neurological toxicity than 40 mg/m² per day (three patients versus one patient with grade 3 cognitive abnormalities and 7 patients versus 3 patients with grade 1–2 impaired gait, respectively). These toxicities were not observed at 120 mg/m². Neurologic toxicities occurred 1–2 days postinfusion, reversed within the week, and were not cumulative. Antitumor activity was observed in patients with breast, testicular, ovarian, and pancreatic cancer. Weekly infusions of KOS-862 were also evaluated in a study in which KOS-862 was administered as an i.v. infusion for 3 of every 4 weeks, and the DLTs were once again primarily neurological [52]. With regard to a continuous i.v. schedule, 24 patients were enrolled into a phase I trial involving a loading dose (75 mg/hour for 30 minutes) followed by a maintenance dose every 2 weeks [53].

Three phase Ib studies investigated the combination of KOS-862 with chemotherapy or targeted therapies. In the first study [54], KOS-862 was combined with gemcitabine in patients with advanced solid tumors. Both drugs were administered weekly for 3 of every 4 weeks. Patients received KOS-862 (50, 60, and 75 mg/m²⁾ and gemcitabine (750 mg/m²) in three cohorts. DLTs observed at KOS-862 (75 mg/m²) and gemcitabine (750 mg/m²) included severe dehydration, diarrhea, and neutropenia. Although there were no DLTs at 60 mg/m², the day 15 dose could not be delivered in one third of patients because of thrombocytopenia, so the study was therefore amended to a 3-week cycle (2 weeks on/1 week off). No PK interaction was found when both drugs were given in combination. In the second trial, the combination of KOS-862 and carboplatin is being evaluated. Patients will receive KOS-862 (50, 75, and 100 mg/m²) and carboplatin (AUC 5 and 6) in four cohorts. Preliminary data [55] revealed that neutropenia was observed more frequently than with single-agent KOS-862 and that PK parameters were not different from those seen with single-agent therapy of each agent. A phase I/II study is evaluating the combination of KOS-862 with trastuzumab in patients with HER-2–overexpressing tumors. The phase I trial is already completed [56]. Trastuzumab was given as a 4-mg/kg loading dose, then 2 mg/kg weekly, and KOS-862 was given as a 90-minute i.v. infusion weekly for 3 weeks every 4 weeks after trastuzumab. KOS-862 dose escalation cohorts were 70, 85, and 100 mg/m². Thirteen patients with metastatic breast cancer were treated. Although no DLTs were observed, cumulative neurotoxicity was important: grade 2 and 3 paresthesias in ten and one patients, respectively, and grade 2 and 3 neuropathic pain in five and two patients, respectively. Other grade 1 and 2 neurological toxicities included dizziness (four patients), dysgeusia (four patients), ataxia (three patients), transient confusion (three patients), dysesthesias (two patients), and insomnia (two patients). Non-neurological toxicities were limited to grade 1 of 2 and included diarrhea, pyrexia, abdominal and back pain, and arthralgias. Three clinical responses were observed. A phase II trial of this combination is ongoing in minimally pretreated metastatic breast cancer patients.

KOS-862 is already being evaluated in phase II trials, not only in patients with breast cancer, but also in patients with colorectal and non-small cell lung cancer. In one study, patients with anthracycline- and taxane-pretreated breast cancer are receiving KOS-862 at 100 mg/m² over 90 minutes 3 times every 4 weeks. Accrual is anticipated to be 53 evaluable patients. Four of the first 29 evaluable women have had confirmed PRs. Overall, 21 patients had peripheral sensory neuropathy and 18.5% of patients reported any grade 3 neurotoxicity [57].

ZK-EPO
ZK-EPO is a fully synthetic epothilone that was reportedly designed to overcome multidrug resistance [58]. In a phase I study, this epothilone analog was given as a 30-minute i.v. infusion once every 3 weeks; the starting dose was 0.6 mg/m². Dose-limiting grade 3 peripheral neuropathy and grade 3 ataxia occurred at the 16-mg/m² dose (one patient) and the 29-mg/m² dose (one patient), respectively. Confirmed PRs were observed in patients with taxane-pretreated breast cancer and prolonged SD was seen in patients with non-small cell lung cancer, cholangiocarcinoma, head and neck cancer uveal, melanoma, and adrenal carcinoma.

ZK-EPO is being evaluated in patients with metastatic breast cancer as a single agent and in combination with carboplatin in patients with platinum-sensitive, recurrent ovarian cancer. The combination of ZK-EPO and prednisone as first-line chemotherapy in patients with metastatic androgen-independent prostate cancer will be evaluated in a phase II trial.

	CONCLUSION

Top Learning Objectives Abstract Introduction Epothilones: Mechanisms of... Epothilones: Clinical Activity... Conclusion Disclosure of Potential... References

 
The natural epothilones and their analogs are a novel class of microtubule-stabilizing agents, derived from the myxobacterium S. cellulosum, that bind tubulin and result in apoptotic cell death. These agents are now in clinical development in a variety of tumor types. Data from completed phase I and phase II studies have demonstrated activity in a variety of tumor types. In breast cancer, responses have been observed both in the neoadjuvant and the metastatic settings. Moreover, an impressive response rate has been achieved even in anthracycline- and taxane-refractory patients. These agents do have significant toxicities, such as neuropathy, and the identification of the right dose and schedule has been complex. It is therefore anticipated that their clinical use will require expertise.

The key question is: what will be the role of epothilones in breast cancer and other tumor types? In breast cancer, results from recently completed phase III studies are eagerly awaited. In addition, clinical studies in a less pretreated population will also be conducted. Future research efforts will have to be directed at identifying the defining genomic signatures of those tumors sensitive to epothilone analogs, differentiating these agents from each other, integrating these agents with conventional therapies, and designing better combinations of treatment.

	DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST

Top Learning Objectives Abstract Introduction Epothilones: Mechanisms of... Epothilones: Clinical Activity... Conclusion Disclosure of Potential... References

 
The authors indicate no potential conflicts of interest.

	REFERENCES

Top Learning Objectives Abstract Introduction Epothilones: Mechanisms of... Epothilones: Clinical Activity... Conclusion Disclosure of Potential... References

 

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