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First Published Online December 16, 2008
The Oncologist, Vol. 13, No. 12, 1207-1223, December 2008; doi:10.1634/theoncologist.2008-0143
© 2008 AlphaMed Press

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Breast Cancer

Clinical Development of Ixabepilone and Other Epothilones in Patients with Advanced Solid Tumors

Edgardo Riveraa, Joyce Leeb, Angela Daviesb

aThe Methodist Hospital/Weill Cornell University, Houston, Texas, USA; bUniversity of California Davis Cancer Center, Sacramento, California, USA

Key Words. Epothilones • Ixabepilone • Multidrug resistance • Breast cancer • Prostate cancer

Correspondence: Edgardo Rivera, M.D., The Methodist Hospital/Weill Cornell University, 6550 Fannin Street, SM701, Houston, Texas 77030, USA. Telephone: 713-441-6710; Fax: 713-790-3038; e-mail: erivera1{at}tmhs.org

Received July 3, 2008; accepted for publication November 7, 2008; first published online in THE ONCOLOGIST Express on December 16, 2008.

Disclosure: Employment/leadership position: None; Intellectual property rights/inventor/patent holder: None; Consultant/advisory role: None; Honoraria: Edgardo Rivera, Bristol-Myers Squibb, Abraxis Oncology; Research funding/contracted research: Edgardo Rivera, Tragara Pharmaceuticals, Bristol-Myers Squibb; Ownership interest: None; Expert testimony: None; Other: None.

The article discusses unlabeled, investigational, or alternative use(s) of a product, device or technique: ixabepilone (Bristol-Myers Squibb), all tumors other than breast cancer; patupilone (Bristol-Myers Squibb/Novartis), solid tumors; sagopilone #4, KOS-1584 (Bayer) solid tumors.

The content of this article has been reviewed by independent peer reviewers to ensure that it is balanced, objective, and free from commercial bias. No financial relationships relevant to the content of this article have been disclosed by the authors, planners, independent peer reviewers, or staff managers.


   ABSTRACT
Top
 Abstract
Current Challenges in...
 Epothilones
 Ixabepilone
 Clinical Evaluation of Other...
 Conclusions
 Author Contributions
 References
 
Chemotherapy efficacy in patients with solid tumors is influenced by primary and acquired multidrug resistance (MDR). Epothilones represent a novel class of microtubule inhibitors with lower susceptibility to drug resistance and efficacy in taxane-resistant tumors. While other epothilones are currently under investigation, ixabepilone is the first epothilone B analogue approved by the U.S. Food and Drug Administration. Ixabepilone has been shown to have preclinical activity in chemotherapy-sensitive and chemotherapy-resistant tumor models, and synergistic antitumor activity with other chemotherapeutic and targeted agents. Single-agent ixabepilone has demonstrated clinical activity in multiple solid tumors including advanced breast, lung, prostate, pancreatic, renal cell, and ovarian cancers. Most notably, efficacy has been demonstrated in patients with metastatic breast cancer (MBC) progressing after treatment with anthracyclines and taxanes. A phase III trial in anthracycline- and taxane-resistant MBC showed superior disease control with ixabepilone plus capecitabine versus capecitabine monotherapy, resulting in its approval. Ixabepilone is also active in chemotherapy-naïve and taxane-resistant hormone-refractory prostate cancer and platinum-resistant non-small cell lung cancer. Neutropenia and peripheral sensory neuropathy are the most common adverse events associated with treatment. This review discusses the challenges of MDR and the data that support the use of epothilones in this setting, focusing on ixabepilone.


   CURRENT CHALLENGES IN CHEMOTHERAPY—DRUG RESISTANCE
Top
 Abstract
 Current Challenges in...
Epothilones
 Ixabepilone
 Clinical Evaluation of Other...
 Conclusions
 Author Contributions
 References
 
Multidrug resistance (MDR) significantly hinders the effectiveness of cancer chemotherapy [1, 2] and is believed to contribute to treatment failure in >90% of patients with metastatic cancer [3]. Drug resistance may present in tumors prior to treatment (de novo or primary resistance) or after exposure to chemotherapeutic agents (acquired resistance). Multiple mechanisms have been proposed to affect drug sensitivity. MDR has been linked to overexpression of P-glycoprotein (P-gp) [3]. Alterations in drug efflux via ATP-binding cassette transporter proteins such as P-gp and multidrug resistance protein (MRP) can modulate intracellular drug concentration. These proteins target natural hydrophobic drugs such as paclitaxel, anthracyclines, and vinca alkaloids for transport out of cells, thereby limiting drug cytotoxicity [3]. Unfortunately, inhibitors of P-gp, including cyclosporin A, valspodar, and verapamil, have shown very limited activity in phase III trials [4–6]. Modifications of the intracellular target of taxanes and vinca alkaloids, the microtubules, such as tubulin mutations, altered expression of tubulin isotypes [7, 8], and modifications in microtubule regulatory proteins [9], have been implicated in drug resistance to microtubule inhibitors [10]. These agents have distinct binding sites on the tubulin dimer and the drug-binding event results in stabilization or destabilization of microtubules. Point mutations in M40 β-tubulin have been identified in paclitaxel-resistant cell lines [11], and overexpression of the βIII-tubulin isotype has been associated with taxane resistance in vitro and in clinical studies [12]. A number of microtubule-associated proteins (MAPs), such as MAP-4 and stathmin, regulate microtubule function and may also play a role in drug resistance. Increased expression of MAP-4, which stabilizes microtubules, is associated with sensitivity to taxanes in vitro [9]. Stathmin destabilizes microtubules and its overexpression has been observed in taxane-resistant cell lines [9].

Microtubule inhibitors have a broad spectrum of activity against breast cancer, ovarian cancer, prostate cancer, and non-small cell lung cancer (NSCLC). The efficacy of these agents is limited by the development of drug resistance, and by cumulative toxicities such as neurotoxicity [1, 13]. Overcoming both primary and acquired resistance to chemotherapy remains a major therapeutic challenge. Therefore, continued development of new microtubule inhibitors with less susceptibility to resistance and lower toxicity is necessary.


   EPOTHILONES
Top
 Abstract
 Current Challenges in...
 Epothilones
Ixabepilone
 Clinical Evaluation of Other...
 Conclusions
 Author Contributions
 References
 
Epothilones are macrolide antibiotics isolated from the myxobacterium Sorangium cellulosum [14]. The class includes naturally occurring epothilones A–F and synthetic derivatives such as ixabepilone, ZK-epothilone, and KOS-1584 (9,10,-didehydroepothilone D). Named for their molecular features (epoxide, thiazole, and ketone), the epothilones promote microtubule stabilization via a mechanism of action similar to that of the taxanes [15]. They bind near the paclitaxel-binding site on microtubules [16, 17], inducing cell-cycle arrest at the G2/M checkpoint, and subsequently, apoptosis [10, 14]. In early preclinical assays, epothilones A and B were more potent than paclitaxel in vitro [18]. More importantly, the epothilones maintained activity against multidrug-resistant cell lines, while paclitaxel was more than twofold less potent than epothilones in these cell lines [14, 19, 20]. The antitumor activity of the natural epothilones and the ability to overcome mechanisms of resistance led to the development of new agents in this drug class. The lactam analogue of epothilone B, ixabepilone, was designed to enhance metabolic stability to plasma esterases [19]. The loss of the epoxide moiety in epothilone D (KOS-862) and its analogue KOS-1584 did not affect the biological potency of these compounds [21, 22]. Ixabepilone and KOS-862 were also more potent than paclitaxel in vitro, producing median 50% inhibitory concentration values in the low nanomolar range in a variety of cell lines [18, 19], including breast, lung, colon, prostate, and ovarian cell lines [15, 18, 22]. KOS-1584 was three- to 12-fold more potent than the parent KOS-862 in vitro [23].

Three of these epothilones are currently in clinical development in solid tumors—patupilone (EPO906, epothilone B), ZK-epothilone (ZK-EPO, ZK-219477, sagopilone), and KOS-1584 (Fig. 1)—whereas ixabepilone is the only epothilone approved by the U.S. Food and Drug Administration (FDA) for the treatment of metastatic breast cancer (MBC) [24].


Figure 1
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  		Figure 1. Structure of epothilones in clinical development.

 

   IXABEPILONE
Top
 Abstract
 Current Challenges in...
 Epothilones
 Ixabepilone
Clinical Evaluation of Other...
 Conclusions
 Author Contributions
 References
 
In preclinical models, ixabepilone induced objective responses in 18 of 29 solid tumor xenograft models at the maximum-tolerated dose (MTD) of 10 mg/kg [25]. Paclitaxel (15–20 mg/kg) administered on the same schedule failed to induce regression of three cell lines highly sensitive to ixabepilone [26]. The ixabepilone exposure achieved at 10 mg/kg in mice was similar to that reached with the 40-mg/m2 dose given once every three weeks (q3w) in phase II and III clinical trials [25, 26]—a regimen that produced significant antitumor activity in patients. Additional preclinical studies have demonstrated the synergistic antitumor activity of ixabepilone with other chemotherapeutic and biologic agents including capecitabine [27], cetuximab [27], trastuzumab [28], and bevacizumab [29].

Ixabepilone possesses high microtubule-stabilizing activity and low susceptibility to key mechanisms of drug resistance such as P-gp and MRP-1, as well as βIII-tubulin overexpression [15, 19, 20]. Although its action is similar to that of paclitaxel [30], the in vivo antitumor activity of ixabepilone is superior to that of paclitaxel in both paclitaxel-sensitive and paclitaxel-resistant cell lines and tumors [19]. Based on preclinical data supporting its efficacy in paclitaxel-sensitive and paclitaxel-resistant cell lines, the clinical development of ixabepilone in breast cancer has focused on patients with tumors that had failed prior treatment with anthracyclines and/or taxanes [19, 20].

Clinical Experience
Ixabepilone has been investigated extensively in a broad range of tumor types, and objective responses have been observed in both chemotherapy-sensitive and anthracycline- and/or taxane-resistant tumors. Phase II and III trials have investigated the efficacy of ixabepilone as monotherapy and in combination with capecitabine in patients with MBC (Table 1) [31–35]. Clinical activity has also been reported in other tumor types (Table 2), including hormone-refractory prostate cancer (HRPC) [36–38], NSCLC [39], pancreatic cancer [40], metastatic gastric adenocarcinoma [41], colorectal carcinoma [42], squamous cell cancer of the head and neck (SCCHN) [43], lymphoma [44], renal cell carcinoma [45], and carcinoma of the urothelium [46]. In addition, ixabepilone has been investigated in patients with soft tissue sarcomas [47], gliomas [48], malignant melanoma [49], and germ-cell tumors [50]. The results of several phase II studies conducted in ovarian, prostate, primary peritoneal, and gastrointestinal cancers are pending (Tables 3 and 4).


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  		Table 1. Completed phase II and III ixabepilone trials in breast cancer

 


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  		Table 2. Completed phase II ixabepilone trials in solid malignancies other than breast cancer

 


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  		Table 3. Selected ixabepilone trials with results pending

 


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  		Table 4. Selected ixabepilone trials recruiting patients

 

Dosing and Schedule
Most studies conducted with ixabepilone used a 32–50 mg/m2 dose infused over 1 or 3 hours on day 1 of a 21-day cycle [31–38]. A 3-hour infusion time is recommended, because a higher risk for neurotoxicity was observed with the shorter infusion time [51–53]. The FDA-approved dose and schedule is 40 mg/m2 i.v. over 3 hours q3w. After reconstitution in polyoxyethylated castor oil/ethanol (Cremophor®; BASF Corp., Ludwigshafen, Germany), ixabepilone is diluted with lactated Ringer's injection, USP, in a non-PVC container and administered within 6 hours of preparation. An analysis of 12 phase I/II monotherapy trials revealed that ixabepilone exposure was not significantly affected by patient characteristics, including age, gender, renal function, body weight, body surface area, and race [54].

The most common grade 3 or 4 toxicity associated with the 40-mg/m2 q3w schedule of single-agent ixabepilone is neutropenia. Depending on the study, the incidence of grade 3 neutropenia was in the range of 10%–33%, whereas grade 4 neutropenia occurred in 7%–32% of patients [31–33, 37, 42, 55]. This wide range in incidence might be a reflection of the number and type of prior therapies. A semimechanistic model accurately described the incidence of ixabepilone-induced neutropenia during cycle 1 of treatment [56]. Covariates including age, baseline absolute neutrophil count, Eastern Cooperative Oncology Group performance status score, and prior taxane therapy had no significant effect on the model-predicted neutropenia incidence during cycle 1 [56]. Febrile neutropenia occurred in up to 6% of patients [31–33, 37, 42, 55]. Grade 3 peripheral sensory neuropathy was experienced by 7%–20% of patients, and 0%–1% had grade 4 peripheral sensory neuropathy [31–33, 37, 42, 55].

Alternative ixabepilone dosing and schedules have been explored in patients with MBC and other solid tumors [39, 41, 57–59], including administration at 6 mg/m2 on days 1–5 of a 21-day cycle, with neutropenia rates of 9%–16% (grade 3) and 6%–19% (grade 4) and peripheral sensory neuropathy rates of 0%–6% (grade 3) and 0% (grade 4) [39, 41, 57, 59]. A phase I trial evaluated two different weekly schedules in patients with advanced solid tumors; the MTDs were 25 mg/m2 administered as a 30-minute infusion on a 21-day cycle and 20 mg/m2 i.v. over 1 hour on a 28-day cycle [58].

Efficacy

Breast Cancer
Evaluation of ixabepilone in breast cancer has been primarily conducted in metastatic disease (Table 1). Several phase II studies with different schedules of ixabepilone in MBC resistant to anthracyclines, taxanes, and/or capecitabine demonstrated objective response rates (ORRs) in the range of 11.5%–57%, and overall survival (OS) times in the range of 7.9–22 months [31–33, 57, 59] (Table 1).

Evaluation of ixabepilone plus capecitabine in early-phase studies [34] showed safety and efficacy with response rates that were superior to those of single-agent capecitabine [60–62]. In a large phase III study, ixabepilone plus capecitabine demonstrated a significantly longer progression-free survival (PFS) time versus capecitabine alone [35]. The median PFS duration was 5.8 (95% confidence interval [CI], 5.5–7.0) months for the combination treatment versus 4.2 months (95% CI, 3.8–4.5) for single-agent capecitabine. There was a 25% lower risk for disease progression (p < .0003) and a twofold higher ORR with combination therapy than with single-agent capecitabine: 34.7% versus 14.3% (p < .0001) [35].

Because of the heterogeneous nature of breast cancer, evaluations of patient subgroups were done to explore the efficacy of ixabepilone in these different populations. In the phase III study, a prospective analysis was performed in anthracycline/taxane-resistant patients whose breast cancer was estrogen receptor, progesterone receptor, and human epidermal growth factor receptor (HER)-2–negative (triple negative); these made up 25% of the total population [35]. The superiority of ixabepilone combination therapy over capecitabine alone in the triple-negative subgroup was similar to that in the overall patient population. The median PFS time was 4.1 months and the ORR was 27% in the combination arm, compared with 2.1 months and 9%, respectively, in the capecitabine monotherapy arm [63]. Consistently, retrospective analyses of patients with triple-negative tumors enrolled in four phase II studies also demonstrated that ixabepilone was effective against triple-negative breast cancers in the advanced/metastatic setting, as well as in the neoadjuvant setting [64]. Similarly, ixabepilone plus capecitabine combination therapy is more effective than capecitabine across all lines of treatment in MBC. In a phase III trial, a retrospective analysis demonstrated that the PFS time was 6.9 months in the first- or second-line metastatic setting (206 patients), versus 4.1 months for capecitabine alone. ORRs with combination therapy were 36% for first- or second-line therapy and 14% with capecitabine alone [65].

Patients not responding to taxane therapy may be considered to have primary resistance to taxanes. Among patients in a phase III trial, 87% exhibited taxane resistance in the metastatic setting (defined as recurrence within 4 months of the last taxane dose), and disease progression had been the best response to previous taxanes in 38% of patients. An exploratory analysis confirmed that the efficacy of combination therapy was similar in this subgroup to that of the overall population, with a median PFS time of 5.6 months and an ORR of 33%. Patients treated with capecitabine alone had a median PFS of 4.9 months and an ORR of 13% [66]. An ORR of 42% was also reported for ixabepilone in combination with carboplatin and trastuzumab in patients with HER-2–positive MBC [67].

In the neoadjuvant setting, ixabepilone has also shown activity as a single agent, with 61% of patients achieving an objective tumor response in a phase II study [68]. A pathologic complete response in the breast (pCRB) was achieved in 19% of patients after a maximum of four cycles of ixabepilone at a dose of 40 mg/m2 on a 21-day cycle; this figure was higher than values for up to four cycles of a single-agent taxane described in other studies (7%–10%) [69]. Although higher pCR rates have been reported with taxanes, these usually require a greater number of cycles and/or combination regimens [70, 71]. The breast-conserving surgery rate after ixabepilone treatment was 32% [68].

Prostate Cancer
Ixabepilone has demonstrated activity, with or without estramustine, when administered at 35 mg/m2 i.v. over 3 hours q3w to chemotherapy-naïve patients with progressive prostate cancer after castration (Table 2) [36]. Post-treatment declines in prostate-specific antigen (PSA) of ≥50% were achieved in 48% of patients receiving ixabepilone alone, and in 69% of those receiving ixabepilone plus estramustine. Thirty-two percent of patients achieved partial tumor responses with ixabepilone, compared with 48% of patients in the ixabepilone plus estramustine arm. Time to PSA progression was 4.4 months with ixabepilone alone versus 5.2 months with the combination [36].

Ixabepilone has also demonstrated activity in the second-line setting in docetaxel-refractory HRPC (Table 2). Participants in a randomized, noncomparative phase II trial achieved a median survival duration of 10.4 months with ixabepilone, and 9.8 months with mitoxantrone plus prednisone (MP). The primary endpoint was the frequency of 50% PSA decline, which was observed in 17% of ixabepilone patients and 20% of MP patients [38].

Lung Cancer
A large phase II trial evaluated the activity of ixabepilone in patients with advanced NSCLC who had progressed after one prior platinum-based chemotherapy; 55.5% of the patients had received prior taxanes [39]. Patients were randomly assigned to receive 32 mg/m2 i.v. over 3 hours q3w (n = 77, arm A) or 6 mg/m2 i.v. over 1 hour on days 1–5 q3w (n = 69, arm B). Patients in arm A had an ORR of 14.3%, compared with 11.6% in arm B, which is consistent with the response rates seen with other agents approved for second-line NSCLC, such as docetaxel, pemetrexed, and erlotinib [72, 73]. The median duration of response was 8.7 versus 9.6 months, with median times to progression of 2.1 and 1.5 months, respectively. Although not powered to compare OS, the median survival times were similar, at 8.3 and 7.3 months, respectively; and the 1-year survival rate was 38% in both treatment arms [39].

SCCHN
Patients with metastatic or recurrent SCCHN were randomized to receive ixabepilone at a dose of 6 mg/m2 as a 1-hour infusion on days 1–5 of a 21-day cycle (arm A) or 20 mg/m2 over 1 hour on days 1, 8, and 15 every 28 days (arm B) [43]. Patients were stratified according to prior exposure to taxanes; 17 patients (53%) and 34 patients (66%) were taxane-naïve (Tax-N) in arms A and B, respectively. Among the taxane-exposed (Tax-E) patients, one response was reported in arm A (6.7%), and five Tax-N patients (14.7%) had a partial response in arm B. No responses were observed in Tax-E patients in arm B. The median survival duration in arm A was 5.6 months in Tax-N patients and 6.5 months in Tax-E patients; in arm B, the median survival times were 7.8 and 6.8 months, respectively [43].

Pancreatic Cancer
Although taxanes are not commonly used for the treatment of pancreatic cancer, ixabepilone (40 mg/m2 q3w) has been demonstrated to have promising activity in chemotherapy-naïve patients with metastatic or recurrent pancreatic adenocarcinoma. The authors of a phase II trial reported an overall response probability of 21.4%, which included five confirmed partial responses (8.9%) and 7 (12.5%) unconfirmed partial responses. The median OS time was 7.2 months and the estimated 6-month survival rate was 60% [40].

Other Tumor Types
An ORR of 12.6% was reported in patients with metastatic renal cell carcinoma treated with ixabepilone monotherapy (6 mg/m2 for 5 days q3w) [74]. Prolonged disease stabilization was observed in response to ixabepilone (6 mg/m2 or 8 mg/m2 for 5 days q3w) in a small subset of children and young adults with refractory solid tumors [75]. Ongoing trials are evaluating ixabepilone in patients with solid tumors or leukemia [76], kidney cancer [77], endometrial cancer [78], metastatic prostate cancer [79], and non-Hodgkin's lymphoma [80].

Safety Profile
The ixabepilone safety profile appears to be similar across trials in patients with different solid malignancies [31–37, 39–47]. In general, adverse events (AEs) are manageable; the principal dose-limiting AEs are neutropenia and peripheral neuropathy (Tables 1 and 2).

Breast Cancer
Most of the toxicity information has been gathered from MBC patients who received ixabepilone at the recommended dose of 40 mg/m2 as a 3-hour infusion q3w. Peripheral neuropathy emerged as a dose-limiting toxicity for ixabepilone, and although cumulative, it is generally reversible with dose adjustments [31–33, 35]. In a phase II study in 126 heavily pretreated MBC patients resistant to an anthracycline, a taxane, and capecitabine, 13% and 1% experienced grade 3 and 4 sensory peripheral neuropathy, respectively, with ixabepilone monotherapy, which resolved in a median of 5.4 weeks despite taxane pretreatment [33]. Grade 3 peripheral motor neuropathy occurred in few patients (1%); no grade 4 peripheral motor neuropathy occurred. A lower rate of neuropathy has been reported in a limited number of MBC patients treated with ixabepilone administered at 6 mg/m2 for 5 days [57, 59]. Peripheral sensory neuropathy (all grades) occurred in 52% of taxane-naïve and 54% of taxane-pretreated patients [57, 59]. Grade 3 neuropathy was reported in 3% of taxane-pretreated patients with no incidence of grade 4 events [59].

When ixabepilone was used in combination with capecitabine, most AEs were consistent with the safety profile of each individual agent [34, 35]. Neuropathy was primarily sensory, cumulative, and generally reversible. Grade 3 and 4 sensory neuropathy occurred in 20% and 0.8% of patients with anthracycline- and taxane-resistant MBC, respectively, in the ixabepilone combination treatment arm of a large phase III study. No grade 3 or 4 peripheral sensory neuropathy was noted in the capecitabine-alone arm [35]. A subgroup analysis by line of therapy received showed that grade 3 and 4 sensory neuropathy occurred in 21.9% and 1% of patients, respectively, treated with combination therapy in the first- or second-line metastatic setting [65]. Complete resolution of grade 3 or 4 sensory neuropathy to baseline or grade 1 occurred over a 6-week time period in 70 patients with anthracycline- and taxane-resistant MBC [35]. Resolution of grade ≥2 sensory neuropathy occurred in a median of 2.6 weeks in 94% of anthracycline- and taxane-pretreated MBC patients in one phase II study [34].

Although the incidence of myelosuppression was relatively high, it was manageable, even in heavily pretreated patients. Neutropenia and leukopenia did not contribute significantly to dose reductions or discontinuations. In trials of ixabepilone as a single agent in pretreated patients, grade 3 neutropenia was noted in 27%–33% of patients, and grade 4 neutropenia occurred in 20%–31% of patients [31–33]. The ixabepilone plus capecitabine combination is associated with a higher risk for grade 3 and 4 neutropenia—32% and 36%, respectively [35]. In the capecitabine-alone group, grade 3 and 4 neutropenia occurred in 9% and 2% of patients, respectively. The incidence of grade 3 or 4 febrile neutropenia was ≤4.8% in the ixabepilone plus capecitabine arm versus ≤1.0% in patients who received capecitabine alone. Ixabepilone did not increase the severity of capecitabine-related toxicities; the incidences of grade 3 or 4 hand–foot syndrome were comparable in the two arms (18% versus 17%) [35].

Patients receiving ixabepilone are premedicated with an oral H1 and an H2 antagonist, such as diphenhydramine, ranitidine, or cimetidine, to prevent hypersensitivity or allergic reactions related to the Cremophor® formulation. Dexamethasone is given shortly before administration of ixabepilone in patients with prior hypersensitivity reactions. Ixabepilone monotherapy is associated with a low incidence of hypersensitivity, which is primarily mild to moderate (4%–8%) [31–33]. A new Cremophor®-free formulation of ixabepilone is being evaluated in patients with advanced solid malignancies [81].

Because ixabepilone is metabolized in the liver, there is the potential for greater risk in patients with moderately or severely impaired hepatic function, and the dose of single-agent ixabepilone should be adjusted according to the degree of impairment [82]. Ixabepilone plus capecitabine combination is contraindicated in patients with aspartate aminotransferase or alanine aminotransferase levels >2.5x the upper limit of normal (ULN), or bilirubin ≥1.0x the ULN [24].

Prostate Cancer
Ixabepilone appears to be well tolerated in patients with HRPC. When patients received ixabepilone at a dose of 35 mg/m2 i.v. on a 21-day schedule with or without estramustine, grade 3 or 4 AEs in >5% of patients in the ixabepilone alone arm included neutropenia (22%), fatigue (9%), and neuropathy (13%). Patients in the ixabepilone plus estramustine arm had grade 3 or 4 neutropenia (29%), febrile neutropenia (9%), fatigue (9%), neuropathy (7%; grade 4, 0%), and thrombosis (8%) [36]. In a clinical trial in which patients were treated with ixabepilone at a dose of 35 mg/m2 over 3 hours q3w or MP as second-line chemotherapy for taxane-refractory HRPC, the most common grade 3 or 4 AE was neutropenia (ixabepilone, 54%; MP, 63%) [38].

Lung Cancer
In a trial comparing ixabepilone at a dose of 32 mg/m2 as a 3-hour infusion q3w (arm A) with 6 mg/m2 as a 1-hour infusion daily for five consecutive days (arm B) in patients with NSCLC who had progressed after platinum-based therapy, both regimens had an acceptable toxicity profile [39]. Common grade 3 or 4 AEs included neutropenia (28% and 17%, respectively) and leukopenia (20% and 9%, respectively); both were manageable. The incidence of grade 3 or 4 peripheral sensory neuropathy was 6% in both treatment arms (grade 4 neuropathy occurred in 1% and 0% of patients in arms A and B, respectively). Grade 3 or 4 peripheral sensory neuropathy was mostly reversible, resolving to grade 1 in 80% and 75% of patients in Arms A and B, respectively.


   CLINICAL EVALUATION OF OTHER EPOTHILONES
Top
 Abstract
 Current Challenges in...
 Epothilones
 Ixabepilone
 Clinical Evaluation of Other...
Conclusions
 Author Contributions
 References
 
Three other epothilones—patupilone, ZK-EPO, and KOS-1584—are being evaluated in patients with advanced solid tumors, including gastric, hepatocellular, ovarian, prostate, and renal cancers. Preliminary results of completed or ongoing trials have been reported, as well as study designs of planned trials.

Patupilone
Patupilone is being evaluated in a variety of solid tumors, including gastric and hepatocellular cancers (Table 5Go). In a phase II trial, patients with advanced gastric cancer received a weekly 5- to 7-minute infusion of patupilone (2.5 mg/m2) on days 1, 8, and 15 of a 28-day cycle. Two patients (9.1%) had a partial response and six patients (27.2%) had disease stabilization [83]. In a two-stage phase II trial, patupilone (10 mg/m2 i.v.) was administered over 20 minutes q3w to patients with metastatic hepatocellular carcinoma. One patient (4%) had a partial response, and disease stabilization was reported in 44% of patients; the median PFS time was 3.0 months. The most common grade 3 or 4 AEs were diarrhea (16%) and electrolyte imbalances (20%) [84]. The trial was terminated early because it did not meet the requirements for the second stage.


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  		Table 5. Selected registered phase II/III patupilone (EPO906) trials

 


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  		Table 5. (Continued)

 
Patupilone has also been demonstrated to have activity (PSA decline) in patients with HRPC (Table 5Go) [85, 86]. Responses have also been reported in advanced ovarian cancer, advanced renal cancer, NSCLC, and advanced colorectal cancer (Table 5Go) [87–90]. An important property of patupilone is its ability to cross the blood–brain barrier. Consistent with these results, patupilone has demonstrated activity against recurrent/progressive metastatic lesions to the brain in patients with NSCLC and MBC (Table 5Go) [91, 92]. Ongoing trials are evaluating patupilone in platinum-refractory ovarian, fallopian, and peritoneal cancers [93], glioblastoma [94], and prostate cancer [95, 96] (Table 5Go).

ZK-EPO
ZK-EPO (ZK-219477, sagopilone) is in phase II clinical development as a single agent and in combination (Table 6). A randomized phase II trial compared two dosing schedules for ZK-EPO (3-hour versus 30-minute infusion of 16 mg/m2) in patients with recurrent ovarian cancer who had disease progression within 6 months of platinum-based treatment [97]. A 31% response rate was reported in patients receiving the 3-hour infusion, versus 8% for patients receiving the 30-minute infusion. The most common grade 3 or 4 AEs included sensory neuropathy, fatigue, arthralgia, and nausea (Table 6). The activity of ZK-EPO has also been reported in glioma, glioblastoma, and metastatic melanoma (Table 6) [98–100]. ZK-EPO in combination with prednisone has demonstrated activity in metastatic prostate cancer (Table 6) [101]. Like patupilone, ZK-EPO crosses the blood–brain barrier [102]. Phase II trials are evaluating the activity of ZK-EPO in advanced MBC patients [103], and in MBC metastatic to the central nervous system [104]. ZK-EPO is being evaluated in combination with carboplatin in patients with platinum-sensitive ovarian cancer [105].


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  		Table 6. Selected registered phase II ZK-EPO (ZK-219477, sagopilone) trials

 
KOS-1584
KOS-1584 is in phase I clinical development. Three ongoing phase I trials are investigating various weekly dosing schedules of KOS-1584 (Table 7). Two studies are investigating a weekly schedule of 0.8–11.3 mg/m2 on days 1, 8, and 15 of a 28-day cycle [106, 107]. A third study is comparing two weekly dosing schedules (days 1, 8, and 15 of a 28-day cycle or days 1 and 8 of a 21-day cycle) [108]. Frequently noted AEs (all grades) include nausea (51%), diarrhea (49%), and fatigue (49%) [108]. All trials were still accruing at the time of reporting. An ongoing phase II trial is evaluating KOS-1584 in patients with advanced or metastatic NSCLC [109].


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  		Table 7. Selected registered phase I KOS-1584 trials

 

   CONCLUSIONS
Top
 Abstract
 Current Challenges in...
 Epothilones
 Ixabepilone
 Clinical Evaluation of Other...
 Conclusions
Author Contributions
 References
 
De novo and acquired tumor resistance to chemotherapy is a primary cause of most treatment failures in patients with advanced disease. Thus, the development of new agents that can overcome the mechanisms of resistance is essential. The epothilones are a new class of antineoplastic agents that demonstrate unique properties with important implications for the treatment of cancer. Ixabepilone, the first epothilone approved by the FDA, in MBC, has shown potent activity as a microtubule inhibitor and the ability to induce effective antitumor responses, even in heavily pretreated patients resistant to multiple chemotherapeutic agents (Tables 1 and 2). As a single agent or in combination, ixabepilone has been demonstrated to have a manageable safety profile that is consistent with other commonly used chemotherapies. Currently, ixabepilone (40 mg/m2 q3w) is indicated in combination with capecitabine to treat MBC resistant to treatment with an anthracycline and a taxane, or as monotherapy in MBC resistant or refractory to anthracyclines, taxanes, and capecitabine. OS data from two large, phase III trials of ixabepilone plus capecitabine in locally advanced breast cancer or MBC are expected in the upcoming months. Other epothilones are under active clinical investigation (phase I/II) in a variety of tumor types. For example, trials evaluating patupilone in patients with NSCLC and HRPC are currently recruiting patients (Table 5Go), and ZK-EPO is being evaluated in patients with recurrent cancers, including ovarian cancers and glioblastoma (Table 6). Early phase I data on KOS-1584 appear to indicate feasibility and safety.

The epothilones have also been demonstrated to have activity and a manageable safety profile in combination with other chemotherapeutic agents, and logical next steps in the development of these agents are the exploration of combinations with targeted agents, evaluation of their activity during earlier stages of disease, and identification of predictive markers to guide therapy. Ongoing studies in combination with targeted agents include a large phase II trial of trastuzumab plus ixabepilone or docetaxel in HER-2–positive MBC patients and a phase II trial of ixabepilone plus cetuximab as first-line therapy for triple-negative MBC patients [110, 111]. Active trials also include phase II studies of ixabepilone plus bevacizumab versus paclitaxel plus bevacizumab as first-line therapy for MBC, ixabepilone and carboplatin with or without bevacizumab in advanced NSCLC, and ixabepilone plus cetuximab as first-line therapy for metastatic pancreatic cancer [112–114]. Validation of predictive techniques and biomarkers that allow prospective identification of patients most likely to respond to ixabepilone is also an area of active investigation. In summary, the epothilones comprise a new class of antineoplastic agents that demonstrate unique properties and provide new therapeutic options for treatment of poor prognosis patients, including those with aggressive and/or multidrug resistant disease.


   AUTHOR CONTRIBUTIONS
Top
 Abstract
 Current Challenges in...
 Epothilones
 Ixabepilone
 Clinical Evaluation of Other...
 Conclusions
 Author Contributions
References
 
Conception/design: Angela Davies, Edgardo Rivera

Collection/assembly of data: Angela Davies

Data analysis: Angela Davies, Edgardo Rivera

Manuscript writing: Angela Davies, Joyce Lee

Final approval of manuscript: Angela Davies, Edgardo Rivera, Joyce Lee

The authors take full responsibility for the content of the article and wish to thank Roy Garcia, Ph.D., from IneXel Medical Communications, supported by Bristol-Myers Squibb, for his assistance in preparing the initial draft of the manuscript.


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 Author Contributions
 References
 

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S. Jacobs, E. Fox, M. Krailo, G. Hartley, F. Navid, L. Wexler, S. M. Blaney, A. Goodwin, W. Goodspeed, F. M. Balis, et al.
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