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Originally published as JCO Early Release 10.1200/JCO.2005.03.8844 on November 21 2005 © 2005 American Society of Clinical Oncology.
The Epothilone DilemmaErasmus University Medical Center, Rotterdam, the Netherlands Because of their potent antitumor activity, drugs targeting microtubules are among the most commonly prescribed anticancer agents. These agents fall into the following two broad categories: agents that inhibit tubulin/microtubule polymerization and agents that stabilize preformed microtubules under depolymerizing conditions (the taxanes). The broad clinical antitumor activity of taxanes has stimulated the search for mechanistically similar agents that overcome the difficulties related to formulation and administration and yet subvert the typical mechanism of cellular resistance conferred by the drug efflux by P-glycoprotein and show preserved activity in paclitaxel-resistant cells with mutations in beta-tubulin.1 The epothilones (a name derived from its molecular features; epoxide, thiazole, and ketone) have emerged as a new class of microtubule-targeting agents and were originally isolated from the broth of a fermenting soil bacteria, Sorangium cellulosum. The epothilones and taxanes have overlapping binding sites to the surface of beta-tubulin, and the microtubule polymerization–inducing mechanism of epothilones seems to be similar to that of taxanes.2 Preclinical studies indicate a relatively broad spectrum of activity for epothilones. They are generally 5 to 25 times more potent than paclitaxel in inhibiting cell growth in cultures. Epothilones and taxanes seem to differ distinctly in their drug-resistance mechanisms because the cytotoxic effects of the epothilones are preserved in multi-drug resistance–expressing cell lines and in cells harboring tubulin mutations, which demonstrate resistance to paclitaxel.2 Five epothilone analogs are currently undergoing clinical assessment; these are ixabepilone (aza-epothilone, BMS-247550), BMS-310705 (a water-soluble analog of epothilone B), patupilone (epothilone B, EPO906), epothilone D (KOS-862), and ZK-EPO. Patupilone was one of the earliest epothilones entering clinical development. It has been evaluated in phase I studies using a 5-minute bolus administration weekly, administered 6 of every 9 weeks or 3 of every 4 weeks, once every 3 weeks, or daily times five as a prolonged infusion.3-6 In this issue, Rubin et al6 describe a dose-finding study of the weekly administration of patupilone in patients with advanced solid tumors. A total of 91 patients were treated at dose levels ranging from 0.3 to 3.6 mg/m2/wk in a classic, phase I, 3 + 3 dose-escalation design. Dose-limiting toxicity consisting of grade 3 diarrhea was observed at both of the dose levels of 3.6 and 3.0 mg/m2 in the 6 weeks on and 3 weeks off dosing schedule. Therefore, the recommended dose for this schedule was set at 2.5 mg/m2/wk. Because the drug-related diarrhea often peaked in severity during the fourth week of treatment, an alternative schedule (3 weeks on and 1 week off) was also studied, resulting in the same recommended dose per administration (2.5 mg/m2/wk). The most common non–dose-limiting toxicities included nausea, vomiting, and fatigue. Importantly and in contrast to the results with taxanes, only one patient developed alopecia, and there was no neurologic toxicity. As with weekly taxane schedules, hematologic toxicity was limited. The pharmacokinetic data revealed that drug clearance was nonrenal and not related to body-surface area (BSA). Over the dose range studied, systemic drug exposure was dose proportional. There were three partial responses, two of which occurred in patients previously treated with taxanes, and 42% of the patients experienced disease stabilization for a median duration of 16.3 weeks. Given the absence of data on tumor growth rate before study entry, the latter data are obviously difficult to interpret. As stated, the side effects observed with weekly administration of patupilone are strikingly different from those associated with weekly administration of taxanes. Yet, it is important to note there are also major differences in adverse effect profiles between the various epothilones presently in clinical development. Ixabepilone (BMS-247550) is formulated in polyoxyethylated castor oil. Not unexpectedly, during phase I studies, hypersensitivity reactions were seen necessitating prophylactic administration of oral histamine-1 and histamine-2 blockers. Both the once every 21 days schedule and the weekly schedule resulted in dose-limiting neutropenia and sensory neuropathy.7,8 Early sensory neuropathic changes were already detectable after two cycles of treatment. During the early phase II studies using the schedule of every 3 weeks, grade 3 or 4 neuropathy occurred in up to 26% of the patients, whereas 51% of patients developed grade 1 and 2 neuropathy.9-11 Neuropathy seems to be schedule dependent and might, in part, be related to the formulation in polyoxyethylated castor oil.12 Shifting drug administration of ixabepilone to either a daily times three or daily times five schedule circumvented occurrence of severe neuropathy but resulted in 11% of the patients experiencing severe diarrhea.13,14 So the shift in schedule created a shift in side effects. For KOS-862, neurologic toxicities were dose limiting regardless of schedule (weekly, every 3 weeks, or daily times three).15,16 Other major side effects included fatigue and nausea and vomiting. The published data on toxicity for the other epothilones in clinical development are currently less mature. BMS-310705, a water-soluble compound, was administered as a 15-minute infusion every 3 weeks or weekly for 3 consecutive weeks out of every 4 weeks.17,18 Because BMS-310705 is water soluble, premedication was not required, and hypersensitivity reactions have not been observed. As for ixabepilone (BMS-247550), neuropathy was dose limiting in the every 3 weeks schedule, and diarrhea was dose limiting for the weekly schedule. However, after several cycles, cumulative neurotoxicity was observed in the majority of the patients, limiting the potential for fruitful development. Also, for ZK-EPO, dose-limiting toxicity was neurologic, consisting of both sensory neuropathy and ataxia.19 Despite the fact that their structural difference involves only a single atom, patupilone seems to have a different toxicity profile compared with ixabepilone, constituting diarrhea and fatigue. This difference might be caused by differences in tissue distribution and formulation. The shift in adverse effect profile with changing schedules of ixabepilone, resulting in more mimicking of the patupilone profile, is interesting. Importantly, the toxicity profiles for these agents will have a restricting impact on the ability to combine them with existing chemotherapy regimens. In the phase I study of Rubin et al6 on patupilone reported in this issue, there was no correlation between the blood clearance of the drug and the BSA. Nevertheless, the dose recommended by the authors was normalized per BSA and was not a flat dose. Although the rationale for using BSA to determine the individualized dose of antineoplastic agents is to limit variations in exposure between individuals, many studies have shown BSA to be a poor predictor of drug exposure, and for most anticancer agents, BSA-based dosing does not result in reducing the interpatient variability in drug clearance.20 In the latter scenario, also applicable to patupilone, the pharmacokinetics do not support the use of BSA in dose calculations, and flat dosing should be incorporated while studying alternative dosing strategies. Rubin et al6 suggest that patupilone might be active in several tumor types. Indeed, early phase II data suggest that both patupilone and ixabepilone show antitumor activity and may induce some responses in patients with taxane-refractory disease.21-24 Disappointingly, however, clinical activity has been limited to taxane-sensitive tumor types (prostate cancer and breast cancer) and does not seem to be distinctly different to the activity of taxanes, albeit that a head-to-head comparison has not been performed yet.10,25 Activity was not seen in taxane-insensitive tumor types, such as colorectal cancer, melanoma, renal cancer, and others.9,11,26-29 This activity profile, balanced against their difficult adverse effect profile, creates concern about the potential of further development of the epothilones. The fact that clinical development up to now has taken as long as it has for this class also casts some doubt on their applicability. Epothilones should certainly not be considered as alternative taxanes, but whether epothilones are here to stay or will fade away has yet to be determined. Authors' Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest. REFERENCES
1. Goodin S, Kane MP, Ruben MH: Epothilones: Mechanism of action and biologic activity. J Clin Oncol 22:2015-2025, 2004 2. Mani S, Macapinlac M Jr, Goel S, et al: The clinical development of new mitotic inhibitors that stabilize the microtubule. Anticancer Drugs 15:553-558, 2004[CrossRef][Medline] 3. Østerlind K, Sánchez JM, Zatloukal P, et al: Phase I/II dose escalation trial of patupilone every 3 weeks in patients with non-small cell lung cancer. J Clin Oncol 23:647, 2005 (abstr 7110, suppl) 4. Melichar B, Tabernero J, Casado E, et al: Phase I dose optimization trial of patupilone in previously treated patients (pts) with advanced colon cancer (ACC). J Clin Oncol 23:292, 2005 (abstr 3688, suppl) 5. Smit WM, Sufliarsky J, Spanik S, et al: Phase I/II dose-escalation trial of patupilone every 3 weeks in patients with relapsed/refractory ovarian cancer. J Clin Oncol 23:468, 2005 (abstr 5056, suppl) 6. Rubin EH, Rothermel J, Tesfaye F, et al: Phase I, dose-finding study of weekly single-agent patupilone in patients with advanced solid tumors. J Clin Oncol 23:9120-9129, 2005 7. Mani S, McDaid H, Hamilton A, et al: Phase I clinical and pharmacokinetic study of BMS-247550, a novel derivative of epothilone B, in solid tumors. Clin Cancer Res 10:1289-1298, 2004 8. Hao D, Hammond LA, deBono JS, et al: Continuous weekly administration of the epothilone-B derivative, BMS247550 (NSC710428): A phase I and pharmacokinetic (PK) study. Proc Am Soc Clin Oncol 21:103a, 2002 (abstr 411) 9. Eng C, Kindler HL, Nattam S, et al: A phase II trial of the epothilone B analog, BMS-247550, in patients with previously treated advanced colorectal cancer. Ann Oncol 15:928-932, 2004 10. Galsky MD, Small EJ, Oh WK, et al: Multi-institutional randomized phase II trial of the epothilone B analog ixabepilone (BMS-247550) with or without estramustine phosphate in patients with progressive castrate metastatic prostate cancer. J Clin Oncol 23:1439-1446, 2005 11. Okuno S, Maples WJ, Mahoney MR, et al: Evaluation of epothilone B analog in advanced soft tissue sarcoma: A phase II study of the phase II consortium. J Clin Oncol 23:3069-3073, 2005 12. ten Tije AJ, Verweij J, Loos W, et al: Pharmacological effects of formulation vehicles: Implications for cancer chemotherapy. Clin Pharmacokinet 42:665-685, 2003[CrossRef][Medline] 13. Abraham J, Agrawal M, Bakke S, et al: Phase I trial and pharmacokinetic study of BMS-247550, an epothilone B analog, administered intravenously on a daily schedule for five days. J Clin Oncol 21:1866-1873, 2003 14. Zhuang SH, Agrawal M, Edgerly M, et al: A phase I clinical trial of ixabepilone (BMS-247550), an epothilone B analog, administered intravenously on a daily schedule for 3 days. Cancer 103:1932-1938, 2005[CrossRef][Medline] 15. Yee L, Lynch T, Villalona-Calero M, et al: A phase II study of KOS-862 (epothilone D) as second-line therapy in non-small cell lung cancer. J Clin Oncol 23:652, 2005 (abstr 7127, suppl) 16. Piro LD, Rosen LS, Parson M, et al: KOS-862 (epothilone D): A comparison of two schedules in patients with advanced malignancies. Proc Am Soc Clin Oncol 22:135, 2003 (abstr 539) 17. Mekhail T, Chung C, Holden S, et al: Phase I trial of novel epothilone B analog BMS-310705 IV q 21 days. Proc Am Soc Clin Oncol 22:129, 2003 (abstr 515) 18. Sessa C, Perotti A, Malossi A, et al: Phase I and pharmacokinetic (PK) study of the novel epothilone BMS-310705 in patients (pts) with advanced solid cancer. Proc Am Soc Clin Oncol 22:130, 2003 (abstr 519) 19. Schmid P, Kiewe P, Kuehnhardt D, et al: A phase I study of the novel, third generation epothilone ZK-EPO in patients with advanced solid tumors. J Clin Oncol 23:147, 2005 (abstr 2051, suppl) 20. Baker SD, Verweij J, Rowinsky EK, et al: Role of body surface area in dosing of investigational anticancer agents in adults, 1991-2001. J Natl Cancer Inst 94:1883-1888, 2002 21. Hussain A, Dipaola RS, Baron AD, et al: A phase IIa trial of weekly EPO906 in patients with hormone-refractory prostate cancer (HPRC). J Clin Oncol 22:397s, 2004 (abstr 4563, suppl) 22. Low JA, Wedam SB, Lee JJ, et al: Phase II clinical trial of ixabepilone (BMS-247550), an epothilone B analog, in metastatic and locally advanced breast cancer. J Clin Oncol 23:2726-2734, 2005 23. Ajani JA, Shah MA, Bokemeyer C, et al: Phase II study of the novel epothilone BMS-247550 in patients (pts) with metastatic gastric adenocarcinoma previously treated with a taxane. Proc Am Soc Clin Oncol 21:155a, 2002 (abstr 619) 24. Vansteenkiste JF, Breton JL, Sandler A, et al: A randomized phase II study of epothilone analog BMS-247550 in patients (pts) with non-small cell lung cancer (NSCLC) who have failed first-line platinum-based chemotherapy. Proc Am Soc Clin Oncol 22:626, 2003 (abstr 2519) 25. Roche HH, Cure H, Bunnell C, et al: A phase II study of epothilone analog BMS-247550 in patients (pts) with metastatic breast cancer (MBC) previously treated with an anthracycline. Proc Am Soc Clin Oncol 22:18, 2003 (abstr 69) 26. Poplin E, Moore M, O'Dwyer P, et al: Safety and efficacy of EPO906 in patients with advanced colorectal cancer: A review of 2 phase II trials. Proc Am Soc Clin Oncol 22:283, 2003 (abstr 1135) 27. Thompson JA, Swerdloff J, Escudier B, et al: Phase II trial evaluating the safety and efficacy of EPO906 in patients with advanced renal cancer. Proc Am Soc Clin Oncol 22:405, 2003 (abstr 1628) 28. Zhuang SH, Menefee M, Kotz H, et al: A phase II clinical trial of BMS-247550 (ixabepilone), a microtubule-stabilizing agent in renal cell cancer. J Clin Oncol 22:394a, 2004 (abstr 4550, suppl) 29. Pavlick AC, Millward M, Farrel K, et al: A phase II study of epothilone B analog (EpoB)-BMS 2477550 (NSC#710428) in stage IV malignant melanoma (MM). J Clin Oncol 22:720s, 2004 (abstr 7542, suppl)
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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