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© 2001 American Society for Clinical Oncology Phase I and Pharmacokinetic Study of BMS-184476, a Taxane With Greater Potency and Solubility Than PaclitaxelFrom the Institute for Drug Development, Cancer Therapy and Research Center and University of Texas Health Science Center at San Antonio; Brooke Army Medical Center, San Antonio, TX; and Bristol-Myers Squibb, Wallingford, CT. Some patients were treated at the Frederic C. Barter General Clinical Research Center of the Audie Murphy Veterans Administration Hospital, supported in part by National Institutes of Health grant no. MO1 RR01346. M.H. is a recipient of grant no. PF 97 52273279 from the Ministerio de Educacion y Cultura, Spain, and a National Cancer Institute–European Organization for Research and Treatment of Cancer Fellowship Award.Presented in part at the Thirty-Fifth Annual Meeting of the American Society of Clinical Oncology, Atlanta, GA, May 15-18, 1999.Address reprint requests to Manuel Hidalgo, MD, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr, Mail Code 7884, San Antonio, TX 78229; email manuelh{at}oncology .uthscsa.edu.
PURPOSE: To assess the feasibility, toxicity, pharmacokinetics, and preliminary activity of BMS-184476 administered as a 1-hour intravenous (IV) infusion every 3 weeks. PATIENTS AND METHODS: Patients with advanced solid malignancies were treated with escalating doses of BMS-184476 as a 1-hour IV infusion every 3 weeks without premedication to prevent hypersensitivity reactions (HSR). Plasma sampling and urine collections were performed to characterize the pharmacokinetics and pharmacodynamics of BMS-184474. RESULTS: Thirty-four patients were treated with 78 courses of BMS-184476 at five dose levels ranging from 20 to 80 mg/m2. Dose-limiting toxicity (DLT), consisting of severe neutropenia with fever, severe diarrhea, and/or severe mucositis, was experienced during course 1 by six of nine minimally pretreated patients treated at the 70 and 80 mg/m2 dose level. In contrast, of 15 assessable patients treated at the 60 mg/m2 dose level, which is the maximum-tolerated dose (MTD) of BMS-184476 on this administration schedule, only one heavily pretreated patient developed DLT (grade 4 neutropenia with fever and grade 3 diarrhea). One patient developed a grade 2 HSR during a second course of BMS-184476 at the 40 mg/m2 dose level. A previously untreated patient with an advanced cholangiocarcinoma experienced a partial response, and a patient with an untreated carcinoma of the gastroesophageal junction had a minor response. The pharmacokinetics of BMS-184476 seemed linear in the dose range studied. Mean ± SD values for clearance, volume of distribution at steady-state, and terminal half-life were 220 ± 89 mL/min/m2, 402 ± 231 L/m2, and 40.8 ± 21.8 hours, respectively. CONCLUSION: The MTD and recommended dose for phase II evaluations of BMS-184476 is 60 mg/m2 as a 1-hour IV infusion every 3 weeks. The results of this study suggest that BMS-184476 may have several advantages compared with paclitaxel in terms of toxicity, pharmacokinetics, pharmaceutics, and administration and warrants further clinical development.
TAXANE ANALOGS with greater therapeutic indexes than the prototypical taxane paclitaxel (Taxol; Bristol-Myers Squibb, Wallingford, CT) are being sought because of the utility and impact of the taxanes in a wide variety of clinical settings.1 Ideal candidates for clinical development are those agents that possess greater cytotoxic potency than paclitaxel and broader spectra of antitumor activity. However, increased cytotoxic potency alone does not necessarily imply that the drug candidate will portend an increased therapeutic index in vivo unless the analog is inherently less toxic to normal tissues. Toxicity may be conferred by the taxane moiety itself, as well as the nature of the vehicle required to formulate the analog.2 The physicochemical properties of the analog, which in turn dictate the nature of the vehicle required to formulate the agent, impact on issues related to drug administration, including route, schedule, and convenience. The results of preclinical studies and an assessment of the inherent physicochemical characteristics of BMS-184476 (7-methylthiomethylpaclitaxel; Bristol-Myers Squibb) indicate that this taxane analog may be more advantageous than paclitaxel from several standpoints.3 From a cytotoxic potency standpoint, the cumulative results of preclinical studies indicate that BMS-184476 is not only inherently more potent than paclitaxel in assays of tubulin polymerization and against taxane-sensitive neoplasms, but it is active against tumors that are taxane resistant because of several mechanisms of potential clinical relevance.3 For example, HCT-116 human colon cancer cells with multidrug resistance due to P-glycoprotein (Pgp) overexpression (HCT-116/MDR) are at least 62-fold more resistant to paclitaxel than the parenteral cells from which they were derived, whereas the resistance factor for BMS-184476 is 15-fold.3 BMS-184476 has also been demonstrated to be more active than paclitaxel against tumor cells with acquired taxane resistance mediated by tubulin mutations.3 For example, the resistance factors of BMS-184476 and paclitaxel against human ovarian cancer A2780 with taxane resistance conferred by a tubulin mutation (A2780/tax22) are ninefold and 32-fold, respectively. The potential superiority of BMS-184476 was also suggested by the results of studies of BMS-184476 against human tumor xenografts with both acquired and primary taxane resistance models.
From a pharmaceutical standpoint, BMS-184476, although still a taxane with relatively poor solubility in aqueous solvents ( The toxicologic and pharmacologic profiles of BMS-18446 have been studied in several animal species.3 BMS-184476 primarily affects rapidly growing gastrointestinal and hematopoietic tissues as manifested by diarrhea, emesis, dehydration, leukopenia, thrombocytopenia, and anemia. Although BMS-184476 is generally more potent than paclitaxel against human cancers in vitro and against human tumor xenografts, minimal doses required to induce peripheral neurotoxicity in rats, as manifested pathologically by axonal degeneration, were approximately three times higher for BMS-184476 (Bristol-Myers Squibb, unpublished data). The pharmacokinetics of BMS-184476 were linear in the dose ranges studied in rodents, dogs, and monkeys and were characterized by a large volume of distribution. The agent is principally metabolized in the liver by the cytochrome P-450 CYP3A4 to a sulfoxide enantiomer metabolites (BMS-246178 and BMS-246180), and minute quantities of paclitaxel are formed in all species except mice. The aforementioned antitumor, toxicologic, and pharmaceutical features of BMS-184476 indicate that the agent may result in a higher therapeutic index than available taxanes. In addition to the potential clinical implications of being more potent and having a broader spectrum against cancers in vitro and in xenografts than available taxanes, its pharmaceutical attributes may reduce concerns regarding safety and premedication, as well as administration issues related to the deleterious effects of the polyoxyethylated castor oil formulation vehicle. The principal objectives of this phase I and pharmacokinetic study were to characterize the toxicities of BMS-184476 administered as 1-hour intravenous (IV) infusion without premedication in patients with advanced solid malignancies; to define the maximum tolerable dose (MTD) and recommend a dose for subsequent disease-directed studies; to characterize the pharmacologic profile of the parent compound and its metabolic species; and to seek preliminary evidence of antitumor activity.
Eligibility Patients with histologically documented advanced solid malignancies refractory to conventional therapy or for whom no effective therapy existed were candidates for this study. Inclusion criteria included the following: age of 18 years or more; an Eastern Cooperative Oncology Group performance status of 2 or less; a life expectancy greater than 12 weeks; no previous chemotherapy or wide-field radiation therapy (involving  30% of hematopoietic reserves) within 4 weeks of entering the study (6 weeks for nitrosoureas and mitomycin C); adequate hematopoietic (absolute neutrophil count [ANC] of 2,000/µL and platelet count of 100,000/µL or more), hepatic (total bilirubin 1.5 mg/dL or less; AST and ALT 2.5 times the upper normal limits or less), and renal (creatinine < 1.5 mg/dL) function; no coexisting medical problem of sufficient severity to limit compliance with the study; no preexisting neurotoxicity from previous therapy greater than National Cancer Institute Common Toxicity Criteria grade 2; no concurrent treatment with corticosteroids, which can confound the evaluation of any HSR; and no active brain metastases defined as peritumoral edema or progression demonstrated on an imaging procedure, no requirement for corticosteroids, or no related neurologic symptoms in a patient who had been treated with brain irradiation. All patients gave written informed consent according to federal and institutional guidelines before treatment. To determine the MTD of BMS-184476 for different functional groups of patients on the basis of hematopoietic reserve, patients were prospectively classified on the basis of the extent of previous myelotoxic therapy. Heavily pretreated patients were defined as patients who had received wide-field irradiation to 30% of bone marrow–bearing bones (whole pelvis = 30%), previous chemotherapy consisting of more than six courses of an alkylating agent–containing chemotherapy regimen (excluding low-dose cisplatin), more than four courses of carboplatin, or more than two courses of a mitomycin C– or nitrosourea-containing chemotherapy regimen. Otherwise, patients were classified as being minimally pretreated.
Dosage and Drug Administration BMS-184476 was administered intravenously over the course of 1 hour every 3 weeks without premedication. The starting dose was 20 mg/m2, which is equivalent to one third of the toxic low dose in dogs. Toxicity was graded according to the National Cancer Institute Common Toxicity Criteria, version 2.0. The dose was increased by 100% increments in groups of three new patients, provided that patients who were treated at the next lower dose level did not experience toxicity of grade 2 toxicity or more, except for nausea, vomiting, alopecia, fatigue, anorexia, anemia, increased serum alkaline phosphatase, fever, and local reactions at the injection site, during course 1. If such toxicity was encountered, dose escalation would then proceed by use of a modified Fibonacci schema with increments of 67%, 50%, 40%, and 33% thereafter. If dose-limiting toxicity (DLT) occurred during the first course of treatment in any patient, as many as six new patients were treated at that dose level. The MTD and recommended phase II dose were defined as the highest dose at which fewer than two of six new patients experienced DLT during the first course. A maximum of 15 new patients were to be evaluated at the MTD. Intrapatient dose escalation by one dose level was permitted for patients who experienced grade 1 toxicity or less in a minimum of two courses at their initial dose level, provided that the next higher dose level was not associated with DLT. Patients who experienced DLT could continue to receive BMS-184476 after dose reduction by one level. DLT was defined as follows: grade 4 neutropenia (ANC < 500/µL) for longer than 5 days or associated with fever (> 38°C); platelets less than 25,000/µL; grade 3 or more neurosensory toxicity; grade 2 or more cardiac, pulmonary, or neurologic (except neurosensory) toxicity; any other nonhematologic toxicity grade 3 or more, except fatigue and asthenia, transient arthralgia, or myalgia (not ameliorated with appropriate medical management), or nausea and vomiting despite optimal antiemetic premedication and management; and unresolved toxicity requiring at least a 2-week delay in recovery. Hypersensitivity phenomena were not considered dose-limiting because these events would prompt the initiation of premedication. Patients who developed HSR were managed according to procedures developed to treat paclitaxel-induced HSR.2,4 Patients who developed HSR could continue to receive BMS-184476 along with premedication. If during the conduct of the study it became evident that the frequency or the severity of HSR could potentially affect the safety of the patients, we planned to implement the routine use of premedication.
Pretreatment and Follow-up Studies
Plasma Sampling and Assay Blood samples for pharmacokinetic studies were centrifuged immediately, and plasma was stored at -20°C until extracted by solid-phase extraction and analyzed by high-performance liquid chromatography (HPLC). A 0.05-mL aliquot of the internal standard (BMS-183061) was added to 1 mL of plasma, votexed, and loaded into an un-endcapped Cyano (CN-U) Bond Elut columns (Varian, Harbor City, CA) that had been previously conditioned with 2 mL of 10% methanol in water and 2 mL of 5% acetonitrile in water. The analytes and internal standard were eluted with 1 mL of 0.1% formic acid in methanol into tubes. The eluents were evaporated, and the dried residues were reconstituted in 50% acetonitrile in water. The reconstituted samples were sonicated for 5 minutes in a Bransonic 52 ultrasonic bath (Branson Cleaning Equipment Co, Shelton, CT), transferred to WISP vials, and then placed in a randomized manner in a Waters Model 717+ autosampler (Waters Associates, Milford, MA) for analysis by HPLC. Aliquots of 100 µL from each sample were injected onto the HPLC system, which consisted of a Waters model 590 solvent pump, a waters temperature control module, and a Waters 484 tunable absorbance detector. Separation was performed with a Zorbax RX-C18, 5 µm, 4.6 x 250 mm column (Hewlett-Packard Co, Wilmington, DE) and a mobile phase consisting of 51.5% acetonitrile in water containing 10 mmol/L ammonium acetate (pH titrated to 5.0 with acetic acid) and 10 mmol/L tetramethylammonium hydroxide (pH titrated to 5.0 with acetic acid) at 40°C. The flow rate was 1.0 mL/min. Peak integration and quantitation from resultant chromatograms were performed with a VG Data Systems Multichrom 2 (Fisons, Cheshire, UK) data collection and processing system. The retention times for BMS-246178, BMS-246180, paclitaxel internal standard, and BMS-184476 were 6.2, 6.5, 8.0, 12.0, and 20.0 minutes, respectively. The ultraviolet absorbance detector was set at 227 nm with a response time of 1.0 second. The 1-V output of the detector was monitored by the chromatography data system. The lower limit of quantitation of the assay was 10 nmol.
Pharmacokinetic and Pharmacodynamic Analyses Simple linear regression analysis was used to determine the relationship between indexes of renal (serum creatinine) and liver functions (bilirubin, AST, ALT, alkaline phosphatase, and albumin) function and drug clearance. The degree of intraindividual variability between pharmacokinetic parameters estimated during the first and second courses was assessed by the Wilcoxon matched-pairs signed-rank test. The variability in the estimated parameters was quantified with the percentage coefficient of variation. One-way analysis of variance with Sheffé correction for multiple comparison was used to determine if the pharmacokinetics of BMS-184476 were independent of dose. Statistical analysis was performed by the JMP, version 3.1, statistical software program (SAS).
The relationships between BMS-184476 systemic exposure and toxicity were explored. Dose, AUC0-
The relationship between BMS-184476 Cmax, AUC0-
General Thirty-four patients, whose characteristics are depicted in Table 1, were treated with 78 courses of BMS-184476 through five dose levels ( Table 2). One patient died secondary to bowel obstruction because of progressive malignancy on day 11 of the first course, and therefore, data from this patient were not completely assessable for toxicity. Thirty patients had been treated previously with chemotherapy, including six patients who had received previous taxane-based treatment and 12 patients who previously received radiation therapy. The median number of courses administered per patient was two (range, 1 to 7 courses). According to the prospective criteria that defined the extent of previous therapy, 10 and 24 patients were considered heavily and minimally pretreated, respectively. Two patients were treated at more than one dose level. In the first subject, the dose of BMS-184474 was increased from 20 to 40 mg/m2 in the fourth course, and the dose was reduced from 70 to 60 mg/m2 in the second course because the second patient experienced toxicity. Treatment was not delayed because of toxicity in any patient.
Initially the dose of BMS-184476 was escalated from 20 to 40 mg/m2, then to 80 mg/m2 in successive cohorts of three patients because there were no drug-related toxicities exceeding grade 1 in severity at the previous dose levels. However, the first two patients, both minimally pretreated, at the 80 mg/m2 dose level experienced grade 4 neutropenia with fever; one of these patients also had grade 3 mucositis. These dose-limiting events led to treatment of three additional heavily pretreated patients at the 40 mg/m2 dose level, all of whom experienced no DLT. Therefore, an intermediate dose level, 60 mg/m2, was evaluated. Of the first three patients treated with BMS-184476 at this dose level, one heavily pretreated subject developed grade 4 neutropenia with fever, grade 3 thrombocytopenia, and grade 3 diarrhea, whereas two minimally pretreated patients did not experience DLT. Because of the early disparity in drug tolerability between the 60 and 80 mg/m2 dose levels among minimally pretreated subjects, we elected to reevaluate the 80 mg/m2 dose level in minimally pretreated patients only. However, two of three additional minimally pretreated patients developed grade 4 neutropenia with fever, and one of these patients also had grade 3 mucositis. Next, the intolerability of doses exceeding 60 mg/m2 was confirmed as minimally pretreated patients were treated at another intermediate dose level, 70 mg/m2, which resulted in DLT in two of four subjects (grade 4 neutropenia and fever in two patients, grade 3 mucositis in one patient, and grade 3 abdominal cramping with grade 2 diarrhea in one patient). Eight additional patients were entered at the 60 mg/m2 dose level to a total of 15 assessable patients (eight minimally pretreated and seven heavily pretreated), and only one additional heavily pretreated patient experienced DLT (grade 3 mucositis) during the first course of treatment. Therefore, 60 mg/m2 was considered the MTD for both minimally and heavily pretreated patients.
Hematologic Toxicity
At the 60 mg/m2 dose level, however, there was only one dose-limiting episode of severe neutropenia and fever involving a 59-year-old heavily pretreated patient with esophageal carcinoma, hypoalbuminemia (1.8 g/dL), and long-standing hepatic dysfunction, which was probably related to alcoholic liver disease. This patient also experienced grade 3 thrombocytopenia (nadir platelet count, 49,000/µL), which was the worst thrombocytopenic event in the study. Overall, grade 3 and 4 neutropenia occurred in seven (41%) of 17 patients involving 6 (15%) of 39 courses at the 60 mg/m2 dose level. Similar to the effects of the drug on platelets, functional effects on red blood cells were minor, with three (9%) of 34 patients requiring red blood cell transfusions (grade 3 anemia) during 4 (5%) of 78 total courses.
Nonhematologic Toxicities
Peripheral neurotoxicity, characterized by paresthesia in a symmetric, glove-and-stocking distribution, occurred in 13 (38%) of patients. Seven (54%) of 13 affected patients were previously treated with chemotherapy agents known to induce peripheral neurotoxicity. Although characterization of the cumulative nature of the neurotoxicity was precluded by insufficient numbers of patients treated with multiple courses of BMS-184476, complete resolution of symptoms was usually evident by day 21. Fourteen (41%) patients complained of arthralgia, myalgia, or both in 27 (36%) courses spanning all dose levels. The onset of myalgia and arthralgia, which typically involved the proximal lower extremity, was 3 to 4 days posttreatment, with complete resolution always documented between days 8 to 15. Only one patient developed severe (grade 3) symptoms, which occurred during a third course of treatment and resulted in the discontinuation of treatment. One patient (2.9%), a 67-year-old woman with metastatic pancreatic cancer, experienced a HSR (grade 2) during her second course of BMS-184476 at the 40 mg/m2 dose level. This patient, who had no history of atopy or drug allergies, experienced no manifestations of hypersensitivity during her first course. Two minutes into her second drug infusion, she developed generalized urticaria, tachycardia, flushing, pruritus, respiratory difficulties, and discomfort in her back and abdomen. The infusion was immediately discontinued and treatment with diphenhydramine 50 mg IV and dexamethasone 10 mg IV was begun. The manifestations of hypersensitivity subsided within 15 to 20 minutes after treatment discontinuation. The patient was successfully rechallenged 24 hours later with the same dose and infusion duration of BMS-184476 after treatment with premedication consisting of dexamethasone 20 mg orally 12 and 6 hours before the BMS-184476 infusion, and both diphenhydramine 50 mg IV and cimetidine 300 mg IV 30 minutes before treatment. Twenty-five (73%) of the patients complained of nausea and vomiting during 42 (57%) courses, which was generally mild to moderate (grade 1 to 2) in severity and managed well with phenothiazine antiemetics; however, antiemetic premedication was not used routinely. Mild to moderate (grade 1 to 2) fatigue or malaise occurred in 23 (68%) of patients during 34 (43%) courses of treatment; three patients experienced severe (grade 3) malaise that was likely due to progressive disease. Only two patients (6%) developed complete alopecia (grade 2) of the scalp, whereas 13 (34%) patients had partial alopecia.
Antitumor Activity
Pharmacologic Studies Pharmacokinetic parameters derived via noncompartmental methods are listed in Table 5. Maximal plasma concentrations were observed at the end on the infusion, and inspection of individual plasma concentration-time data sets indicated that drug disposition was multiexponential, as shown in Fig 1. Patients treated at dose below 60 mg/m2 did not have measurable plasma levels of BMS-184476 at time points beyond the first 24 hours after dosing, and therefore the elimination phase of the agent could not be characterized in these individuals. The pharmacokinetics of BMS-184476 seemed independent of dose, with both Cmax and AUC values increasing proportionally as the dose was increased from 20 to 80 mg/m2 ( Fig 2A and 2B). This was supported by the nonsignificant changes in Cl at the different dose levels explored. (P = .476, one-way analysis of variance). At the recommended phase II dose of 60 mg/m2 dose level, interpatient variability in the principal pharmacokinetic parameters was moderate, with coefficients of variation percentages of 41, 46, and 51 for Cl, Vss, and t1/2, respectively. Intrapatient patient variability in those subjects in whom pharmacokinetic studies were performed during both courses 1 and 2 was minimal, without significant differences in any of the parameters studied. The metabolites BMS-246178, BMS-246180, and paclitaxel were sporadically quantifiable and the ratios of mean quantifiable metabolite exposure to parent BMS-184476 was 7% or less. The cumulative urinary excretion of both parent compound and metabolites was less than 5%.
Pharmacodynamic relationships between indexes reflecting BMS-187746 exposure (Cmax, and AUC0-  ) and the principal toxicities were evaluated. The relationship between BMS-184476 exposure as determined by the AUC0- and the percentage decrease in ANC during course 1 was well described (R2 = 0.61) by a sigmoid Emax model, as shown in Fig 3. Values for AUC50 and  were 3,568 nmol/h and 3.26, respectively. In addition, the propensity to develop any DLT was related to AUC0-, as demonstrated by the significantly higher AUC0- in subjects who developed DLT (8,346 ± 4,511 nmol/h) than those who did not (5,514 ± 2,153 nmol/h; P = .01, Mann-Whitney U test). With regard to Cmax, although Cmax values were higher in patients who experienced DLT than those who did not, the difference was not statistically significant (2,720 ± 939 nmol v 2,101 ± 1,297 nmol; P = .15). In addition, neither the propensity to develop any of the principal toxicities of BMS-184476 nor the severity of these effects were related to plasma concentrations of both sulfoxide metabolites and paclitaxel.
The unique mechanism of action of the taxanes and their broad clinical utility in both early and advanced oncologic settings support evaluations of taxane analogs that may have greater therapeutic indexes than currently available taxanes. Desirable candidates for further development include those taxanes with greater potency against drug-resistant neoplasms, broader antitumor spectrum, and more favorable toxicologic and pharmaceutical properties than the first generation of taxanes. In essence, BMS-184476 fulfills these criteria. The agent is not only more potent against most taxane-sensitive tumors than paclitaxel, but BMS-184476 is generally more active in vitro and in vivo against neoplasms with both primary and acquired taxane resistance. Additionally, BMS-184476 is more soluble than paclitaxel in aqueous cosolvent systems containing polyoxyethylated castor oil. This physicochemical attribute markedly reduces the concentration of the polyoxyethylated castor oil vehicle required to formulate BMS-184476, thereby increasing the feasibility of the use of shorter, more convenient administration schedules and potentially reducing requirements for premedication to prevent HSR related to the vehicle. This phase I and pharmacokinetic study demonstrated that BMS-184476 doses exceeding 60 mg/m2 IV every 3 weeks result in an unacceptably high incidence of intolerable toxicities in both minimally and heavily pretreated patients with advanced solid malignancies. Therefore, 60 mg/m2 is the MTD and recommended dose for subsequent disease-directed studies of BMS-184476, irrespective of the extent of previous therapy. On the basis of relative taxane doses associated with equivalent degrees of myelosuppression, BMS-184476 is roughly threefold to fourfold more potent than paclitaxel and 1.2- to 1.5-fold more potent than docetaxel, respectively.1,8 Neutropenia, abdominal cramping with diarrhea, and mucositis were the principal dose-limiting toxicities of BMS-184476 administered as a 1-hour IV infusion every 3 weeks. The relatively high rate of severe neutropenia with fever at BMS-184476 doses exceeding 60 mg/m2 is likely due to the concurrent development of gastrointestinal mucosal barrier disruption as manifested by both mucositis and diarrhea. Seventeen (50%) of 34 patients treated with BMS-184476 developed diarrhea during 22 (28%) courses, and one patient experienced severe (grade 3) diarrhea. On the other hand, diarrhea is relatively uncommon (< 5%) with paclitaxel and docetaxel on similar dose schedules that produce severe neutropenia.1,8 It is possible that these difference are because BMS-184476 is a much poorer substrate for the Pgp multidrug transporter pump, which is constitutively overexpressed in gastrointestinal mucosal cells, as compared with paclitaxel and docetaxel. In contrast, the rates of neuromuscular toxicity and alopecia with BMS-184476 were generally lower than those associated with paclitaxel and docetaxel administered on equivalent dose schedules.1,8-11 The low incidence of peripheral neurotoxicity with BMS-184476 was predicted in preclinical models. However, peripheral neurotoxicity and other chronic toxicities, in general, are optimally characterized in clinical research settings in which larger numbers of patients are treated with higher cumulative doses and a greater number of courses at the MTD than in traditional phase I studies. In the present study, only four patients were treated with at least four courses of BMS-184476, limiting the adequate evaluation of cumulative neurotoxicity. Further attention to neurotoxicity and other potential chronic toxicities in subsequent clinical trials is needed to properly assess this issue. If this preliminary observation is confirmed in future studies, it may suggest that the development of chemotherapy regimens consisting of BMS-184476 combined with cisplatin or other peripheral neurotoxins will be more feasible than comparable paclitaxel-based regimens, in which neurotoxicity often precludes chronic treatment.12,13 Interestingly, alopecia was also uncommon with BMS-184476 compared with that noted with paclitaxel and docetaxel, which may have definite psychosocial implications and impact on quality of life. The solubility advantages of BMS-184476 enable its formulation with substantially less polyoxyethylated castor oil, which would render short IV administration schedules feasible, reduce the requirement for premedication, or both. Although the etiology of the HSR associated with paclitaxel treatment is not completely understood and it is possible that HSRs are caused by either paclitaxel itself or its polyoxyethylated castor oil vehicle, the latter is most likely responsible because it induces similar manifestations in dogs, and other drugs formulated in it induce nearly identical reactions.4,14 Most experimental data and circumstantial evidence suggest that the polyoxyethylated castor oil vehicle mediates HSR nonimmunologically by releasing histamine or other vasoactive substances, possibly through complement activation.15,16 Although the rate of infusion is related to the frequency of HSR and the use of 3- to 24-hour administration schedules with premedication (which consists of corticosteroids and both H1 and H2 histamine antagonists) have enabled the successful development and broad use of paclitaxel, both measures are not completely effective at preventing both minor and serious reactions, even on 3- and 24-hour infusion schedules.2,4,17 Approximately 10% to 30% of patients treated with paclitaxel over the course of 1 hour or less after premedication develop symptoms of HSR.9 Several other drugs are also formulated in polyoxyethylated castor oil, such as cyclosporine, teniposide, and vitamin K, but the clinical formulation of paclitaxel requires the highest concentration of this vehicle compared with these other agents, which have a much lower propensity to induce HSR than paclitaxel and are most commonly administered as short IV infusions without premedication.14,18 In the present study, one (2.9%) of 34 patients experienced a minor HSR during one (1.3%) of 78 courses of BMS-184476 administered as a 1-hour infusion without premedication. In contrast to the HSR typically reported with paclitaxel, this reaction was experienced during a second course. Further experience in larger numbers of patients is required to gauge the relative advantage of BMS-184476 in terms of hypersensitivity phenomena. Although these results support further development of the agent without an obligatory premedication regimen, this strategy may require modification as clinical development proceeds.
The pharmacokinetics of BMS-184476 were characterized by a large volume of distribution (mean, 405 ± 227 L/m2) and a long half-life of elimination (mean, 40.8 hours). In contrast to the nonlinear pharmacokinetic behavior of paclitaxel, which is accentuated on shorter administration schedules, the pharmacokinetics of BMS-184476 seemed independent of dose, with AUC and Cmax values proportionally related to dose.6,7 Several explanations to account for the differences in the pharmacokinetic profiles of paclitaxel and BMS-184476 may be proposed. First, both saturable distribution and elimination processes are in part responsible for the nonlinear pharmacokinetic behavior of paclitaxel. Although these processes may also be inherently nonlinear for BMS-184476, its greater potency indicates that lower BMS-184476 doses relative to paclitaxel can achieve similar effects, which decreases the likelihood of detecting significant nonlinearity in the clinic. For docetaxel, which is also more potent than paclitaxel in vitro, pharmacokinetics seem linear at clinically relevant doses (eg, 60 to 100 mg/m2), but nonlinear pharmacokinetics are evident at higher doses ( Except for an apparently steep, although readily predictable, dose-toxicity relationship at BMS-184476 doses exceeding 60 mg/m2 on a schedule of 1-hour IV infusion every 3 weeks, the results of this early study suggest that the agent may be more advantageous than paclitaxel in several respects. The results of this study indicate that BMS-184476 may be advantageous in terms of pharmacokinetics, pharmaceutics, and administration, which may relate to its greater potency and solubility, its weakness as a Pgp substrate, and the decreased requirements for polyoxyethylated castor oil in its clinical formulation. Preliminary clinical activity was noted against tumor types, such as cholangiocarcinom and gastroesophageal carcinoma, that are not particularly sensitive to available taxanes. On the basis of the results of this study, further development of BMS-184476 on the feasible administration schedule evaluated in the present study, the use of alternative schedules, or both is warranted.
1. Rowinsky E, Donehower R: Paclitaxel. N Engl J Med 332: 1004-14, 1995 2. Rowinsky EK, Eisenhauer EA, Chaudhry V, et al: Clinical toxicities encountered with paclitaxel (Taxol). Semin Oncol 20: 1-15, 1993[Medline] 3. Rose WC, Lee FY, Fairchild CR, et al: Preclinical antitumor activity of a new paclitaxel analog BMS-184476. Proc 11th NCI-EORTC-AACR Symposium 2000 (abstr 552) 4. Weiss R, Donehower R, Wierneik P, et al: Hypersensitive reactions from Taxol. J Clin Oncol 8: 1263-1268, 1990[Abstract]
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Copyright © 2001 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
0.1 µg/mL), is more soluble than paclitaxel in aqueous vehicles containing polyoxyethylated castor oil. In addition to the greater potency of BMS-184476, which indicates that a smaller quantity of the analog is required to produce equivalent cytotoxicity compared with paclitaxel, the amount of polyoxyethylated castor oil required to formulate each milligram of BMS-184476 is threefold less than that required to formulate paclitaxel. Because polyoxyethylated castor oil is not inert and may contribute to several undesirable characteristics of paclitaxel treatment, such as hypersensitivity reactions (HSR) and nonlinear pharmacokinetics, a significant reduction in the amount of the vehicle administered with each treatment may reduce premedication requirements and increase the safety and feasibility of shorter administration schedules.
), 60 mg/m2 (
), 70 mg/m2 (
), and 80 mg/m2 (•) dose levels.
