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© 2003 American Society for Clinical Oncology Phase I Trial and Pharmacokinetic Study of BMS-247550, an Epothilone B Analog, Administered Intravenously on a Daily Schedule for Five Days
From the Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, WV; National Cancer Institute Center for Cancer Research, Bethesda, MD; and Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ. Address reprint requests to Tito Fojo, MD, PhD, Center for Cancer Research, National Cancer Institute, Bldg 10, Rm 12N226, 9000 Rockville Pike, Bethesda, MD 20892; email: tfojo{at}helix.nih.gov.
Purpose: The epothilones are a novel class of nontaxane microtubule-stabilizing agents. BMS-247550 is a semisynthetic analog of the natural product epothilone B. We conducted a phase I study administering BMS-247550 as a 1-hour intravenous infusion daily for 5 consecutive days every 21 days. Patients and Methods: Twenty-one patients received BMS-247550 without filgrastim in the first cycle. An additional six patients were enrolled at a starting dose of 8 mg/m2/d with filgrastim support. Twenty-one of the 27 patients had received prior paclitaxel, docetaxel, or both. Results: One hundred seven cycles were administered to 27 patients. The maximum-tolerated dose was 6 mg/m2 of BMS-247550 administered as a 1-hour intravenous infusion daily for 5 consecutive days every 21 days. Dose-limiting toxicity at a dose of 8 mg/m2/d was neutropenia with or without filgrastim support. Nonhematologic grade 3 toxicities included fatigue (seven cycles), stomatitis (two cycles), and anorexia (one cycle). The mean terminal half-life of BMS-247550 was 16.8 ± 6.0 hours, the volume of distribution at steady-state was 798 ± 375 L, and the clearance was 712 ± 247 mL/min. Objective responses were observed in patients with breast, cervical, and basal cell cancer. Reductions in CA-125 levels were noted in patients with ovarian cancer. Conclusion: The recommended phase II dose of BMS-247550 on the daily schedule for 5 days is 6 mg/m2/d. Neutropenia was dose limiting, but higher doses were tolerated by a large fraction of patients with filgrastim support. Peripheral neuropathy was mild, even after multiple cycles of therapy, and was not dose limiting.
BMS-247550 (NSC 710428) is a member of the novel class of nontaxane microtubule-stabilizing compounds known as epothilones. Similar to taxanes, epothilones bind tubulin, stabilize microtubules, and block cells in mitosis, resulting in cell death.1–6 The epothilones are obtained from the fermentation of the cellulose-degrading myxobacterium, Sorangium cellulosum.7 These natural products are polyketide-derived, 16-membered ring macrolides. BMS-247550 [1S-[1R*, 3R*(E), 7R*, 10S*, 12R*, 16S*]]-7,11-dihydroxy-8, 8,10,12,16-pentamethyl-3- [1-methyl-2- (2-methyl-4-thiazolyl) ethenyl]-17-oxa-4-azabicylo [14.1.0] heptadecane-5, 9-dione, is a semisynthetic derivative of epothilone B in which the macrolide ring oxygen atom has been replaced with a nitrogen atom to give the corresponding macrolactam.8 Preclinical studies have shown that BMS-247550 is more potent than the taxanes in inducing microtubule polymerization in vitro, is cytotoxic at low nanomolar concentrations, is orally efficacious (the antitumor activity produced after oral administration is comparable to that produced by parenteral administration), is synergistic with a number of antineoplastic agents in vitro, and is more active against in vivo models when administered frequently. BMS 247550 has a broad spectrum of activity in vitro and in vivo against cancer models that are naturally insensitive to the taxanes or have developed resistance to the taxanes. BMS-247550 has shown impressive and broad-spectrum activity against paclitaxel-sensitive tumors (A2780, HCT116, and LS174T) as well as paclitaxel-resistant human colon (HCT116/VM46), ovarian (Pat-7 and A2780Tax), and breast (Pat-21) carcinoma models. These data suggest that BMS-247550 may offer improved clinical efficacy in taxane-insensitive and -sensitive cancers. This phase I study was designed to establish the maximum-tolerated dose (MTD) for BMS-247550 administered as a 1-hour infusion on 5 consecutive days every 3 weeks. In selecting patients, emphasis was placed on recruiting patients previously treated with a taxane.
Patient Selection Twenty-eight patients were enrolled onto the trial, which had been reviewed and approved by the institutional review board of the National Cancer Institute (NCI). Verbal and written informed consent was obtained from all patients. Enrollment criteria included an Eastern Cooperative Oncology Group performance status of 0 to 2, without serious intercurrent medical illness, and bidimensionally measurable disease by radiographic means or physical examination, or relevant tumor markers (ie, CA-125 and prostate-specific antigen  2 times the upper limit of normal). A period 4 weeks was required to have elapsed since the last radiation or chemotherapy treatment ( 6 weeks from prior treatment with nitrosoureas or mitomycin) and 2 weeks since the last hormonal therapy for breast cancer. Patients were required to have AST and ALT  2.5 times the upper limit of normal, bilirubin 1.5 times the normal limit, serum creatinine 1.5 mg/dL (or if > 1.5 mg/dL, measured creatinine clearance 50 mL/min), absolute neutrophil count (ANC) 1,500/mL, and platelet count 100,000/mL. Patients could be excluded from study entry if they had a history of CNS malignancy; were considered poor medical risk because of other nonmalignant systemic disease or active, uncontrolled infection; were human immunodeficiency virus seropositive; had received myeloablative chemotherapy followed by bone marrow or stem-cell rescue within the past 4 months; or had received prior craniospinal radiation or total-body irradiation. However, no patient was denied entry on these grounds.
Drug Supply and Treatment Schema The maximum-administered dose (MAD) was defined as the dose at which DLT occurred in at least two of six patients treated at that dose level. The dose just below the MAD was considered the MTD, providing that DLT was observed in fewer than two of six treated patients (or fewer than one third if more than six patients were treated) at that dose level. Determination of MAD and MTD was based on DLT observed during the first treatment cycle. DLT was defined as grade 3 or greater nonhematologic toxicity or grade 4 hematologic toxicity. Once the MTD without filgrastim support was defined, the dose level was expanded to 16 patients to establish the recommended dose for phase II studies. All adverse events in this trial were graded using the NCI common toxicity criteria version 2.0 (available at http://ctep.cancer.gov/reporting/ctc.html).
Intrapatient dose escalations were allowed if the nadir ANC was
Dose modifications were based on the toxicity from the previous cycle. If the ANC was BMS-247550 was dissolved in a Cremophor-EL-containing vehicle and routine premedication was administered to prevent hypersensitivity reactions. The treatment regimen was similar to the standard paclitaxel premedication regimen but did not include corticosteroids. It consisted of diphenhydramine 50 mg administered intravenously (IV) and either cimetidine 300 mg or ranitidine 50 mg IV, 30 to 60 minutes before the administration of BMS-247550.
Response Evaluation
Pharmacokinetics A liquid chromatography/mass spectrometry/mass spectrometry method for quantification of BMS-247550 in 0.2 mL of human EDTA plasma was developed at Bristol-Myers Squibb. After the addition of an internal standard (BMS-212188) to 0.2 mL of each calibration standard, quality control sample, and study sample, and precipitation with acetone, the supernatant was extracted with 1-chlorobutane. After centrifugation, the lower aqueous layer was frozen and the organic layer was transferred to a clean tube and evaporated to dryness. The residue was reconstituted and injected into the liquid chromatography/mass spectrometry/mass spectrometry system. Chromatographic separation was achieved, isocratically, on a model ODS-AQ column (4.6 x 50 mm) with detection by electrospray tandem mass spectrometry. The standard curve, which ranges from 2 to 500 ng/mL, was fitted to a 1/x weighted quadratic regression model. The intra-assay precision for BMS-247550 was within 9% relative standard distribution. The inter-assay precision for BMS-247550 was within 12% relative standard distribution. The assay accuracy for BMS-247550 was within 6% of the nominal values. At the lower limit of quantification (LLQ) of 2 ng/mL, the deviations of the predicted concentrations from the nominal value for all six replicates were within 11% for BMS-247550. BMS-247550 was stable in human EDTA plasma for up to 2 hours at room temperature and up to 3 weeks at -20°C after three freeze-thaw cycles. The processed samples were stable for up to 24 hours at 4°C. BMS-247550 was stable over a 1-hour period in fresh human EDTA whole blood at 4°C. On the basis of the results of this validation, the acceptance criteria for sample analysis were defined as follows: the predicted concentrations of at least three fourths of all calibration standards must be within 15% of their nominal concentrations (20% for the LLQ); at least one replicate of the lowest concentration in the standard curve must be within 20% of the nominal concentration for that level to qualify as the LLQ; and the predicted concentrations of at least two thirds of all quality control samples must be within 15% of their individual nominal concentrations.
The area under the plasma BMS-247550 concentration-time curve (AUC) was calculated using the trapezoidal method and extrapolated to infinity. The terminal slope of the plasma concentration-time curve was derived by linear regression after log transformation of the plasma concentrations, and this slope was used in the extrapolation of the AUC to infinity and estimation of the terminal half-life. The total body clearance was derived from the dose/AUC0-
Patient Characteristics Table 1  lists the diagnosis, performance status, age, and prior therapy of patients enrolled onto the trial. All patients had an Eastern Cooperative Oncology Group performance score of 2 or better. Most of the patients were heavily pretreated; the median number of prior regimens was five, with 10 of the 27 patients having received six or more prior regimens. The median number of prior drugs was also five, reflecting the large number of experimental trials in which the patients had been enrolled, and the frequent re-treatment with platinum or paclitaxel. Twenty-one patients had received prior taxane therapy. Five of the 21 taxane-treated patients had received paclitaxel or docetaxel less than 6 months before receiving BMS-247550.
Dose Escalation Tables 2 and 3 present the dose-escalation schedule for BMS-247550. The trial design was an accelerated dose escalation and allowed for intrapatient dose escalation. The starting dose was 1.5 mg/m2/d for 5 days (x 5 days). Patients were also enrolled at dose levels using 3, 6, and 8 mg/m2/d. A total of 107 cycles were administered to 27 patients, with a median of three cycles per patient. Thirteen patients received four or more cycles. One hundred four of the 107 cycles were given at a dose of 6 mg/m2/d or greater. A dose of 8 mg/m2/d or higher was administered in 52 cycles to 20 patients. All 27 patients received at least one cycle at 6 or 8 mg/m2/d x 5 days, either initially or after an intrapatient dose escalation; 25 patients received at least two cycles at 6 or 8 mg/m2/d x 5 days. In all, 52 cycles of BMS-247550 were administered to 22 patients at 6 mg/m2/d x 5 days. One patient with basal cell carcinoma has received one cycle at 8 mg/m2/d, eight cycles at 10 mg/m2/d, and one cycle at 12 mg/m2/d and is continuing therapy at 10 mg/m2/d; all cycles for this patient were administered with filgrastim support. One patient with adrenocortical cancer received one cycle each of 10, 12, and 14 mg/m2/d x 5 days without grade 3 or 4 toxicity and was removed from the study at 14 mg/m2/d because of documented brain metastases. We have previously noted in other studies that patients with adrenocortical cancer, especially those whose tumors are hormone-producing, often tolerate higher doses of chemotherapy.
Toxicities Neutropenia was the DLT observed in three of three patients at 8 mg/m2/d. Subsequently, 6 mg/m2/d was identified as the MTD without filgrastim and is the recommended phase II dose. Only one of the 16 patients started at 6 mg/m2/d x 5 days had grade 3 neutropenia in the first cycle. An additional six patients were then enrolled at a starting dose of 8 mg/m2/d with filgrastim support. Two of these patients developed grade 4 neutropenia, and no further escalation was attempted. All other toxicities are listed in Tables 2  , 3, and 4. Nonhematologic grade 3 toxicities included fatigue, mucositis, and anorexia. All other nonhematologic toxicities were grade 2 or less, including neurotoxicity.
Neurotoxicity was recorded in 17 patients (10 patients with grade 1 and seven patients with grade 2). Five of the seven patients who developed grade 2 neurotoxicity and four patients in whom grade 1 neurotoxicity was recorded had grade 1 neurotoxicity at the time of enrollment. Of the seven patients with grade 2 neurotoxicity, three were noted to have grade 2 neurotoxicity after the first cycle. These three patients had grade 1 neurotoxicity on study entry. The other four patients were first noted to have grade 1 (in two patients, grade 1 was pre-existing) and progressed to grade 2 after four (three patients) or five (one patient) cycles. Neurotoxicity included episodes of distal extremity pain and myalgias occurring in the days after therapy, which resolved by the start of the next cycle, as well as numbness, tingling, and other dysesthesias, which in some cases were also transient. With the exception of one patient treated with 8 mg/m2/d x 5 days, no patient was removed from the study because of neurotoxicity. This one patient in whom therapy was discontinued had recently completed a regimen containing cisplatin and had experienced severe neurotoxicity. After the first cycle at 8 mg/m2/d, he developed grade 2 neurotoxicity and a decision was made to discontinue therapy. Seven episodes of diarrhea were recorded in six patients (one patient had diarrhea in two cycles). Three of the episodes were grade 1 and four were grade 2; however, no premedication or intervention was needed to manage the diarrhea. Hypersensitivity reactions were not observed using the premedication regimen described in Patients and Methods.
Pharmacokinetics
The plasma concentration-time profile of BMS-247550 was characterized by a steep 1-log decline during the first hour after the completion of the 1-hour infusion (Fig 1
Pharmacodynamics There was no relationship between drug exposure, as measured by the AUC after the first dose on cycle 1, and the severity of neutropenia, as measured by the neutrophil nadir and the percentage drop in neutrophil count from baseline after cycle 1 (data not shown).
Response Evaluation
This study describes the results of a phase I trial using the novel epothilone B analog, BMS-247550, administered as a 1-hour infusion on 5 consecutive days. A dose of 6 mg/m2/d x 5 days was established as the MTD and is the recommended phase II dose. The DLT was neutropenia. Nonhematologic toxicities observed in a total of 107 cycles included seven episodes of grade 3 fatigue in this patient population with advanced cancer, two episodes of grade 3 mucositis, and one episode of grade 3 anorexia. The severity of neurotoxicity did not exceed grade 2 in any patient, including the 13 patients who received more than four cycles at the MTD or higher. Responses were seen in patients who had received prior taxane therapy, including a patient with recent docetaxel exposure. These results support additional trials using this regimen. Recently, there has been considerable interest in new designs for phase I clinical trials because of concern that with conventional phase I designs, many patients are treated with biologically inactive doses, minimizing the opportunity for antitumor response.9–13 Simon et al9 proposed three alternative designs for phase I trials so that fewer patients are treated at subtherapeutic dose levels, trials are of reduced duration, and important information needed to plan phase II trials is obtained. However, to date there are few data on the prevalence of alternative designs for phase I trials and their success in achieving the goals delineated by Simon et al9 without compromising patient safety. In this study, we used the Simon 3b design, an accelerated dose-escalation design beginning with escalation increments of 100%. The 100% dose-escalation increments were abandoned at the third dose level (6 mg/m2/d) because information from concurrent phase I trials using an every 3 weeks schedule of administration indicated that we were approaching the MTD. If we had not terminated the 100% dose-escalation increments, the fourth patient on this study would have received 12 mg/m2/d, a dose 100% greater than the MTD. Although two patients received 12 mg/m2/d as a result of intrapatient dose escalations and tolerated it, 12 mg/m2/d may still have caused excessive toxicity. Had we instead escalated doses in 40% increments, the dose levels would have been 1.5, 2.1, 2.9, 4.1, 5.7, 8, and 11.2 mg/m2/d. With this strategy, 5.7 mg/m2/d, a dose close to the MTD, would have been administered, followed by 8 mg/m2/d. Although 8 mg/m2/d resulted in grade 4 neutropenia in the three patients initially enrolled at this dose level, the possibility that the 11.2 mg/m2/d dose would not have been administered cannot be ruled out, because of the seven patients whose dose was escalated to 8 mg/m2/d without filgrastim in cycle 2 or beyond, four had nadir neutrophil levels of 2,443/µL, 2,890/µL, 4,032/µL, and 6,120/µL. The accelerated design did succeed in achieving the goal of treating fewer patients with and administering fewer cycles at subtherapeutic dose levels. All 27 patients on this study received at least one cycle at the recommended phase II dose of 6 mg/m2/d or higher, and only three cycles in two patients were given at a dose less than 6 mg/m2/d. If we had used an alternate schema with 40% dose increments, two additional patients would have been required to determine the MTD, and a total of 10 cycles in four patients would have been administered at doses below 5.7 mg/m2/d. Thus the 100% dose-escalation design allowed all patients to be treated at a biologically active dose, and compared with a 40% dose increment, resulted in the administration of seven fewer cycles at subtherapeutic doses. Although this study cannot resolve the issue of which trial design is optimal, it could be argued that 100% dose increments may make it more likely that a patient will experience unacceptable toxicity. However, although smaller dose increments may be safer, they require the administration of more cycles at lower doses. Intrapatient dose escalations allow more patients to receive biologically active doses, but the optimal dose-escalation schema needs further evaluation. The efficiency of dose escalation should be balanced with patient safety, and further systematic review of other phase I designs and their outcomes is needed to define the optimal phase I design. On the basis of the similar mechanisms of action and the preclinical data, the expectations clinically were that drugs from this class of agents would behave similar to the taxanes. Thus the observation that myelosuppression was the DLT was not unexpected. As for nonhematologic toxicities at the MTD, these were limited in scope and severity. Neurotoxicity was observed in 17 patients. These toxicities were grade 1 or 2 and included both transient pains in the extremities and myalgias, as well as the more common sensory disturbances frequently observed with microtubule active agents. Other phase I studies using BMS-247550 in either a once every 3 weeks schedule or a weekly regimen have been reported in abstract form.14–21 Two studies using a 1-hour infusion every 3 weeks encountered grade 4 neutropenia as the DLT at doses of 50 and 56 mg/m2; the recommended phase II dose was 40 mg/m2/cycle.17,18 Another study using a once every 3 weeks schedule encountered grade 4 neutropenia and grade 3 neuropathy as the DLT at a dose of 65 mg/m2, and recommended 50 mg/m2/cycle as the phase II dose.14 Additional toxicities reported with the every 3 weeks regimens included grade 3 to 4 emesis and fatigue and grade 1 to 2 myalgia, arthralgia, rash, paresthesias, mucositis, and a hand-and-foot syndrome. Objective responses were reported in patients with ovarian, non–small-cell lung, and breast carcinomas, as well as melanoma. Other studies have administered BMS-247550 weekly as a 30- to 60-minute infusion, with DLT of grade 3 fatigue seen in three of four patients treated at 30 mg/m2/wk in one study.19,20 Additional toxicities include cumulative neuropathy, arthralgia, myalgia, anorexia, nausea, and diarrhea. Objective responses were noted in patients with colon, ovarian, and breast cancer. The available data indicate that a dose of 20 to 30 mg/m2/wk will likely be the recommended dose, with higher doses administered to patients who have received less prior chemotherapy. In an attempt to reduce the incidence of neurotoxicity, an intermittent schedule of weekly for 3 weeks and every 4 weeks and extending the infusion from 30 minutes to 1 hour are planned. That the recommended dose for the daily x 5 regimen (30 mg/m2 every 3 weeks) is less than that recommended for the once every 3 weeks schedule (40 mg/m2) is not unlike what is commonly practiced with paclitaxel, when one compares the dose used most frequently when paclitaxel is used as a single agent in short infusions (175 mg/m2) with the 96-hour infusion dose (105 mg/m2 without filgrastim support).22,23 The reduced dose that can be administered in the daily x 5 schedule is likely due to the schedule dependency of the epothilones.24 Like most microtubule-active agents, less is likely to be tolerated when cells (in this case, bone marrow) are exposed to drug for a more prolonged period of time.25 Although it is too early to draw firm conclusions, the daily x 5 schedule may prove to be less neurotoxic, as was seen with prolonged administration of paclitaxel.22 Because neutropenia emerged as the DLT, an additional six patients were enrolled at a starting dose of 8 mg/m2/d with filgrastim support. However, two of these patients developed grade 4 neutropenia, and no further escalation was attempted. Although if strictly interpreted this means that the MTD with or without filgrastim support is the same, and that the addition of filgrastim did not allow the dose to be escalated, we would point out the following: First, the granulocyte nadirs in the first cycle in this six-patient cohort ranged from a low of 352/µL to a high of 4,072/µL, with a median of 1,594/µL and a mean of 1,693/µL—values that are not dissimilar to the results at 6 mg/m2/d, the recommended phase II dose without filgrastim (mean 1,807/µL; median, 1,763/µL for 6 mg/m2/d). Second, similar to the other study patients, the six patients in this cohort had received multiple prior therapies; the two patients with grade 4 neutropenia had received eight and 15 prior regimens, respectively. Third, a dose of 8 mg/m2/d or higher was administered in 18 cycles to these six patients, and as a result of intrapatient escalations in the second and subsequent cycles, 21 times to 14 other patients, for a total of 39 cycles to 20 patients. For these 39 cycles, the mean granulocyte nadir was 1,437/µL, the median was 1,431/µL, and there were 12 episodes of grade 3 to 4 neutropenia. This included seven patients who received a cycle without filgrastim support, with a median granulocyte nadir of 2,443/µL, a mean of 2,392/µL, and two grade 4 neutropenias. Thus in this study population, a large number of patients were able to tolerate 8 mg/m2/d. However, we still believe that a dose of 6 mg/m2/d is a better recommendation, because all responses were noted at this dose, and its overall tolerability indicates that this effective dose possibly can be used in combinations without adjustment. Because like paclitaxel, BMS-247550 is dissolved in cremophor EL, there has been some concern that hypersensitivity reactions could occur. Of the other phase I studies of BMS-247550 that have been presented, three have reported hypersensitivity reactions (two patients in the weekly regimen and one patient in the every 3 weeks regimen). Two studies began using routine premedications with H1/H2 blockers, and no further episodes of hypersensitivity occurred. A third study has reported the use of prophylactic corticosteroids, although the need for this is unclear. We did not observe any instances of hypersensitivity reactions in our patients, including a patient with a history of a paclitaxel allergy. There are several reasons for this lack of hypersensitivity, including the routine premedications used, the fact that the drug was administered over 5 days and each day over a 1-hour period, and the greater potency of this drug compared with paclitaxel, which meant that despite the higher Cremophor-EL concentration of the stock solution, less Cremophor-EL was administered in each course over a longer time period. The rate of Cremophor-EL administration (5,123 mg/h/m2) for a 175 mg/m2 dose of paclitaxel given over 3 hours is 3.2 times the rate of Cremophor-EL administration (1,557 mg/h/m2) in the 6 mg/m2/d x 5 days dose in which each daily dose was given over 1 hour (BMS-247550 contains 398 mg of Cremophor-EL and 2 mg of BMS-247550 per milliliter; paclitaxel contains 527 mg of Cremophor-EL and 6 mg of paclitaxel per milliliter). The pharmacokinetics of BMS-247550 were characterized by rapid tissue distribution and extensive tissue binding, as evidenced by the large Vdss. Drugs that are extensively tissue bound usually also have a prolonged elimination phase and a long terminal half-life. The terminal half-life (mean, 16.8 hours) derived from the plasma concentrations sampled over the 24 hours after the first dose may be an underestimate of true terminal half-life. The mean trough concentrations 24 hours after the third and fourth doses at the 6 mg/m2/d x 5 days dose level were 6.6 and 6.7 ng/mL, respectively, and the mean concentration 48 hours after the fifth dose was 4.8 ng/mL. This indicates that the terminal half-life may be 24 to 48 hours. The doses and schedule tested in this phase I trial may not allow for an accurate assessment of the terminal half-life. The lack of correlation among pharmacokinetic parameters (clearance and Vdss) and body weight and surface area suggests that dosing the drug based on body-surface area may not reduce interpatient variability in drug exposure (AUC). In summary, we found the MTD dose (6 mg/m2/d x 5 days) to be well tolerated. In all, 52 cycles were administered at this level, without difficulty, and 104 cycles were administered at this or a higher dose level. Only one patient of the 16 patients who started at 6 mg/m2/d x 5 days experienced neutropenia in the first cycle. The mean granulocyte nadir for these 16 patients in the first cycle was 1,807, with a median granulocyte nadir of 1,763, values that should be interpreted in the context of this heavily pretreated population. This can be contrasted with the data of Nabholtz et al,26 who reported grade 3 to 4 neutropenia in 34% of first cycles using 175 mg/m2 paclitaxel in patients with only one prior chemotherapy regimen. Together with the observation that clinical activity was observed at this dose, we would recommend that when a second agent is added to BMS-247550, this be attempted with a BMS-247550 dose of 6 mg/m2/d x 5 days.
The order of the first two authors is arbitrary.
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13. Dent SF, Eisenhauer EA: Phase I trial design: Are new methodologies being put into practice? Ann Oncol 7:561–566, 1996 14. Spriggs D, Soignet S, Bienvenu B: Phase I first-in-man study of the epothilone B analog BMS-247550 in patients with advanced cancer. Proc Am Soc Clin Oncol 20:108a, 2001 (abstr 428) 15. Mani S, McDaid H, Shen H: Phase I evaluation of an epothilone B analog (BMS-247550): Clinical findings and molecular correlates. Proc Am Soc Clin Oncol 20:68a, 2001 (abstr 269) 16. Lo Russo P, Wozniak A, Flaherty L: Phase I clinical trial of BMS-247550 (aka epothilone B analog: NSC710428) in adult patients with advanced solid tumors. Proc Am Soc Clin Oncol 20:94b, 2001 (abstr 2125) 17. Tripathi R, Gadgeel SM, Wozniak A, et al: Phase I clinical trial of BMS-247550 (epothilone B derivative) in adult patients with advanced solid tumors. Proc Am Soc Clin Oncol 21:102a, 2002 (abstr 407) 18. Mani S, McDaid H, Shen H: Phase I pharmacokinetic and pharmacodynamic study of an epothilone B analog (BMS-247550) administered as a 1-hour infusion every 3 weeks: An update. Proc Am Soc Clin Oncol 21:103a, 2002 (abstr 409) 19. Awada A, Burris D, de Valeriola D: Phase I clinical and pharmacology study of the epothilone analog BMS-247550 given weekly in patients with advanced solid tumors. AACR-NCI-EORTC 2001. Clin Cancer Res 7:3801S, 2001 (suppl, abstr 779) 20. Hao D, Hammond LA, de Bono JS: Continuous weekly administration of the epothilone-B derivative, BMS-247550 (NSC710428): A phase I and pharmacokinetic (PK) study. Proc Am Soc Clin Oncol 21:103a, 2002 (abstr 411) 21. Burris HA, Awada A, Jones S: Phase I study of the novel epothilone BMS-247550 administered weekly in patients with advanced malignancies. Proc Am Soc Clin Oncol 21:104a, 2002 (abstr 412)
22. Wilson WH, Berg SL, Bryant G, et al: Paclitaxel in doxorubicin-refractory or mitoxantrone-refractory breast cancer: A phase I/II trial of 96-hour infusion. J Clin Oncol 12:1621–1629, 1994 23. Rowinsky EK: The taxanes: Dosing and scheduling considerations. Oncology (Huntingt) 11:7–19, 1997[Medline] 24. Zhan Z, Scala S, Monks A, et al: Resistance to paclitaxel mediated by P-glycoprotein can be modulated by changes in the schedule of administration. Cancer Chemother Pharmacol 40:245–250, 1997[CrossRef][Medline]
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26. Nabholtz JM, Gelmon K, Bontenbal M, et al: Multicenter, randomized comparative study of two doses of paclitaxel in patients with metastatic breast cancer. J Clin Oncol 14:1858–1867, 1996 Submitted March 12, 2002; accepted February 1, 2003. This article has been cited by other articles:
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ABSTRACT
INTRODUCTION
, and the volume of distribution at steady-state (Vdss) was calculated from the area under the moment curve extrapolated to infinity. A sigmoid Emax model was used to relate the AUC0-
