Oncologist. The. Breast Cancer. Clinical Development of Ixabepilone and Other Epothilones in Patients with Advanced Solid Tumors

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1 The Oncologist Breast Cancer Clinical Development of Ixabepilone and Other Epothilones in Patients with Advanced Solid Tumors EDGARDO RIVERA, a JOYCE LEE, b ANGELA DAVIES b a The Methodist Hospital/Weill Cornell University, Houston, Texas, USA; b University of California Davis Cancer Center, Sacramento, California, USA Key Words. Epothilones Ixabepilone Multidrug resistance Breast cancer Prostate cancer 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 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. Singleagent 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 hormonerefractory prostate cancer and platinum-resistant nonsmall 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. The Oncologist 2008;13: Correspondence: Edgardo Rivera, M.D., The Methodist Hospital/Weill Cornell University, 6550 Fannin Street, SM701, Houston, Texas 77030, USA. Telephone: ; Fax: ; erivera1@tmhs.org Received July 3, 2008; accepted for publication November 7, 2008; first published online in THE ONCOLOGIST Express on December 16, AlphaMed Press / 2008/$30.00/0 doi: /theoncologist The Oncologist 2008;13:

2 1208 Activity of Ixabepilone in Solid Tumors CURRENT CHALLENGES IN CHEMOTHERAPY DRUG RESISTANCE 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 -tubulin have been identified in paclitaxel-resistant cell lines [11], and overexpression of the III-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 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 (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 G 2 /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 , 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]. IXABEPILONE 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/m 2 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].

3 Rivera, Lee, Davies 1209 Figure 1. Structure of epothilones in clinical development. 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 III-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 paclitaxelsensitive 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 hormonerefractory 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). Dosing and Schedule Most studies conducted with ixabepilone used a mg/m 2 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/m 2 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/m 2 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].

4 1210 Activity of Ixabepilone in Solid Tumors Table 1. Completed phase II and III ixabepilone trials in breast cancer Study Efficacy Safety (grade 3 4 AEs) Combination therapy: ixabepilone capecitabine Phase III: Thomas et al. (2007) [35] MBC, pretreated/resistant to anthracycline and taxane resistant; Ixabepilone (40 mg/m 2 i.v. over 3 hours q3w) capecitabine (2,000 mg/m 2 orally days 1 14 q3w) versus capecitabine alone (2,500 mg/m 2, same schedule); n 752 enrolled, 737 treated Phase I/II: Bunnell et al. (2008) [34] MBC, pretreated/resistant to anthracycline and taxane resistant; ixabepilone (40 mg/m 2 i.v. over 3 hours q3w) capecitabine (2,000 mg/m 2 orally days 1 14 q3w); n 74 enrolled in phase I, 72 treated; n 62, phase II Monotherapy Phase II: Perez et al. (2007) [33] MBC refractory to anthracycline, taxane, and capecitabine; ixabepilone (40 mg/m 2 i.v. over 3 hours q3w); n 128 enrolled, 126 treated Phase II: Thomas et al. (2007) [32] MBC, taxane resistant; ixabepilone (40 mg/m 2 i.v. over 3 hours q3w); n 49 treated Phase II Roché et al. (2007) [31] Prior anthracycline; ixabepilone (40 mg/m 2 i.v. over 3 hours q3w); n 93 enrolled, 65 treated at this dose Phase II: Low et al. (2005) [59] Locally advanced BC or MBC, taxane pretreated; ixabepilone (6 mg/m 2 i.v. over 1 hour days 1 5 q3w); n 37 enrolled and treated Phase II: Denduluri et al. (2007) [57] Locally advanced BC or MBC, no prior taxane; ixabepilone (6 mg/m 2 i.v. over 1 hour days 1 5 q3w); n 23 enrolled and treated Phase II: Baselga et al. (2005) [68] Neoadjuvant, invasive breast cancer; ixabepilone (40 mg/m 2 i.v. over 3 hours q3w, 4 cycles maximum); n 164 enrolled, 161 treated ORR, 35 %; SD, 41%; MDR, 6.4 mos; median PFS, 5.8 mos ORR, 30 %; SD, 32%; MDR, 6.9 mos; median PFS, 3.8 mos ORR, 11.5%; SD, 50%; MDR, 5.7 mos; median PFS, 3.1 mos; median OS, 8.6 mos ORR, 12%; SD, 41%; MDR, 10.4 mos; median TTP, 2.2 mos; OS, 7.9 mos ORR, 42%; SD, 35%; MDR, 8.2 mos; median TTP, 4.8 mos; median OS, 22 mos ORR, 22%; SD, 35%; MDR, 3.9 mos; median TTP, 2.6 mos ORR, 57%; SD, 26%; MDR, 5.6 mos; median TTP, 5.5 mos ORR, 61%; SD, 31%; pcr B, 18%; BCS, 32% Neutropenia, 68%; febrile neutropenia, 5% a ; sensory neuropathy, 21%; myalgia/arthralgia, 11%; fatigue, 9% Neutropenia, 69%; febrile neutropenia, 2%; sensory neuropathy, 19%; myalgia/arthralgia, 25%; fatigue, 34% Neutropenia, 54%; febrile neutropenia, 3%; infection with neutropenia, 2%; sensory neuropathy, 14%; myalgia/ arthralgia, 8%; fatigue/asthenia, 14% Neutropenia, 53%; febrile neutropenia, 6%; sensory neuropathy, 12%; myalgia/arthralgia, 12%; fatigue, 27% Neutropenia, 58%; febrile neutropenia, 3%; infection with neutropenia, 6%; sensory neuropathy, 20%; myalgia/ arthralgia, 13%; fatigue, 6% Neutropenia, 35%; febrile neutropenia, 14%; sensory neuropathy, 3%; myalgia/arthralgia, 3%; fatigue, 13% Neutropenia, 22%; febrile neutropenia, 0%; sensory neuropathy, 0%; myalgia/ arthralgia, 4%; fatigue, 13% Neutropenia, 14%; febrile neutropenia, 3%; sensory neuropathy, 1%; myalgia/ arthralgia, 3%; fatigue, 1% a Grade 5 in three patients. Abbreviations: AE, adverse event; BCS, breast-conserving surgery; MBC, metastatic breast cancer; MDR, median duration of response; ORR, overall response rate; OS, overall survival; pcr B, pathological complete response in the breast; PFS, progression-free survival; SD, stable disease; TTP, time to progression.

5 Rivera, Lee, Davies 1211 Table 2. Completed phase II ixabepilone trials in solid malignancies other than breast cancer Study Efficacy Safety (grade 3 4 AEs) Prostate cancer Randomized phase II: Galsky et al. (2005) [36] Androgen-independent prostate cancer; ixabepilone, 35 mg/m 2 over 3 hours q3w (arm A) versus ixabepilone, 35 mg/m 2 over 3 hours on day 2 q3w oral estramustine phosphate every 21 days, 280 mg orally 3 daily on days 1 5 q3w (arm B); n 92 enrolled and treated Randomized phase II: Rosenberg et al. (2007) [38] HRPC, taxane-resistant; ixabepilone, 35 mg/m 2 over 3 hours q3w versus MP; n 86 enrolled, 82 treated Phase II: Hussain et al. (2005) [37] HRPC, chemotherapy-naïve; ixabepilone, 40 mg/m 2 i.v. over 3 hours q3w; n 48 enrolled, 42 treated NSCLC Phase II: Vansteenkiste et al. (2007) [39] NSCLC that failed first-line platinum-based chemotherapy; ixabepilone, 32 mg/m 2 over 3 hours q3w versus 6 mg/m 2 over 1 hour daily 5 days q3w; n 201 enrolled, 146 treated SCCHN Randomized phase II: Burtness et al. (2006) [43] Metastatic or recurrent SCCHN; ixabepilone, 6 mg/m 2 5 days every 21 days versus 20 mg/m 2 i.v. over 1 hour on days 1, 8, 15 q4w; n 84; Tax-E patients, 33; Tax-N patients, 51 Ixabepilone monotherapy: 50% 2PSA, 48%; PR, 32%; median time to PSA progression, 4.4 mos. Ixabepilone estramustine: 50% 2PSA, 69%; PR, 48%; median time to PSA progression, 5.2 mos Ixabepilone monotherapy: 50% 2PSA, 17%; MDR, 3.8 mos; PR, 4.2%; median time to PSA progression, 2.2 mos; median survival 10.4 mos. MP: 50% 2PSA, 20%; MDR, 5.9 mos; PR, 9.5%; median time to PSA progression, 2.3 months; median survival, 9.8 mos Ixabepilone monotherapy: 80% 2PSA, 72%; PSA response, 33%; median PFS, 6 mos; median survival, 18 mos Ixabepilone, 32 mg/m 2 : ORR, 14.3%; TTP, 2.1 mos; MDR, 8.7 mos; median survival, 8.3 mos. Ixabepilone, 6 mg/m 2 : ORR, 11.6%; TTP, 1.5 mos; MDR, 9.6 mos; median survival, 7.3 mos Ixabepilone, 6 mg/m 2 : ORR, 6.7% (1 Tax- E patient); median survival, 5.6 mos (Tax- N), 6.5 mos (Tax-E). Ixabepilone 20 mg/ m 2 : ORR, 14.7% (5 Tax-N patients); median survival, 7.8 mos (Tax-N), 6.8 mos (Tax-E) Ixabepilone: neutropenia, 22%; febrile neutropenia, 4%; fatigue, 9%; neuropathy, 13%. Ixabepilone estramustine: neutropenia, 29%; febrile neutropenia, 9%; fatigue, 9%; neuropathy, 7%; thrombosis, 8% Second line: Ixabepilone: neutropenia, 54%; febrile neutropenia, 5% a ; fatigue, 2%. MP: neutropenia, 63%; febrile neutropenia, 10%; fatigue, 0% Neutropenia, 17%; leukopenia, 12%; anemia, 2%; peripheral sensory neuropathy, 17% Ixabepilone, 32 mg/m 2 (n 76): neutropenia, 28%; febrile neutropenia, 7%; fatigue, 5%; peripheral sensory neuropathy, 6%. Ixabepilone, 6 mg/m 2 (n 66): neutropenia, 17%; febrile neutropenia, 1%; fatigue, 9%; peripheral sensory neuropathy, 6% Ixabepilone, 6 mg/m 2 (Tax-N): anemia, 13%; fatigue, 25%; Tax-E not reported. Ixabepilone, 20 mg/m 2 (Tax- N): anemia, 9%; fatigue, 21%; peripheral sensory neuropathy, 27%. Ixabepilone, 20 mg/m 2 (Tax-E): neutropenia, 10%; anemia, 0%; fatigue, 29%; peripheral sensory neuropathy, 10% a One patient died of neutropenic sepsis. Abbreviations: HRPC, hormone-refractory prostate cancer; MDR, median duration of response; MP, mitoxantrone plus prednisone; NSCLC, non-small cell lung cancer; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; PR, partial response; PSA, prostate-specific antigen; SCCHN, squamous cell cancer of the head and neck; Tax-E, taxane-exposed; Tax-N, taxane naïve; TTP, time to progression. 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/m 2 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,

6 1212 Activity of Ixabepilone in Solid Tumors Table 3. Selected ixabepilone trials with results pending Study Outcome measures Breast Phase III Anthracycline- and taxane-pretreated MBC OS, PFS, ORR, response duration, AEs, QOL Ixabepilone (40 mg/m 2 i.v. over 3 hours q3w) capecitabine (2,000 mg/m 2 orally days 1 14 q3w) versus capecitabine alone (2,500 mg/ m 2, same schedule) n 1,200 Ovarian and endometrial cancer Phase II Relapse or refractory stage III IV ovarian epithelial cancer after ORR, PFS, AEs first-line platinum plus taxane therapy Ixabepilone i.v. over 1 hour q3w n 37 Phase II Recurrent or persistent platinum and paclitaxel refractory ovarian or ORR, PFS, survival, AEs primary peritoneal cancer Ixabepilone i.v. over 1 hour q3w n 51 Phase II Recurrent or persistent endometrial carcinoma ORR, PFS, survival AEs Ixabepilone i.v. over 3 hours q3w n 51 Pancreatic adenocarcinoma Phase II Locally advanced or metastatic pancreatic adenocarcinoma 6-mo survival rate, ORR, PFS, OS Ixabepilone i.v. over 3 hours q3w cetuximab weekly n 52 Colorectal cancer Phase II Metastatic colorectal cancer after fluoropyrimidine and irinotecan ORR, TTP, OS, safety therapy Ixabepilone i.v. over 1 hour on days 1 5 q3w n 55 Abbreviations: AE, adverse event; MBC, metastatic breast cancer; MDR, median duration of response; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; QOL, quality of life; q3w, every 3 weeks; TTP, time to progression. Available at accessed September 23, , 57, 59]. A phase I trial evaluated two different weekly schedules in patients with advanced solid tumors; the MTDs were 25 mg/m 2 administered as a 30-minute infusion on a 21-day cycle and 20 mg/m 2 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 months [31 33, 57, 59] (Table 1). Evaluation of ixabepilone plus capecitabine in earlyphase 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

7 Rivera, Lee, Davies 1213 Table 4. Selected ixabepilone trials recruiting patients Study Outcome measures Metastatic breast cancer Phase II HER-2 positive MBC RR, TTP, toxicity Ixabepilone i.v. over 3 hours trastuzumab i.v. over minutes q3w n 60 Prostate cancer Phase II HRPC PSA response Ixabepilone i.v. over 1 hour on days 1, 8, and 15 q4w n 83 Phase I/II HRPC with previous chemotherapy RR, safety Ixabepilone i.v. over 3 hours q3w mitoxantrone q3w prednisone twice daily on days 1 21 n 94 Renal cell carcinoma Phase II Renal cell carcinoma RR, measure NGF levels Ixabepilone i.v. over 1 hour on days 1 5 q3w n 114 Abbreviations: HER, human epidermal growth factor receptor; HRPC, hormone-refractory prostate cancer; NGF, nerve growth factor; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; PSA, prostate-specific antigen; q3w, every 3 weeks; q4w, every 4 weeks; RR, response rate; TTP, time to progression. Available at accessed September 23, progression-free survival (PFS) time versus capecitabine alone [35]. The median PFS duration was 5.8 (95% confidence interval [CI], ) months for the combination treatment versus 4.2 months (95% CI, ) for singleagent 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 triplenegative tumors enrolled in four phase II studies also demonstrated that ixabepilone was effective against triplenegative 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

8 1214 Activity of Ixabepilone in Solid Tumors 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 (pcr B ) was achieved in 19% of patients after a maximum of four cycles of ixabepilone at a dose of 40 mg/m 2 on a 21-day cycle; this figure was higher than values for up to four cycles of a singleagent 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/m 2 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/m 2 i.v. over 3 hours q3w (n 77, arm A) or 6 mg/m 2 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/m 2 as a 1-hour infusion on days 1 5 of a 21-day cycle (arm A) or 20 mg/m 2 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 taxanenaïve (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/m 2 q3w) has been demonstrated to have promising activity in chemotherapynaïve 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/m 2 for 5 days q3w) [74]. Prolonged disease stabilization was observed in response to ixabepilone (6 mg/m 2 or 8 mg/m 2 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;

9 Rivera, Lee, Davies 1215 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/m 2 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/m 2 for 5 days [57, 59]. Peripheral sensory neuropathy (all grades) occurred in 52% of taxanenaïve 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 H 1 and an H 2 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 singleagent 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 2.5 the upper limit of normal (ULN), or bilirubin 1.0 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/m 2 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/m 2 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/m 2 as a 3-hour infusion q3w (arm A) with 6 mg/m 2 as a 1-hour infusion daily for five consecutive days (arm B) in patients

10 1216 Activity of Ixabepilone in Solid Tumors Table 5. Selected registered phase II/III patupilone (EPO906) trials Study Outcome/outcome measures Completed studies Phase II: Hsin et al. (2006) [83] Advanced local or metastatic gastric cancer PR, 9%; SD, 27% EP0906, 2.5 mg/m 2 i.v. over 5 7 minutes weekly 3 wks, then 1 wk off; n 22 Phase II: Venook et al. (2007) [84] Advanced unresectable and/or metastatic hepatocellular carcinoma EPO906 monotherapy, 10 mg/m 2 i.v. over 20 minutes q3w; n 25 enrolled, 24 evaluable; study terminated Phase II: Chi et al. (2008) [85] Metastatic HRPC progressing within 6 mos after docetaxel therapy EPO906A, 8 10 mg/m 2 q3w; n 33 enrolled, 19 evaluable Phase IIa: Hussain et al. (2004) [86] HRPC with documented metastases or PSA progression 20 ng/ml EPO906A (2.5 mg/m 2 ) over 15 minutes weekly q3w, then 1 wk off; n 37 Phase II: Smit et al. (2005) [87] Advanced ovarian carcinoma that failed to respond or relapsed within 6 mos of first-line platinum therapy EPO906A ( mg/m 2 ) over minutes weekly q3w; n 31, 29 evaluable Phase II: Thompson et al. (2003) [88] Advanced renal cancer RR, 4%; SD, 46% EP0906 (2.5 mg/m 2 ) over 5 minutes weekly q3w; n 53, 52 evaluable Grade 3 4 AEs: diarrhea, 18%; nausea, 9%; vomiting, 18%; fatigue, 5%; dehydration, 5%; gastric outlet obstruction, 5% PR, 4%; SD, 44%; median PFS, 3 mos Grade 3 4 AEs: diarrhea, 16%; electrolyte imbalances, 20%; DVT, 4%; abdominal pain, 4%; cardiac arrest, 4%; GI hemorrhage, 4% PSA response, 42%; measurable disease response, 88% SD (7 patients) Grade 3 4 AEs (8 mg/m 2 dose): diarrhea, 15%; fatigue, 8%; abdominal pain, 8% PSA response, 22%; measurable disease response, 20% PR (20 patients) Grade 3 4 AEs: diarrhea, 19%; fatigue, 14%; dehydration, 8%; abdominal pain, 5%; vomiting, 5% RR, 10.5% (19 patients); CA-125 response, 29% PR (24 patients) Grade 3 4 AEs: diarrhea, 17%; fatigue/malaise, 14%; vomiting, 7%; neuropathy/paresthesia (3%) Grade 3 4 AEs: diarrhea, 8%; asthenia, 4%; anemia, 4%; septic shock, 2% Phase I/II: Sanchez et al. (2006) [89] Stage IIIB/IV NSCLC RR (phase I), 10%; SD (phase I), 32% EP0906 (10 mg/m 2 ) over 20 minutes weekly q3w, Grade 3 4 AEs (phase I): diarrhea, 14%; asthenia, 2% then 1 wk off; n 53 Phase II: Poplin et al. (2003) [90] Advanced colorectal cancer RR (2.5 mg/m 2 ), 2%; SD (2.5 mg/m 2 ), 13%; RR (6 mg/m 2 ), 7%; SD (6 mg/m 2 ), 2% EP0906, 2.5 mg/m 2 weekly q3w, then 1 wk off, or 6 mg/m 2 q3w; n 96 Grade 3 4 AEs (combined trials): diarrhea, 29%; dehydration, 8%; nausea, 5%; vomiting, 5%; thrombocytopenia, 1% Phase II: Abrey et al. (2008) [91] NSCLC patients with brain metastases and disease RR, 32% (25 patients); SD, 28% (25 patients) progression after chemotherapy EP0906, 10 mg/m 2 over 20 minutes weekly; n 27 Grade 3 4 AEs: diarrhea, 22%; colitis, 3% Phase II: Conlin et al. (2008) [92] MBC patients with brain metastases with disease RR, 6%; SD, 12%; PFS (3-mo, CNS), 8% progression after whole-brain radiation therapy EP0906, 10 mg/m 2 over 20 minutes weekly; n 17 Grade 3 4 AEs: diarrhea, 12% (continued)

11 Rivera, Lee, Davies 1217 Table 5. (Continued) Study Studies recruiting Phase III [93] Taxane/platinum-refractory ovarian, fallopian, peritoneal cancer EPO906 versus pegylated liposomal doxorubicin; n 810 Study results pending Phase I/II [94] Recurrent or progressive glioblastoma EPO906; accrual, not reported Phase II [95] Prostate cancer that has progressed after hormone treatment and docetaxel chemotherapy EPO906; accrual, 73 Phase II [96] Metastatic HRPC EPO906; accrual, 150 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 Three other epothilones patupilone, ZK-EPO, and KOS 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. Outcome/outcome measures ORR, OS, TTP, PFS 2-year PFS PSA response, ORR, DOR, time to PSA progression, TTF PSA response, tumor response Abbreviations: AE, adverse event; CA-125, cancer antigen 125; CNS, central nervous system; DOR, duration of response; DVT, deep venous thrombosis; GI, gastrointestinal; HRPC, hormone-refractory prostate cancer; MDR, median duration of response; NSCLC, non-small cell lung cancer; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; PR, partial response; PSA, prostate-specific antigen; q3w, every 3 weeks; RR, response rate; SD, stable disease; TTF, time to treatment failure; TTP, time to progression. Available at accessed September 23, Patupilone Patupilone is being evaluated in a variety of solid tumors, including gastric and hepatocellular cancers (Table 5). In a phase II trial, patients with advanced gastric cancer received a weekly 5- to 7-minute infusion of patupilone (2.5 mg/m 2 ) 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/m 2 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. Patupilone has also been demonstrated to have activity (PSA decline) in patients with HRPC (Table 5) [85, 86]. Responses have also been reported in advanced ovarian cancer, advanced renal cancer, NSCLC, and advanced colorectal cancer (Table 5) [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 5) [91, 92]. Ongoing trials are evaluating patupilone in platinumrefractory ovarian, fallopian, and peritoneal cancers [93], glioblastoma [94], and prostate cancer [95, 96] (Table 5).

12 1218 Activity of Ixabepilone in Solid Tumors Table 6. Selected registered phase II ZK-EPO (ZK , sagopilone) trials Study Outcome/outcome measures Completed studies Randomized phase II: Rustin et al. (2007) [97] Recurrent ovarian cancer progressing within 6 mos of platinum chemotherapy ZK (16 mg/m 2 ) 3-hour infusion versus 30-minute infusion q3w; n 63, 30 evaluable RR (3-hour arm), 31% (13 patients); RR (30-minute arm), 8% (13 patients) Grade 1 AEs: sensory neuropathy (3-hour arm), 60%; sensory neuropathy (30-minute arm), 33%; fatigue, 10%; arthralgia, 10%; nausea, 10%; lethargy, 7% Randomized phase II: Silvani et al. (2008) [98] Pretreated (2 lines of therapy) or recurrent ( 3 lines of SD ( 6 wks), 60%; PFS ( 6 mos), 33% therapy) glioma ZK (16 mg/m 2 ) 3-hour infusion q3w; n 15 Grade 3 4 AEs: sensory neuropathy, 27%; neutropenia, 7% Randomized phase II: Stupp et al. (2008) [99] Recurrent glioblastoma SD, 36%; PFS ( 6 mos), 6% ZK (16 mg/m 2 ) 3-hour infusion q3w; n 36 Grade 3 4 AEs: neutropenia, 8%; leukopenia, 6%; fatigue, 6%; neuropathy, 3% Randomized phase II: Wenk et al. (2008) [100] Metastatic melanoma (stage III or IV) with 2 prior RR, 10%; SD, 20% chemotherapy regimens ZK (16 mg/m 2 ) 3-hour infusion q3w; n 20 Grade 3 4 AEs: hypotension, 5%; pneumonia, 5% Phase II: Graff et al. (2008) [101] ZK prednisone as first-line therapy in metastatic androgen-independent prostate cancer ZK (16 mg/m 2 ) 3-hour infusion q3w plus prednisone 5 mg orally twice daily; n 29 Studies recruiting Phase I/II [105] ZK carboplatin in platinum-sensitive recurrent ovarian cancer; accrual, not reported Phase II [103] MBC progressing following previous therapy with anthracyclines and taxanes ZK (16 mg/m 2 or 22 mg/m 2 ) over 3 hours q3w; accrual, 75 Phase II [104] MBC with measurable CNS disease; at least one prior standard CNS-directed therapy for treatment of brain metastases ZK over 3 hours q3w; accrual, 37 PSA response, 21% (24 patients); measurable disease response, 50% PR (12 patients) Grade 3 4 AEs: neuropathy, 24%; fatigue, 8%; diarrhea, 4%; dizziness, 4% RR, safety, tolerability RR, safety, tolerability RR (in CNS), safety, tolerability, RR (non-cns sites), TTP, PFS Abbreviations: CNS, central nervous system; MBC, metastatic breast cancer; MDR, median duration of response; OS, overall survival; PFS, progression-free survival; PR, partial response; PSA, prostate-specific antigen; q3w, every 3 weeks; RR, response rate; SD, stable disease; TTP, time to progression. Available at accessed September 23, ZK-EPO ZK-EPO (ZK , 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/m 2 ) 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

13 Rivera, Lee, Davies 1219 Table 7. Selected registered phase I KOS-1584 trials Study Final study results pending Villalona-Calero et al. (2006) [106] KOS-1584 ( mg/m 2 ) i.v. over 3 hours q3w; advanced solid tumors Stopeck et al. (2006) [107] KOS-1584 ( mg/m 2 ) i.v. over 1 hour on days 1, 8, and 15 q4w; advanced solid tumors Stopeck et al. (2007) [108] KOS-1584 ( mg/m 2 ) i.v. over 1 hour on days 1, 8, and 15 q4w or on days 1 and 8 q3w; advanced solid tumors Study recruiting Phase II [109] Metastatic stage IIIB/IV NSCLC (prior treatment with first-line chemotherapy); accrual, 48 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]. 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 mg/m 2 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]. CONCLUSIONS 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 Outcome measures MTD, DLT, PK, PD MTD, DLT, PK, PD MTD, DLT, PK, PD RR, PFS, TTP, TTF, TTR, DOR, OS, safety, tolerability Abbreviations: DLT, dose-limiting toxicity; DOR, duration of response; MTD, maximum-tolerated dose; NSCLC, nonsmall cell lung cancer; OS, overall survival; PD, pharmacodynamics; PFS, progression-free survival; PK, pharmacokinetics; q3w, every 3 weeks; q4w, every 4 weeks; RR, response rate; TTF, time to treatment failure; TTP, time to progression; TTR, time to response. 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/m 2 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 5), 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