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Journal of Clinical Oncology, Vol 22, No 10 (May 15), 2004: pp. 2015-2025 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.12.001
Epothilones: Mechanism of Action and Biologic ActivityFrom the Department of Medicine, Department of Pharmacology, University of Medicine and Dentistry of New Jersey/Robert Wood Johnson Medical School; and The Cancer Institute of New Jersey, New Brunswick, NJ. Address reprint requests to Eric H. Rubin, MD, The Cancer Institute of New Jersey, 195 Little Albany St, New Brunswick, NJ 08901; e-mail: ehrubin{at}umdnj.edu
Drugs that target microtubules are among the most commonly prescribed anticancer therapies. Although the mechanisms by which perturbation of microtubule function leads to selective death of cancer cells remain unclear, several new microtubule-targeting compounds are undergoing clinical testing. In part, these efforts focus on overcoming some of the problems associated with taxane-based therapies, including formulation and administration difficulties and susceptibility to resistance conferred by P-glycoprotein. Epothilones have emerged from these efforts as a promising new class of anticancer drugs. Preclinical studies indicate that epothilones bind to and stabilize microtubules in a manner similar but not identical to that of paclitaxel and that epothilones are effective in paclitaxel-resistant tumor models. Clinical phase I and early phase II data are available for BMS-247550, BMS-310705, EPO906, and KOS-862. The results suggest that these compounds have a broad range of antitumor activity at doses and schedules associated with tolerable side effects.
Drugs that target microtubules are among the most commonly prescribed anticancer therapies. Paclitaxel (Taxol; Bristol-Myers Squibb, New York, NY; and Onxol; IVAX, Miami, FL) accounted for more than $300 million in total acquisitions costs to hospitals in 2001, and docetaxel (Taxotere; Aventis, Bridgewater, NJ), not yet available as a generic, accounted for more than $151 million.1 The broad-spectrum anticancer activity of the taxanes is striking and has engendered considerable interest in identifying mechanistically similar but structurally distinct compounds. In part, these efforts have focused on overcoming some of the problems associated with taxane-based therapy, including difficulties with formulation and administration and susceptibility to resistance conferred by the drug efflux protein P-glycoprotein. Epothilones have emerged from these efforts as a new class of microtubule-targeting drugs (Fig 1). These macrolides were initially discovered as cytotoxic metabolites from the myxobacterium Sorangium cellulosum.2 Subsequently, they were identified as microtubule-stabilizing drugs that competitively inhibit binding of paclitaxel to microtubules in vitro.3 Preclinical studies indicate a relatively broad spectrum of action for epothilones, including activity in paclitaxel-resistant models. Furthermore, promising antitumor activity has been observed in initial clinical trials with several epothilone analogs.
There is substantial evidence that some of the most active anticancer drugs, such as the taxanes and vinca alkaloids, function by perturbing the dynamic equilibrium of microtubule polymerization and depolymerization.4 Formation of microtubules involves polymerization of heterodimeric  /ß-tubulin subunits with multiple isoforms of both - and ß-tubulin present in human cells. Polymerization of the heterodimeric subunits involves hydrolysis of guanosine 5'-triphosphate and is regulated by several microtubule-associated proteins.5 Intact microtubule function is required for formation and functioning of the mitotic spindle, and cells treated with agents that bind either tubulin subunits or polymerized microtubules exhibit alterations in spindle formation, as well as arrest at the G2/M phase of the cell cycle, which is associated with induction of apoptosis.6-8 Compounds that target microtubules are potent cytotoxic agents, exemplified by the convergent evolution of microtubule-targeting compounds by a variety of plant and marine species. Although the taxanes and vinca alkaloids are broadly active anticancer drugs, the mechanisms underlying the selectivity of these compounds towards cancer versus normal cells are poorly understood, and not all compounds that affect microtubule function are useful as anticancer drugs (eg, colchicine). Furthermore, recent data suggest that at least part of the anticancer activity exhibited by this class of drugs involves antiangiogenic effects on tumor-associated endothelial cells.9,10 In addition, certain genetic alterations in cancer cells may confer hypersensitivity to microtubule-targeting agents, thereby explaining their therapeutic efficacy. For example, loss of p53 function, which is common in many types of cancer, may confer hypersensitivity to taxanes as a result of altered expression of genes that are regulated by p53.8 Indeed, loss of p53 function results in upregulation of the microtubule-associated protein 4 (MAP-4), which enhances microtubule polymerization and results in increased intracellular concentrations of taxanes in cells lacking functional p53.11,12 The usefulness of the vincas and taxanes in the treatment of many malignancies stimulated screens and development of additional microtubule-targeting compounds. Included among these are the epothilones, discodermolide,13 eleutherobins14 dolastatins,15 cryptophycins,16 indanocine,17 halicondrin B,18 and peloruside A.19
Epothilones Target Microtubules In Vitro and in Cells Although epothilones were originally described as natural product fungicidal macrolides,2 interest significantly increased when these compounds were identified in an in vitro screen for agents that induced microtubule polymerization at submicromolar concentrations.3 These studies indicate that similar to taxanes, epothilones induce microtubule bundling, formation of multipolar spindles, and mitotic arrest.3,20 Given the frequent use of macrolides in the treatment of bacterial infection, it is important to note that not all macrolides induce microtubule polymerization at these concentrations, given that erythromycin was inactive in the assay that identified epotholines.3 A variety of epothilone analogs have been synthesized in efforts to improve antitumor efficacy relative to both paclitaxel and the originally identified natural products epothilone A and B (Fig 1).
The mechanism by which epothilones induce microtubule polymerization appears to be similar to that of paclitaxel, in that epothilones compete with paclitaxel for binding to microtubules and suppress microtubule dynamics in a manner similar to that of paclitaxel.3,13,21 This conjecture is supported by the finding that cell lines selected for resistance to epothilones contain mutations in ß-tubulin that map near the taxane-binding site identified in a crystal structure of a docetaxel- Existing structure-activity data provide some insight into the interaction between epothilones and microtubules. Results from several groups indicate that modifications at or near the C12–13 epoxide can affect microtubule-stabilizing activity.26 For example, addition of a methyl group to epothilone A at position C12 yields epothilone B, which is approximately twice as potent as epothilone A or paclitaxel in inducing tubulin polymerization in vitro.13,27 In addition, it is clear that an epoxide at C12–13 is not required for microtubule-binding, because desoxyepothilone B (also known as epothilone D or KOS-862) lacks the C12–13 epoxide and is a more potent microtubule stabilizer in vitro than epothilone A or B.27 Less data are available regarding the effects of modifying other regions of epothilone. Despite attempts to improve microtubule binding by altering the C9–C12 region (on the basis of molecular modeling), alterations in this area resulted in loss of cytotoxic activity.26 By contrast, replacement of the lactone oxygen of epothilone B with a lactam (aza-epothilone B, also known as BMS-247550) does not impair microtubule-polymerizing activity or cytotoxicity.20 Although a variety of other epothilone analogs have been synthesized, it should be noted that increasing microtubule-stabilizing activity does not always result in increased cytotoxicity, presumably because of the importance of other variables such as cellular accumulation and metabolic stability.26 Indeed, replacement of the methyl group at C12 position of desoxyepothilone B with a propanol group results in a compound that is as effective as desoxyepothilone B against the leukemic cell line CCRF-CEM but is significantly less active against a P-glycoprotein-overexpressing subline (IC50 of 17 nmol/L for desoxyepothilone B v 167 nmol/L for the propanol derivative).28 Additional modifications of naturally occurring epothilones have been made in an effort to improve solubility, such as BMS-310705, which is a C-21-substituted derivative of epothilone B.29
Preclinical Antitumor Activity of Epothilones
Preclinical studies also demonstrated important differences with regard to drug resistance mechanisms between epothilones and taxanes. In particular, overexpression of P-glycoprotein minimally affects the cytotoxicity of epothilone B, aza-epothilone B, and desoxyepothilones in cell culture models (Table 1).3,20,26,28 Not surprisingly and as indicated earlier, certain epothilone structural modifications appear to influence susceptibility to P-glycoprotein-mediated resistance. Comparison of the cytotoxic effects of epothilone B, aza-epothilone B, and desoxyepothilone B among P-glycoprotein-overexpressing cell lines suggests that desoxyepothilone B is least affected, whereas aza-epothilone B is most affected by P-glycoprotein expression (Table 1).20,26,31 However, it should be noted that differences among the IC50s of these compounds in P-glycoprotein–overexpressing cell lines are small compared with the differences between these values and IC50s for paclitaxel in these cell lines. Although the significance of P-glycoprotein expression in clinical resistance to taxanes remains uncertain, these results suggest that epothilones may be more active than taxanes in patients with malignancies characterized by high levels of P-glycoprotein expression. In vivo studies indicate that epothilones are active in paclitaxel-sensitive and -resistant tumor models using a variety of schedules. When administered intravenously (using an ethanol:Cremophor formulation) to mice using intermittent daily or weekly schedules, aza-epothilone B is highly active in ovarian, colon, and breast xenografts and induces cures in an ovarian xenograft model (Pat-7) that is resistant to paclitaxel.20 Notably, unlike paclitaxel, aza-epothilone B is effective when administered orally in preclinical models.20 This phenomenon likely relates to the expression of P-glycoprotein in intestinal mucosa,32 resulting in poor absorption of paclitaxel but not epothilones. Similarly, when administered intravenously using a weekly schedule (using a PEG300/water formulation), epothilone B produces either growth inhibition or tumor regression in lung, breast, colon, and prostate xenografts.33 Sustained regressions were observed in a P-gp–overexpressing, paclitaxel-resistant KB-8511 xenograft model.33 The weekly dosing regimen was associated with approximately 10% to 20% weight loss and some deaths, indicating that this schedule is associated with a relatively narrow therapeutic window in these xenograft models. Similar results were reported in studies of epothilone B administered intraperitoneally (every 2 days) in an MX-1 breast cancer xenograft model, in which this compound produced significant toxicity and less antitumor activity relative to desoxyepothilone B.28 When administered every 2 days via intaperitoneal or intravenous (IV) dosing, desoxyepothilone B is very active against certain multidrug resistant xenografts, including a doxorubicin-resistant MCF-7 breast cancer xenograft and a vinblastine-resistant CCRF-CEM leukemic cell xenograft.28,31 IV dosing of the drug involved administration over the course of 6 hours, using an ethanol:Cremophor formulation.31 More rapid IV administration of desoxyepothilone B (eg, over 1 or 30 minutes) using this formulation was associated with toxic deaths.28 Desoxyepothilone B treatment was associated with cures in mice harboring paclitaxel-resistant CCRF-CEM xenografts.28 Similarly, in studies using MX-1 breast carcinoma xenografts (which are not resistant to paclitaxel), administration of 30 mg/kg desoxyepothilone B intravenously over 6 hours every 2 days (for six doses) was associated with minimal toxicity and cures. By contrast, administration of 6 mg/kg of aza-epothilone B using the same schedule did not produce cures and was associated with some toxicity.31 Nevertheless, these results should be interpreted with caution, since the plasma half-lives of these compounds in mice are quite different (see next section), and it is not clear that this schedule is optimal for aza-epothilone B. Epothilones and taxanes also differ in terms of resistance conferred by specific point mutations in ß-tubulin. Epothilone cytotoxicity is unaffected by an alanine to threonine substitution at residue 364 in ß-tubulin that confers resistance to paclitaxel.13,34 Thus, it is possible that cells containing a mutant ß-tubulin that confers resistance to taxanes will remain sensitive to epothilones. However, resistance to epothilones may also result from ß-tubulin mutations. For example, mutation of threonine to isoleucine at residue 274 and arginine to glutamine at residue 282 in a ß-tubulin isotype were found in ovarian cell lines selected for resistance to epothilones.24 Notably, these cells are cross-resistant to paclitaxel.24 Similarly, cells selected for resistance to desoxyepothilone B were found to harbor an alanine-to-threonine mutation in ß-tubulin at residue 231 and to be cross-resistant to paclitaxel.35 Although ß-tubulin mutations may cause resistance to taxanes in cell culture models, the significance of these mutations in clinical drug resistance is not clear. Although mutations in ß-tubulin isotypes were reported in clinical specimens,36 these amino acid changes are present in a ß-tubulin pseudogene.37,38 Pseudogenes represent inactive copies of true genes and are believed to originate by gene duplication and mutation.39 Thus, there is concern that the previously described ß-tubulin "mutations" are an artifact related to polymerase chain reaction–based amplification of pseudogene sequences. Consequently, the significance of the activity of epothilones in paclitaxel-resistant cell lines with mutant ß-tubulin is uncertain.
Preclinical Pharmacology
Four epothilone analogs are currently in clinical trials, including aza-epothilone B (BMS-247550), a water-soluble semi-synthetic analog of epothilone B (BMS-310705), epothilone B (EPO906), and epothilone D (KOS-862). Results of early clinical trials of these agents are available as abstracts and recent publications. These preliminary results are discussed below and are summarized in comparison with taxane schedules and toxicities in Table 2.
BMS-247550 (aza-epothilone B) Phase I trials. The phase I evaluation of BMS-247550 included a number of different schedules using a Cremophor–based formulation: an every 21-day schedule, a weekly schedule, a daily-times-five every 21-days schedule, and a daily times three schedule given every 21 days. Antitumor responses were observed in all of the phase I trials, including responses in patients with melanoma, ovarian, non–small-cell lung, and breast cancers. Many of these patients had previously been treated with paclitaxel or docetaxel. In several trials, BMS-247550 was administered intravenously over 60 minutes every 21 days.41-43 A hypersensitivity reaction (HSR) was observed in one patient who received 30 mg/m2, resulting in prophylaxis with oral histamine-1 (H1) and histamine-2 (H2) blockers in subsequent patients.41 Dose-limiting toxicities (DLTs) included neutropenia and sensory neuropathy using this schedule, with a recommended phase II dose of 50 mg/m2 in one of the trials41 and 40 mg/m2 in another.44 Early sensory neuropathic changes (increased vibration sensation) were evident after two cycles of treatment in some patients.44 Other significant toxicities associated with this schedule included fatigue, usually occurring within the first and second week of each treatment course; arthralgias; myalgias; and emesis. Weekly infusions of BMS-247550 administered in Cremophor over 30 minutes or 60 minutes were also evaluated.45-47 With the 30-minute infusion schedule, HSRs were observed and resulted in administration of prophylactic H1 and H2 blockers at doses greater than 10 mg/m2.45 DLTs observed with the weekly infusion schedule included neutropenia, sensory neuropathy, and fatigue, and an MTD of 25 mg/m2 was proposed for weekly 30-minute infusions.47 In one trial, the schedule was amended to a 1-hour infusion given weekly for 3 weeks, followed by a 1-week break. This schedule was associated with similar toxicities as the 30-minute infusion but allowed continuation of therapy for greater than 4 months in several patients.47 With regard to the daily-times-five every-21-days schedule, 27 patients were enrolled onto a phase I trial involving 1-hour infusions of BMS-247550, which employed an accelerated dose-escalation design.48 All but six patients had received taxane therapy previously. Neutropenia was dose-limiting, and the MTD was 6 mg/m2/d. Notably, unlike the every-3-week and weekly schedules, grade 3 neurotoxicity was not observed in this trial. However, seven patients experienced grade 2 neurotoxicity, characterized by distal extremity pain and myalgias during the days of treatment. There were four episodes of grade 2 diarrhea and no HSRs. Partial responses were observed in five patients, including two patients with breast cancer, two patients with cervical cancer, and one patient with basal cell carcinoma. The responding patients with breast and cervical cancer had received taxanes previously. These promising results led to modification of ongoing phase II trials to employ this schedule (see next section). Based on the results of the daily-times-five every-21-days schedule, a daily-times-three every-21-days schedule was evaluated.49 As with the previous phase I trials, patients were heavily pretreated, and the majority had received prior taxane therapy. Neutropenia was the dose-limiting toxicity, and the recommended phase II dose on this schedule was 8 mg/m2/d. No grade 3 or 4 neurotoxicity was observed during this trial. There are also ongoing phase I evaluations of BMS-247550 in combination with other cytotoxic agents, including carboplatin,50 as well as estramustine in prostate cancer patients.51 Significant neurotoxicity, related to the dose level and infusion rate, was observed in the trial involving the combination of estramustine and BMS-247550. This toxicity occurred after a median of five cycles and appeared more severe with shorter infusions. Nevertheless, a significant decrease (> 50%) in prostate specific antigen was reported in 11 of 12 assessable patients in this trial.51 The recommended phase II dose from this trial is 35 mg/m2 BMS-247550 over 3 hours on day 2 every 3 weeks, estramustine 280 mg three times a day, days 1–5, and warfarin 2 mg daily. Phase II trials. Preliminary results are available for several phase II trials evaluating administration of 50 mg/m2 of BMS-247550 over 1 hour every 21 days in patients with previously treated malignancies. Patients received a premedication regimen involving oral H1 and H2 antihistamines to prevent Cremophor-mediated HSRs. In patients with metastatic gastric cancer previously treated with one taxane-based chemotherapy, two partial responses (9%) among 23 assessable patients were observed while stable disease was reported in 52% (12 of 23) of patients.52 Significant (grade 3 to 4) toxicities included leukopenia (45%), neutropenia (41%), fatigue (39%), and sensory neuropathy (8%). To reduce the neurotoxic side effects, the trial was amended to 6 mg/m2 administered intravenously over 1 hour daily-times-five every 3 weeks, a schedule that was not associated with neurotoxicity in phase I trials.48 In patients with metastatic breast cancer previously treated with an anthracycline and a taxane, 49 patients were enrolled on a dose of 40 mg/m2 over 3 hours every 3 weeks. An extended infusion schedule and then a lower dose than recommended by the phase I trials were used after initial patients experienced treatment-limiting neuropathy and mucositis, respectively. There were six partial responses among 49 assessable patients and stable disease in 22 patients.53 Grade 3 and 4 neutropenia occurred in 40% and 20% of patients, respectively, and febrile neutropenia occurred in 5% of patients. Other significant (grade 3 or 4) toxicities included fatigue, nausea and vomiting, mylagia/arthralgia, constipation, and diarrhea. Grade 3 sensory neuropathy occurred in 7% of patients treated with the lower dose and prolonged infusion, compared with a 25% rate in patients treated using the original recommended dose and schedule. In a similar trial involving patients with metastatic breast cancer previously treated with an anthracycline in either the neoadjuvant or the adjuvant setting, there were 15 partial responses among 44 assessable patients.54 The every-21-day schedule of BMS-247550 50 mg/m2 (administered over 1 hour) was also evaluated in a phase II trial in patients with metastatic non–small-cell lung cancer previously treated with one platinum-based regimen for recurrent or metastatic disease.55 Available response data for 22 assessable patients indicates an 18% partial response rate and a 45% stable disease rate for this dosing regimen. The occurrence of neurotoxicity prompted amendment to a randomized phase II trial comparing 40 mg/m2 over 3 hours every 21 days versus 6 mg/m2 administered over 1 hour daily times 5 days every 3 weeks. Because of the frequency of mucositis and neutropenia in the first 18 patients on the single-dose every-3-week schedule, the dose was reduced to 32 mg/m2. Significant (grade 3 or 4) toxicities occurred in 34% and 22% of patients, respectively, with fatigue the most common toxicity. Although grade 3 neuropathy occurred in 6% of patients receiving the daily-times-five regimen, it was not reported in patients treated with the alternate schedule. Responses were observed in both treatment groups (every-3-week schedule: seven partial responses, 14 instances of stable disease in 49 assessable patients; daily-times-five schedule: one complete response, six partial responses, and 17 instances of stable disease in 62 assessable patients). Patients with tumors of the gastrointestinal tract have also been a focus of the development of BMS-247440, with two trials evaluating 40 mg/m2 over 3 hours in this patient population. In colorectal patients with disease refractory to irinotecan/fluorouracil/leucovorin, there were no objective responses in twenty-three assessable patients, despite a significant neurotoxicity rate.56 In fifteen patients with hepatobiliary cancer treated with this schedule, there were two partial responses in 12 assessable patients, with a median survival of 5.7 months and a progression-free survival of 4.3 months.57 Significant neutropenia occurred in 53% of patients, and three patients were removed from the study because of persistent neuropathy. These preliminary phase II results are consistent with preclinical data and suggest that BMS-247550 is a broadly active anticancer drug and may produce responses in patients with taxane-resistant disease. A schedule involving daily administration for 5 days every 3 weeks is associated with less neurotoxicity than the single-dose every-21-day administration schedule, but whether these schedules differ in terms of anticancer efficacy remains to be determined. Clinical pharmacokinetics and pharmacodynamics. When administered as a 1-hour infusion at doses of 7.4 to 59.2 mg/m2, plasma areas under the concentration curve (AUCs) of BMS-247550 appear to be linear with respect to dose, with an overall mean half-life of approximately 36 hours.44 Mean volume of distribution values at steady-state ranged from 932 to 2,780 L/m2, suggesting extensive extravascular distribution.44 In one trial, myelotoxicity correlated with the AUC and Cmax of BMS-247550.43 However, in other trials involving both daily 1-hour infusions and a single dose every 3 weeks, there was no correlation between AUC and neutropenia.44,48 In addition, total body clearance of BMS-247550 did not correlate with body weight or surface area,48 suggesting that non–BSA-based dosing strategies should be explored in an effort to reduce intrapatient variability in systemic exposure. Detailed evaluation of microtubule alterations in peripheral blood mononuclear cells obtained from patients given a 1-hour infusion of BMS-246550 indicated that microtubule bundling was present in these cells in most patients 1 hour after the infusion.58 In addition, the extent of microtubule bundling correlated positively with AUC and negatively with clearance. Microtubule bundling was also observed at 1 and 24 hours after the infusion in biopsies of a chest wall tumor obtained from a patient with breast cancer.58 These important results indicate that following a 1-hour infusion, epothilones are able to accumulate in patient tissues in concentrations sufficient to affect microtubules and suggest that the extent of microtubule bundling in normal and tumor tissues may be predictive of toxicity and antitumor activity, respectively.
BMS-310705 (water-soluble epothilone B analog) Responses were documented with both schedules, including partial responses in patients with ovarian, bladder, stomach, and breast cancer, and a complete response in a patient with non–small-cell lung cancer. Clinical pharmacokinetics and pharmacodynamics. Preliminary pharmacokinetic data for BMS-310705 suggest linearity in the range of doses evaluated in these trials.59,60 Mean volume of distribution at steady-state was 443 L/m2 with an elimination half-life of 42 hours.
EPO906 (epothilone B) Preliminary results from two phase I trials evaluating the combination of EPO906 with carboplatin suggest that the combination is active and well tolerated.63 One trial evaluated escalating doses of EPO906 given weekly for three of four weeks (with weekly carboplatin administered at an AUC of 2), whereas the other trial evaluated escalating doses of EPO906 given once every 3 weeks (with carboplatin administered at an AUC of 6). In the combination study using weekly EPO906, diarrhea and paresthesias were the dose-limiting toxicities. Other toxicities included fatigue and an HSR to carboplatin. In the combination study of EPO906 administered once every 3 weeks, diarrhea was also noted, but the MTD was not reported. Partial responses to EPO906 in phase I trials were noted in patients with breast, colorectal, endometrial, and ovarian cancers, including patients who had received taxanes previously. Phase II trials. The preliminary results of several phase II trials of EPO906 were reported at the 20th Chemotherapy Foundation Symposium (http://www.mssm.edu/tcf/archives/symposiumxx/index.shtml). These trials involved administration of EPO906 intravenously over 5 minutes at a dose of 2.5 mg/m2 weekly for 3 weeks, followed by a 1-week rest period. All of these trials involved patients with previously treated and often resistant disease. In patients with advanced ovarian cancer whose disease progressed during or within 6 months of completing firstline therapy with carboplatin/paclitaxel, a partial response was observed in 12% (two of 17) of assessable patients, and 21% (five of 17 patients) experienced stable disease. A decrease in CA-125 with variable degrees of radiologic response was observed in four of the five patients with stable disease. In patients with hormone-refractory prostate cancer and progressive disease after one chemotherapy regimen, one partial response (in one of eight patients) was reported, whereas 50% of the patients (four of eight patients) experienced stable disease. An advanced breast cancer trial enrolled patients with disease progression after one prior therapy for metastatic disease or adjuvant chemotherapy containing a taxane and/or an anthracycline. Partial response was observed in 13% (two of 15) of assessable patients. Toxicity was modest in these studies, with only three grade 3 or 4 toxicities (diarrhea, constipation, nausea/vomiting) reported at the time of the symposium. Preliminary results are available for two phase II trials of EPO906 in patients with advanced colorectal cancer.64 These trials included patients with disease progression after treatment with a fluoropyrimidine and either irinotecan or oxaliplatin. Different dosing schedules were evaluated in each trial: 2.5 mg/m2 weekly for 3 weeks followed by 1 week of rest in one trial, and 6 mg/m2 once every 3 weeks in the other. A total of 96 patients were assessable for toxicity in both trials, and there were no differences in toxicity between the two dosing schedules. For both studies combined, grade 3 or 4 diarrhea were reported 26% and 3% of patients, respectively. Preliminary results demonstrate minor activity in patients with refractory colorectal cancer, regardless of schedule. Among the 47 assessable patients treated with the weekly schedule, there was one partial response and six patients with stable disease. In the 44 assessable patients treated with the every-3-week schedule, there were three partial responses and one patient with stable disease. EPO906 was evaluated in 53 patients with metastatic renal cell carcinoma in a phase II trial,65 involving weekly dosing for 3 weeks followed by 1 week off. Although there was one grade 4 event (septic shock), toxicity rates were relatively low, with grade 3 diarrhea occurring in only 8% of patients. There were two partial responses and 24 patients with stable disease, suggesting promising activity for this relatively chemoresistant tumor. These early phase II results suggest that EPO906 is a broadly active anticancer drug and is able to induce responses in at least some patients with taxane-resistant disease. Clinical pharmacokinetics and pharmacodynamics. When given as a short IV infusion at doses from 0.3 to 8 mg/m2, blood levels of EPO906 can be fit to a three-compartment model with zero-order input and first-order elimination.66 Volume of distribution in the central compartment is about 46 L, suggestive of extensive tissue distribution. This result is consistent with the finding that the EPO906 concentration in a tumor biopsy obtained 1 hour after infusion from a patient with a soft tissue sarcoma was about 10-fold higher than the blood level at this time.62 Elimination of EPO906 is prolonged in humans, with a mean terminal half-life of about 4 days with negligible renal clearance. This result indicates that the presence of a lactone at position 16 does not confer rapid metabolism of epothilones in humans, in contrast to results obtained in murine models. Systemic exposure of EPO906 correlates nearly linearly with dose.66 In phase I trials, the occurrence and severity of diarrhea correlated with dose, systemic exposure, and Cmax (Calvert et al, Rubin et al, submitted for publication).
KOS-862 (epothilone D) Clinical pharmacokinetics and pharmacodynamics. Analysis of the pharmacokinetics of KOS-862 reveal that AUC increases linearly with dose regardless of schedule of administration.67-69 The mean half-life is approximately 10 hours, with a mean volume of distribution of 78 to 121 L/m2. Evidence of increased tubulin-polymerization in peripheral blood mononuclear cells was observed 1-hour postdose.67
Although there are currently insufficient data to make conclusions regarding the usefulness of epothilones in specific cancers, early clinical results with several different epothilone analogs are promising. Administration of these compounds at tolerable doses and schedules is associated with partial or complete responses in patients with a variety of tumor types. Interestingly, despite a structural difference involving only a single atom, the epothilone EPO906 and BMS-247550 have distinct toxicity profiles, with dose-limiting toxicity involving diarrhea for EPO906, but not neurotoxicity or myelosuppression, which is dose-limiting for BMS-247550. The distinct toxicity profiles for these drugs will likely influence their combination with existing chemotherapy regimens. Although administration of BMS-247550 or EPO906 is associated with responses in patients with taxane-resistant cancers, the response rates in this setting are somewhat disappointing in light of the preclinical data for these compounds. In addition, it is not yet clear that epothilones will be clinically useful in diseases for which taxanes are not effective, such as colon cancer. However, given the utility of microtubule targeting as a strategy in the treatment of malignancy, the availability of a new and clinically active class of microtubule-targeting compounds represents an important advance.
The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Performed contract work within the last 2 years: Eric H. Rubin, Novartis, Bristol-Myers Squibb.
We thank William N. Hait, MD, PhD, for helpful discussions and for comments regarding the manuscript.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
