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Clinical Cancer Research Vol. 9, 5221-5227, November 1, 2003
© 2003 American Association for Cancer Research

Clinical Trials

Phase I and Pharmacokinetic Trial of the Novel Taxane BMS-184476 Administered as a 1-Hour Intravenous Infusion in Combination with Cisplatin Every 21 Days

Weijing Sun, James P. Stevenson, Maryann L. Gallagher, David Vaughn, Steven M. Hahn, Daniel G. Haller, Marvin Cohen, Justin Kopit, Gilles Gallant and Peter J. O’Dwyer1

Abrahmson Family Cancer Center of the University of Pennsylvania, Philadelphia, Pennsylvania [W. S., J. P. S., M. L. G., D. V., S. M. H., D. G. H., P. J. O.]; Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey [M. C.]; Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, Connecticut [G. G.]


   ABSTRACT
Top
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 Patient Benefits
 DISCUSSION
 REFERENCES
 
BMS-184476 is a 7-methylthiomethyl ether derivative of paclitaxel that displays potency superior to paclitaxel against tumor cells in culture and human tumor xenografts. It also inhibits the growth of paclitaxel-resistant human tumor cell lines with multidrug resistance mediated by either P-glycoprotein or mutated tubulin. Given the known synergy between taxanes and cisplatin in vitro and their clinical activity in combination, we performed a Phase I trial of BMS-184476 as a 1-h i.v. infusion followed by cisplatin every 21 days. Twenty-seven patients with a variety of solid tumors and good performance status received 116 cycles of therapy at BMS-184476 doses of 40–60 mg/m2 together with cisplatin at 75 mg/m2. The early observation of hypersensitivity reactions required prophylactic premedication in all patients. At the planned highest dose of BMS-184476 (60 mg/m2) and cisplatin (75 mg/m2), we observed dose-limiting toxicity in the form of neutropenia and diarrhea. Also at this level, five patients experienced grade 3 or worse nausea and vomiting. Aggressive prophylactic treatment eliminated the gastrointestinal toxicity. Mild to moderate peripheral neuropathy was infrequent, as was alopecia. Patient benefits included three partial responses in patients with mesothelioma, esophageal cancer, and head and neck cancer, and two additional minor responses. Plasma pharmacokinetic data are available for 23 patients treated at 40–60 mg/m2. The mean maximum plasma concentrations and areas under the curves increased in a dose-related manner. The pharmacokinetics of BMS-184476 appeared independent of dose. The mean (± SE) values for clearance, volume of distribution at steady state, and the apparent terminal half-lives of the three dose groups during cycle 1 were 243 ± 5 ml/min/m2, 423 ± 58 l/m2, and 32.2 ± 4.5 h, respectively. BMS-184476 60 at mg/m2 with cisplatin at 75 mg/m2 with appropriate supportive therapy is the dose recommended for further evaluation.


   INTRODUCTION
Top
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 Patient Benefits
 DISCUSSION
 REFERENCES
 
The available taxanes (paclitaxel and docetaxel) have a broad spectrum of antitumor activity as either single agents or in combination, and are widely used clinically for cancer treatment (1, 2, 3) . Taxanes are active on multiple schedules and have radiation-sensitizing effects that are being studied in clinical trials (4) . However, resistance is constitutive for many of the major epithelial tumors and is frequently acquired for tumors that are initially sensitive. The taxanes used at present also have some undesirable toxic effects, including hypersensitivity, neuropathy, and alopecia. Great efforts have been expended in a search for taxane analogues with a more favorable therapeutic index (5) . BMS-184476 (7-methylthiomethylpaclitaxel), a second-generation taxane, demonstrates characteristics that suggested an advantage over paclitaxel in preclinical and early clinical studies (5 , 6) . It has been shown in several in vivo tumor models that BMS-184476 is more potent than paclitaxel and docetaxel and that in some models it has the capacity to overcome paclitaxel resistance. Evidence suggests that BMS184476 may overcome two different mechanisms of resistance to paclitaxel: less resistance was observed with BMS-184476 than with paclitaxel, both in the P-glycoprotein 170-mediated multidrug-resistant cell line HCT/MDR and in the A2780/tax cell line, in which resistance is attributable to mutated tubulin. In xenograft tumor models, BMS-184476 was more effective than paclitaxel and docetaxel, and curative responses were reported in a paclitaxel-resistant human colon cancer model. BMS-184476 also enhances the effects of radiation in human lung cancer cells both in vitro and in vivo (6) .

A recent Phase I and pharmacokinetic study of BMS-184476 as a 1-h i.v. infusion every 3 weeks showed that this taxane is well tolerated with predictable patterns of toxicity (7) . Neutropenia and, unusually for a taxane, diarrhea and mucositis were dose limiting. There was no grade 3 or 4 peripheral neurotoxicity. Partial and minor responses were observed in patients with gastrointestinal carcinomas. The dose recommended for Phase II evaluation was 60 mg/m2. Combinations of paclitaxel with cisplatin or carboplatin are widely used in the treatment of many cancers (8, 9, 10, 11) . The combination of BMS-184476 and cisplatin has the potential to yield greater efficacy, less toxicity, and a broader range of susceptible tumors. In the described Phase I study, we studied the combination of escalating doses of BMS-184476 as a 1-h i.v. infusion, followed by cisplatin at a standard dose of 75 mg/m2 every 21 days in patients with advanced solid tumors. The goals were to characterize the toxicities of the combination, to define the appropriate dose for Phase II studies, and to establish the pharmacokinetic profile of BMS-184476 in combination with cisplatin.


   MATERIALS AND METHODS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 Patient Benefits
 DISCUSSION
 REFERENCES
 
Patient Population.
Patients eligible for this study had a histological diagnosis of a malignant solid tumor and had exhausted the standard therapeutic options for their disease or had a malignant disease for which no established therapy exists. Patients had either measurable or evaluable disease. They had adequate bone marrow (absolute granulocyte count >=1,500/mm3; platelet count >=100,000/mm3), hepatic (serum bilirubin <=2.0 mg/dl; serum aspartate aminotransferase and alanine aminotransferase <=2.5 times the institutional upper limits of normal or <=5 times the institutional upper limit of normal for patients with liver metastases), and renal (serum creatinine <=1.5 times the institutional upper limit of normal or measured or calculated creatinine clearance >=60 ml/min) function. All toxicities of previous treatment had recovered to baseline or <=grade 1, and no previous chemo-, immuno-, or radiotherapy was allowed within 4 weeks of entry (6 weeks for drugs with delayed toxicity, such as nitrosoureas or mitomycin C). Patients were 18 years of age or older, with an Eastern Cooperative Oncology Group performance status of 2 or better. The study was approved by the institutional review board of the University of Pennsylvania. Patients gave written informed consent in accordance with federal, state, and institutional guidelines before therapy. The exclusion criteria included the following: no intolerable toxicity to previous cisplatin therapy; no serious uncontrolled medical disorder or active infection that would impair the ability of the patient to receive study treatment; no previous severe HSRs2 to agents containing Cremophor EL (polyoxyethylated castor oil); no psychiatric or other disorders, such as dementia, that would impair a patient’s understanding of the investigational nature of the treatment or his or her compliance with treatment and follow-up; no preexisting neurological toxicity (National Cancer Institute Common Toxicity Criteria grade 1 or greater) based on signs and/or symptoms of neurosensory or neuromotor toxicity; and no active brain metastases.

Before therapy, a medical history, physical examination, complete blood count, biochemical profile, electrocardiogram, urinalysis, and chest X-ray were performed. Patients were monitored with complete blood counts twice weekly and biochemical profiles weekly; patients who experienced myelosuppression had counts performed every 2 days until recovery. Physical examinations and appropriate imaging procedures to assess the response of the patient’s disease were performed and repeated every other course.

Treatment Plan.
BMS-184476 for i.v. injection was supplied as a two-vial system by Bristol-Myers Squibb Pharmaceutical Research Institute. The BMS-184476 solution (1.5 mg/ml) was obtained by mixing the vial contents of BMS-184476 solution (15 mg/ml; 5 ml/vial) and the diluent for BMS-184476 injection. This solution was further diluted with 250 ml of 5% dextrose or 0.9% NaCl to a final drug concentration in the range of 0.1–1.2 mg/ml and kept in a non-polyvinyl chloride infusion bag or a glass bottle.

BMS-184476 was administered as a zero-order infusion i.v. by infusion pump over 1 h on day 1 of each cycle at a dose of 40–60 mg/m2 depending the treatment cohort (Table 1)Citation . Cisplatin at a dose of 75 mg/m2 was administered in 250 ml in 0.9% NaCl over 30–60 min within 1 h of completion of the BMS-184476 infusion on day 1. No dose escalation was permitted in individual patients. The dose for subsequent cycles of treatment was determined by the toxicity experienced in the first course. Toxicity was graded using the Revised Common Toxicity Criteria, version 2.0 (Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD). Cohorts of at least three patients were treated at each dose level. Dose escalation proceeded if no patients had DLT. DLT was defined as any one of the following: (a) ANC <500/mm3 for 5 or more consecutive days or febrile neutropenia (defined as fever >38.0°C with ANC <500/mm3 and requiring hospitalization); (b) platelet count <25,000/mm3 or grade III or IV thrombocytopenia with a bleeding episode requiring platelet transfusion; (c) grade III or greater nausea and/vomiting despite the use of adequate/maximal medical intervention and/or prophylaxis; (d) any other grade III or greater nonhematological toxicity except for fatigue/asthenia, or transient arthralgia/myalgia (unless unresponsive to maximum medical intervention). Dose escalation was continued until DLT was observed in two of six patients treated at that cohort level. Patients with stable disease or response to therapy were continued on the therapy. Responses were evaluated according to WHO criteria (12) .


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  		Table 1 Planned dose escalation schema

 
Adequate hydration before and after cisplatin administration was given in accordance with standard practices. Immediately before cisplatin, patients received 12.5 g of mannitol i.v. and 20 mg of dexamethasone i.v., together with either 2 mg of granisetron p.o. or 32 mg of ondansetron i.v. Additional fluid was administered in the 2–4 h after cisplatin administration. When nausea and vomiting became a common cause of DLT at the highest dose level, a standard regimen was instituted for its more aggressive prophylaxis. In addition to the foregoing, this consisted of 20 mg of dexamethasone on day 2, 8 mg on day 3, and 4 mg on day 4; 8 mg of ondansetron three times a day for 3 days; and 10 mg of metoclopramide four times a day for 4 days.

Premedication for taxane-induced HSRs was not given initially; however, patients were monitored closely. After the observation of HSRs in two treated patients, we implemented a regimen of 50 mg of diphenhydramine, 10 mg of dexamethasone, and 300 mg of cimetidine administered i.v. 30 min before BMS-184476 administration as prophylaxis against such reactions. For patients who experienced HSRs of Common Toxicity Criteria grade 2 or greater (urticaria, drug fever >=38°C, and/or asymptomatic bronchospasm), the following standard treatment was applied: the infusion of BMS-184476 was interrupted, and antihistamine (25–50 mg of diphenhydramine) was given; after recovery from symptoms, the planned dose of BMS-184476 was administered later at a slower rate and with appropriate premedication. For Common Toxicity Criteria grade 3 or 4 allergies (symptomatic bronchospasm requiring i.v. medication or anaphylaxis), the infusion of BMS-184476 was stopped, and epinephrine (1:1000, as a 0.35–0.5 ml i.v. bolus) was administered, together with 50 mg of diphenhydramine i.v.

Other supportive measures were routine. Antidiarrheal therapy was given as required and consisted of loperamide and/or diphenoxylate. Colony-stimulating factors were not administered prophylactically, and their use was not encouraged. They were allowed in the case of febrile neutropenia if deemed absolutely necessary by the treating physician. Prophylactic or therapeutic use of erythropoietin was permitted.

Sample Collection and Analysis.
Serial blood samples were collected predose and at 0.5, 1, 1.25, 1.5, 2, 2.5, 3, 4, 6, 24, 48, and 72 h after the start of the 1-h infusion of BMS-184476. Blood samples (5 ml) were collected from a peripheral vein, from a site contralateral to the BMS-184476 infusion. Within 1 h of collection, the plasma was separated by centrifugation at ~1000 rpm for 15 min at 4°C. Plasma was stored at or below -20°C until analysis.

Plasma samples were analyzed for concentrations of BMS-184476, its sulfoxide metabolites (BMS-246178 and BMS-246180), and paclitaxel by a validated HPLC method. After the addition of internal standard, BMS-183061, to 1.0 ml of plasma, the sample was vortexed and loaded on an non-endcapped Cyano (CN-U) solid-phase extraction column (Varian, Harbor City, CA). The compounds were eluted with 0.1% formic acid in methanol, the eluent was evaporated to dryness, and the residue was reconstituted. Chromatographic separation of the compounds was achieved on a Zorbax RX-C18 column (5-µm bead size; 4.6 x 250 mm; Hewlett Packard Co., Wilmington, DE) using 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. Detection was by UV absorbance at 227 nm. The lower limits of quantitation of the assay were 9.14 ng/ml for BMS-184476, 4.65 ng/ml for BMS-246178, 4.65 ng/ml for BMS-246180, and 8.54 ng/ml for paclitaxel.

Pharmacokinetic and Pharmacodynamic Analyses.
Estimates of pharmacokinetic parameters for BMS-184476 were derived from individual concentration–time data sets by noncompartmental analysis methods performed with the PKMENU application written in SAS version 6.12 (SAS, Cary, NC; Ref. 13 ). The maximum plasma concentration (Cmax) values were recorded directly from experimental observations. The AUC for the plasma concentration-versus-time curve from time zero to the time (t) of the last measurable concentration (AUC0-t) was calculated by use of a combination of linear and log trapezoidal summations. The first-order rate constant of decrease in BMS-184476 concentrations in the terminal phase of the plasma concentration–time dataset, {lambda}, was estimated by log-linear regression, using no weighting factor, of at least three data points yielding a minimum mean square error. The absolute value of {lambda} was used to estimate the apparent terminal elimination half-life (t1/2) The last measurable concentration and the rate constant {lambda} were used to extrapolate the AUC0-t to estimate the AUC from time zero to infinity (AUC0-{infty}). The total body clearance (Cl) was calculated by dividing the dose by AUC0-{infty}. The volume of distribution at steady state (VSS) was calculated by standard noncompartmental methods.

The relationships between BMS-184476 systemic exposure and toxicity as indicated by the percentage of decrease in the ANC were explored. The percentage of decrease in ANC was calculated as follows:

The relationship between BMS-184476 AUC0-{infty} and the percentage of decrease in the ANC was evaluated using Kinetica 4.0.2 (InnaPhase Corporation, Philadelphia, PA). Discrimination between pharmacodynamic models was guided by minimization of the weighted sum of squares and SE for the pharmacodynamic parameters, examination of the dispersion of the residuals, and use of the Objective function, Akaike criteria, and Schwartz criteria.


   RESULTS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
Patient Benefits
 DISCUSSION
 REFERENCES
 
Patient Characteristics
The demographic characteristics of the patients entered on this study are shown (Table 2)Citation . Twenty-seven patients with a median age of 57 years were enrolled, of whom 20 had been treated previously with chemotherapy [median number of chemotherapy regimens (range), 1 (0–6)]. Of note, six patients had previously received paclitaxel-based treatment. A total of 116 courses of BMS-184476 and cisplatin treatment were given, for a median of 4 courses/patient (range, 1–14).


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  		Table 2 Patient characteristics

 
Toxic Effects of Treatment
HSRs.
Premedication for HSRs was not routinely administered initially because the low content of Cremophor EL in the BMS-184476 injection was thought to pose a lesser risk of such responses. One patient developed grade 3 HSR at cohort level 1, and another had grade 2 HSR at cohort level 2. Both patients recovered well after interruption of infusion and treatment with antihistamine and steroids. After the second patient developed a HSR, a premedication containing 50 mg of diphenhydramine, 10 mg of dexamethasone, and 300 mg of cimetidine was given i.v. to all patients 30 min before BMS-184476 administration. No further HSR was observed after premedication was instituted, except in one patient who had facial flushing and transient abdominal pain at cohort level 3.

Hematological Toxicities.
Myelosuppression consisting principally of dose-related neutropenia was the major and DLT of the combination of BMS-184476 and cisplatin (Table 3Citation A). At cohort level 1, other than a single patient with mesothelioma who developed grade 4 neutropenia and grade 3 thrombocytopenia, only minimal myelosuppression was observed. Two patients in cohort 2 had grade 2 neutropenia. More severe myelosuppression developed in cohort 3. Three patients experienced grade 4 neutropenia, only one episode of which lasted >5 days; no treatment delay was required. Four patients had grade 3 neutropenia at this level, and one patient experienced grade 3 thrombocytopenia. It was also noted that the severity of neutropenia increased cumulatively in subsequent cycles at this cohort level (Table 3B)Citation . This level of toxicity is consistent with an aggressive regimen and was not complicated by febrile neutropenia.


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  		Table 3 Hematological toxicity

 
Nonhematological Toxicity.
Grade 3 and 4 diarrhea, nausea, and vomiting were observed to be dose related and met the criteria for DLTs (Table 4)Citation . At 40 and 50 mg/m2 BMS-184476, only mild to moderate (grade 1/2) nausea/vomiting and diarrhea were reported. At 60 mg/m2 BMS-184476 with 75 mg/m2 cisplatin, 5 the first 12 patients developed grade 3 nausea and vomiting, and grade 3 diarrhea was observed in 2 patients. Six additional patients were added to this level with a defined prophylactic regimen (described above) of ondansetron, dexamethasone, and metoclopramide together with loperamide as needed. No further episodes of grade 3 or 4 nausea/vomiting or diarrhea were observed.


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  		Table 4 Nonhematological toxicity (cycle 1)

 
Sensory neuropathy was reported in 31% of all courses administered (Table 5)Citation . Severe grade 3 sensory or motor neuropathy was reported in only three courses (two patients). Most of the other nonhematological toxicities were mild to moderate. Other severe (grade 3) toxicities reported included fatigue, nausea, vomiting, diarrhea, and mucositis. No grade 4 nonhematological toxicities were reported. Of note, no mucositis was reported.


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  		Table 5 Worst nonhematological toxicity (per course)

 
Pharmacokinetics and Pharmacodynamics.
Evaluable plasma concentration–time profiles were obtained from 23 patients during the first cycle of treatment; 1 patient at the 60 mg/m2 dose level had no samples collected, and 1 patient at the 40 mg/m2 dose level and 2 patients at the 60 mg/m2 dose level were excluded from pharmacokinetic evaluation because an insufficient number of samples were collected to permit a reliable analysis. Plasma concentrations were quantifiable in all patients through 48–72 h.

The mean (± SD) plasma concentration–time profiles for BMS-184476 are shown in Fig. 1Citation , and the mean BMS-184476 pharmacokinetic parameters are listed in Table 6Citation . The pharmacokinetics of BMS-184476 appeared independent of dose. The mean ± SE values for Cl, VSS, and t1/2 of the three dose groups during cycle 1 were 243 ± 5 ml/min/m2, 423 ± 58 l/m2, and 32.2 ± 4.5 h, respectively. At the recommended Phase II dose of 60 mg/m2, interpatient variability in the principal pharmacokinetic parameters was moderate, with coefficients of variation of 31, 39 and 48% for Cl, VSS, and t1/2, respectively. The mean values of Cmax and AUC0-{infty} at each dose increased in a dose-related manner. At the 60 mg/m2 dose level, there was a 3.0-fold range of AUC0-{infty} values. The relationships between individual values of Cmax and AUC0-{infty} and dose are plotted in Fig. 2Citation . There was overlap in Cmax and AUC0-{infty} values among the doses. The metabolites BMS-246178, BMS-246180, and paclitaxel were sporadically quantifiable with concentrations much less than BMS-184476.



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  		Fig. 1. Mean BMS-184476 concentration–time profiles after administration of 40 mg/m2 ({diamond}), 50 mg/m2 ({triangledown}), or 60 mg/m2 ({circ}) BMS-184476. Error bars, SD.

 

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  		Table 6 Pharmacokinetic parameters of BMS-184476 in patients during cycle 1a

 


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  		Fig. 2. Individual BMS-184476 Cmax and AUC values ({circ}) fit of the data derived from linear least-squares regression (dashed line).

 
A scatter plot of the pharmacodynamic relationship between the percentage of decrease in ANC during course 1 and the BMS-184476 exposure as determined by the AUC0-{infty} is shown in Fig. 3Citation . The relationship in this study was not well described by models of drug action, including linear, log-linear, Emax, or sigmoid Emax.



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  		Fig. 3. Scatter plot showing the relationship between BMS-184476 AUC0-{infty} and percentage of decrease in ANC during course 1 (•).

 

   Patient Benefits
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 Patient Benefits
DISCUSSION
 REFERENCES
 
In this trial we observed a high rate of disease stabilization or better (14 of 27 patients; 52%). There were three partial responses. A 71-year-old patient with mesothelioma, previously treated with radiation therapy, had a partial response at the 40 mg/m2 BMS-184476 and 75 mg/m2 cisplatin dose level. The patient received three cycles. Two patients had partial responses at the 60 mg/m2 BMS-184476 and 75 mg/m2 cisplatin level. One was a 44-year-old previously untreated patient with esophageal cancer, who had total of 14 cycles of treatment. The other was a 49-year-old patient with squamous cell carcinoma of the head and neck, who had previously been treated with paclitaxel and carboplatin and radiation therapy. This patient received a total of five cycles. Of note, two patients (mesothelioma and cholangiocarcinoma) also achieved minor responses. The nine patients with stable disease (for an average of 6 cycles/patient; range, 3–14 cycles) included three with mesothelioma, two with esophageal cancer, and one each with pancreatic cancer, lung cancer, ovarian cancer, and endometrial cancer. Of the five patients treated previously with paclitaxel, one had a partial response (head and neck cancer), and three had stable disease (mesothelioma, ovarian, endometrial, and esophageal cancers). No episodes of peripheral neuropathy occurred in the patients treated previously with taxanes.


   DISCUSSION
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 Patient Benefits
 DISCUSSION
REFERENCES
 
The present trial demonstrates that a full dose of BMS-184476 is well tolerated with a full dose of cisplatin. Neutropenia and diarrhea were dose limiting: 3 of 18 patients (17%) at this dose level developed grade 4 neutropenia in the first cycle. When all cycles are considered, 7 of 18 patients had this degree of toxicity. The neutropenia was clearly dose related with respect to the taxane. The duration of neutropenia was short, and only one patient required a treatment delay in the first course, the single patient with a neutropenic DLT at this dose level. Examination of Table 3ACitation and 3BCitation reveals, however, that some cumulative myelosuppression was observed, with increasing neutropenia in later courses. It is therefore unlikely that further dose escalation could be safely accomplished. Neutropenia was reported as dose limiting in previous studies of BMS-184476 both as a single agent (7) or in combination with doxorubicin (14) or carboplatin (15) . At the recommended dose, the degree of myelosuppression is consistent with community standards for taxane/platinum agent combinations (16) .

Dose-limiting diarrhea (grade 3) was also observed in two patients treated at the highest level. We found that the diarrhea could be ameliorated by an aggressive approach to its management, using loperamide in a manner similar to that used for irinotecan: no dose-limiting diarrhea was observed in the final six patients treated with this approach. The occurrence of diarrhea, noted also in the single-agent trials and not a feature of paclitaxel treatment, may suggest that BMS-184476 has the capacity to circumvent the P-glycoprotein pump, high expression of which is found in the colon mucosa (17) . It may be of interest to test this agent in tumors in which resistance is specifically associated with the multidrug-resistance phenotype.

Premedication for prevention of HSRs was not considered necessary initially because it was thought that the lower Cremophor EL content would markedly decrease the incidence of such reactions. In the single-agent trial, only one patient developed a mild HSR, and that during the second course of treatment. However, in the present trial, two patients developed HSR in the first two dose levels. A similar rate of HSRs was observed in the combination of BMS-184476 and carboplatin (15) , but none was reported in a combination study of BMS-184476 with doxorubicin (14) . In response to these observations, we implemented a prophylactic regimen of 50 mg of diphenhydramine, 10 mg of dexamethasone, and 300 mg of cimetidine given i.v. 30 min before BMS-184476 administration and recommend that premedication be administered to all patients in future studies of BMS-184476.

The pharmacokinetics of BMS-184476 combined with cisplatin in this study were similar to those of BMS-184476 as a single agent and were characterized by a large volume of distribution and a long apparent terminal elimination half-life (7) . In addition, there was no indication that cisplatin affected the metabolism of BMS-184476 to its sulfoxide metabolites (BMS-246178 and BMS-246180) or paclitaxel. The pharmacokinetics of BMS-184476 in combination with cisplatin in this study appeared linear, as was observed for BMS-18476 as a single agent (7) . This is in contrast to the nonlinear pharmacokinetic behavior of paclitaxel (18 , 19) . As with paclitaxel, the kinetics provided a poor predictor of toxicity, although the very narrow dose range may have limited the power of this analysis.

In conclusion, a 1-h infusion of BMS-184476 followed by cisplatin every 21 days is feasible and tolerable. Doses of 60 mg/m2 BMS-184476 with 75 mg/m2 cisplatin are recommended for further study. Neutropenia and diarrhea are dose limiting but manageable with appropriate prophylactic treatment.


   ACKNOWLEDGMENTS
 
We gratefully acknowledge Glenn Duncan for analysis of BMS-184476 and its metabolites in plasma samples.


   FOOTNOTES
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 To whom requests for reprints should be addressed, at Abrahmson Family Cancer Center of the University of Pennsylvania, 51 North 39th Street, MAB, Philadelphia, PA 19104. Phone: (215) 662-8947; Fax: (215) 243-3269; E-mail: peter.odwyer{at}uphs.upenn.edu Back

2 The abbreviations used are: HSR, hypersensitivity reaction; DLT, dose-limiting toxicity; ANC, absolute neutrophil count; AUC, area under the curve. Back

Received 2/20/03; revised 6/25/03; accepted 7/ 2/03.


   REFERENCES
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 Patient Benefits
 DISCUSSION
 REFERENCES
 

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