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Clinical Cancer Research 13, 3906, July 1, 2007. doi: 10.1158/1078-0432.CCR-06-2875
© 2007 American Association for Cancer Research
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Cancer Therapy: Clinical

A Phase I Safety and Pharmacologic Study of a Twice Weekly Dosing Regimen of the Oral Taxane BMS-275183

Linda E. Bröker1, Stephan A. Veltkamp2, Elisabeth I. Heath3, Bart C. Kuenen1, Helen Gall1, Ludovic Astier4, Susan Parker4, Louis Kayitalire4, Patricia M. Lorusso3, Jan H.M. Schellens2,5 and Giuseppe Giaccone1

Authors' Affiliations: 1 VU University Medical Center, 2 The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands; 3 Karmanos Cancer Institute, Detroit, Michigan; 4 Bristol-Myers Squibb, Wallingford, Connecticut; and 5 Utrecht University, Utrecht, the Netherlands

Requests for reprints: Giuseppe Giaccone, Department of Medical Oncology, VU University Medical Center, De Boelelaan 1117, 1081 HV Amsterdam, the Netherlands. Phone: 31-20-4444-321; Fax: 31-20-4444-079; E-mail: g.giaccone{at}vumc.nl.


   Abstract
Top
 Abstract
Patients and Methods
 Results
 Discussion
 References
 
Purpose: BMS-275183, an orally administered C-4 methyl carbonate paclitaxel analogue, showed promising activity in a phase I trial investigating a weekly treatment regimen, but was associated with a relatively high incidence of neuropathic side effects. The current dose escalation phase I trial was initiated to investigate whether twice weekly administration of BMS-275183 would improve its safety and tolerability. Additionally, the pharmacokinetics and possible antitumor activity were studied.

Experimental Design: A cycle consisted of 4 weeks (i.e., eight twice weekly oral doses). The starting dose was 60 mg/m2 and the dose was increased by 20 mg/m2 increments. Cohorts consisted of three patients and were expanded to at least six patients when toxicity was encountered. Plasma pharmacokinetics were done on days 1 and 15.

Results: A total of 38 patients were enrolled. The maximum tolerated dose was 100 mg/m2 twice weekly. Seventeen patients were treated at the maximum tolerated dose; 3 of 17 patients experienced a dose-limiting toxicity, consisting of a combination of neutropenia, neuropathy, and diarrhea. BMS-275183 seemed to have a considerably lower incidence of neuropathic side effects compared with the weekly treatment regimen. Confirmed partial responses were observed in two patients with non–small cell lung cancer, one patient with prostate cancer, and one patient with melanoma. In addition, a long-lasting prostate-specific antigen response was observed in a patient with prostate carcinoma with nonmeasurable disease.

Conclusions: BMS-275183 is preferably given in a twice weekly regimen and has considerable antitumor activity. A phase II trial in non–small cell lung cancer using the twice weekly schedule has been initiated.

BMS-275183 is an orally administered C-4 methyl carbonate analogue of paclitaxel containing additional modifications to the side chain (1). BMS-275183 has a higher oral bioavailability compared with paclitaxel. This is at least partially due to a lower affinity for the P-glycoprotein pump, which is abundantly present in the intestinal brush border and limits the oral bioavailability of paclitaxel (1–3). The antitumor activity of BMS-2715183 was similar to i.v. paclitaxel in preclinical models (4). Paclitaxel is known to be a schedule-dependent drug that benefits from prolonged tumor exposure times (5). Therefore, oral administration may be preferable over i.v. administration, as it allows more prolonged or continued schedules. In addition, oral administration is often more convenient and is preferred by the majority of patients (6). BMS-275183 does not require the vehicle Cremophor EL, which has been reported to be at least partially responsible for the hypersensitivity reactions and the nonlinear pharmacokinetic behavior of i.v. paclitaxel (7–9).

BMS-275183 has promising antitumor activity in patients. A recent phase I trial exploring once weekly dosing of BMS-275183 showed a 24% response rate with a median duration of 8.7 months in a heavily pretreated group of patients with solid tumors. Most activity was observed in non–small cell lung cancers (NSCLC) and prostate carcinoma (10). Interestingly, the toxicity profile of oral BMS-275183 differs from that of i.v. paclitaxel. On a weekly treatment regimen, the main dose limiting toxicity (DLT) of BMS-275183 was peripheral neuropathy, whereas severe hematologic side effects were infrequent (10). This is remarkable because hematologic toxicity, and not neuropathy, was dose-limiting for both paclitaxel and docetaxel (11, 12). For paclitaxel, it is known that short infusion times (1-3 h) allow higher doses to be administered but neuropathy is a common side effect, whereas prolonged infusion times of 24 h or longer are associated with less neuropathy, but yield a higher incidence of myelosuppression (13). Mielke et al. showed that patients with a peripheral neuropathy had significantly higher overall systemic exposures to paclitaxel than those who did not develop a peripheral neuropathy (14). As neutropenia was not an important DLT in the previous phase I study with once weekly dosing of BMS-275183, and systemic exposure to BMS-275183 proved to be predictive for toxicity (10), we hypothesized that spreading the systemic exposure over a longer period of time would decrease the side effects of BMS-275183 and, in particular, neuropathy. We therefore amended the phase I trial in order to investigate a twice weekly administration of BMS-275183. The aims of the amended dose-escalating phase I trial were to investigate the safety, tolerability, pharmacokinetics, and possible antitumor activity of BMS-275183 given in a twice weekly dosing regimen, and to define the recommended phase II dose.


   Patients and Methods
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 Abstract
 Patients and Methods
Results
 Discussion
 References
 
Patients. Adult patients with a histologically or cytologically confirmed diagnosis of a solid tumor not amenable to standard therapy were eligible for this study. They had to have an Eastern Cooperative Oncology Group performance status of ≤2, a life expectancy of at least 3 months, and adequate renal, liver, and bone marrow function, defined as creatinine <1.5 times the upper limits of normal, bilirubin <1.5 times the upper limits of normal, alanine-aminotransferase <2.5 times the upper limits of normal, absolute neutrophil count >1.5 x 109/L, and platelets >100 x 109/L. An adequate method of birth control had to be used, and women of child-bearing potential had to have a negative serum or urine pregnancy test. At least 4 weeks had to have elapsed from prior anticancer treatment (including taxanes) and toxicities (except alopecia) had to be recovered to lower than grade 1 (according to National Cancer Institute-Common Toxicity Criteria version 2.0; ref. 15). Excluded were patients with a serious uncontrolled medical disease, active infection, significant pulmonary or cardiovascular disorder, QTc interval >450 ms, sensory or motor neuropathy higher than grade 2, active brain metastasis, inability to swallow capsules, history of gastrointestinal disease, surgery or malabsorption that could impair the uptake of BMS-275183, concomitant use of known inducers or inhibitors of cytochrome P450 isoform CYP 3A4, and any psychiatric or other disorders such as dementia that would impair compliance. Concomitant radiotherapy or systemic anticancer therapy was not allowed. During the trial, the concomitant use of proton pump inhibitors (PPI) was added as an exclusion criterion, as an association between PPI use and elevated exposure to BMS-275183 was found in ongoing clinical trials, suggesting a potential drug-drug interaction. The study was approved by the medical ethics committees of the three participating institutes, and all patients gave written informed consent prior to study entry.

Study design. BMS-275183 (Bristol-Myers Squibb) was given orally on a continuous twice weekly schedule on an outpatient basis. One cycle consisted of 4 weeks of treatment, and the drug was given on days 1, 4, 8, 11, 15, 18, 22, and 25 of each 4-week treatment cycle. The starting dose was 60 mg/m2, an estimation of a reasonably safe dose below the maximum tolerated dose (MTD) of 200 mg/m2 identified with the weekly treatment regimen. Three patients were treated per cohort. Dose escalation took place according to predefined dose steps of 20 mg/m2 (i.e., 80, 100 mg/m2, etc.), until a DLT was encountered. The cohort was then expanded to six patients, and dose escalation continued until a DLT was observed in two out of two to six patients. The MTD was defined as the highest dose at which no more than one out of six patients experienced a DLT. A minimum of 15 patients were to be treated at the MTD to further establish the safety profile of a recommended phase II dose.

DLTs were predefined as any of the following drug-related side effects occurring during the first cycle: grade 4 neutropenia for ≥5 consecutive days, febrile neutropenia (fever ≥38.5°C), grade 4 thrombocytopenia (or grade 3 with a bleeding episode requiring platelet transfusion), any nonhematologic toxicity higher than grade 3, retreatment delay of >1 week due to drug-related toxicity, dose reduction or omission due to any drug-related toxicity before completion of the first cycle, QTc interval >500 ms, and any clinically significant arrhythmia within 24 h following drug administration. Hypersensitivity reactions were not defined as DLTs. Dose reductions by one level were done when a DLT or grade 2 neurotoxicity occurred.

Drug administration. BMS-275183 was provided in 5 and 25 mg capsules solubilized in polyethylene glycol 400/1450 with Gelucire 44/14 as the excipient system at a loading of 4% w/w. The calculated dose was rounded to the nearest 5 mg. Patients ingested the capsules with 150 mL of water within 10 min. Patients were fasting for at least 8 h prior to drug administration and for 2 h post-dose. No prophylactic medication was prescribed. Patients were planned to receive at least two cycles, unless toxicity or progressive disease required drug discontinuation.

Patient evaluation. Pretreatment evaluation included a complete history and physical examination, urinalysis including pregnancy test, a complete blood count, coagulation tests, serum chemistries, determination of serum tumor markers, tumor assessment, chest X-ray, and ECG. Toxicity assessment and all blood tests except serum tumor markers, were repeated weekly. Physical examination was repeated before each cycle. Toxicities were graded according to National Cancer Institute-Common Toxicity Criteria version 2.0 (15). Patients were considered evaluable for toxicity if they received at least one dose of the study drug.

Because BMS-275183 moderately prolonged the action potential duration in isolated Purkinje fibers,6 ECG monitoring was done prior to drug administration and 2, 6, and 24 h after the first drug administration to assess potential prolongation of the QTc interval (calculated using the Bazett formula QTc = QT / {surd}R-R'). If a QTc interval of >450 ms was observed, ECG monitoring was again done after the second dose.

Objective response to therapy was assessed every other cycle according to WHO criteria (16). To be evaluable for response, patients had to complete at least two cycles, unless they had to prematurely discontinue treatment because of rapidly progressive disease.

Blood sampling and pharmacokinetic analysis. Pharmacokinetic monitoring was done on days 1 and 15 of the first cycle (after the first and fifth dose). Blood samples of 5 mL were collected via an indwelling catheter in potassium-EDTA vacutainers (Becton Dickinson) up to 72 h after drug administration (time points 0, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 24, and 72 h). After collection, the tube was placed on ice for 10 to 30 min, centrifuged for 5 min at 2,000 x g at 0°C to 4°C, and plasma was separated and stored at –80°C until analysis. Plasma concentrations of BMS-275183 were determined by a validated liquid chromatography/mass spectrometry method, as described previously (10). Pharmacokinetic profiles were evaluated by noncompartmental analysis using the software package Kinetica version 4.2 (InnaPhase Corporation). The elimination half-life (T1/2) was assessed from the elimination rate constant, estimated by linear regression of the terminal phase of the semilogarithmic concentration versus time curve. The area under the plasma concentration versus time curve (AUC) was estimated by the linear-logarithmic trapezoidal method up to the last measured concentration-time point and extrapolated to infinity (AUCinf). The maximal observed drug concentration (Cmax) and the time to maximal observed drug concentration (Tmax) were obtained directly from experimental data.

Statistical analysis. Descriptive statistics were used for baseline characteristics, safety assessment, and pharmacokinetic variables (Cmax, Tmax, AUCinf, T1/2). The software package SAS (version 8.2 for Unix) was used for statistical analyses. ANOVA was used to estimate intrasubject variability in AUCinf.


   Results
Top
 Abstract
 Patients and Methods
 Results
Discussion
 References
 
Patients and treatment. Between January 2004 and December 2005, 38 patients were enrolled and treated in the trial at two participating centers in the Netherlands, and one center in the U.S. Patient characteristics are summarized in Table 1 . In summary, most patients were male (74%) with a median age of 61 years, and 89% had an Eastern Cooperative Oncology Group performance status of 0 to 1. There were relatively large subgroups of patients with NSCLC (13 patients) and prostate carcinoma (6 patients).


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  		Table 1. Patient characteristics

 
The patients were treated at the following dose levels: 60 mg/m2 (n = 3), 80 mg/m2 (n = 10), 100 mg/m2 (n = 17), and 120 mg/m2 (n = 7). Inadvertently, one patient was treated for two doses with 140 mg/m2. This patient experienced noncomplicated grade 4 neutropenia 9 days after the first BMS-275183 administration (duration, 3 days), and no further treatment was given. In addition, one patient receiving 80 mg/m2 died a few days after his first dose due to disease-related complications, leaving nine evaluable patients in this cohort. The median number of cycles administered was 2, with a range of 1 to 22 cycles.

Adverse events induced by BMS-275183. Table 2 summarizes the drug-related adverse events. Clinically relevant toxicity was encountered from the 80 mg/m2 dose level. In the expanded cohort of six patients treated at this dose level, one DLT consisting of grade 2 neuropathy was observed. In addition, one patient omitted a dose in the first cycle due to ongoing diarrhea which lasted only 1 day and never exceeded grade 2. After thorough discussion, this episode was considered too mild to qualify for a DLT, but for safety reasons, we further expanded this cohort to nine evaluable patients. In total, two DLTs were observed in nine evaluable patients treated at the 80 mg/m2 dose level, consisting of grade 3 fatigue and grade 2 neuropathy, respectively. Both events led to dose omission and reduction in the first cycle. Subsequently, we explored the 100 mg/m2 dose level. Although the first three patients tolerated this dose level well, we decided to expand the cohort to six patients because one patient experienced a potentially drug-related grade 3 hematuria and increased urinary frequency during the first week of cycle 2. The first cycle in these additional three patients was uneventful, and the next dose level of 120 mg/m2 was explored. This dose level proved to be unfeasible, as two DLTs were seen in seven patients, consisting of dose omissions and reductions in the first cycle due to grade 2 neuropathy and grade 2 gastrointestinal symptoms/grade 2 fatigue, respectively. In addition, one patient treated by mistake with 140 mg/m2 developed grade 4 neutropenia after only two doses of BMS-275183.


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  		Table 2. Adverse events caused by BMS-275183 (any cycle)

 
We thus defined the MTD as 100 mg/m2, and expanded this cohort to further assess this dose as the potentially recommended phase II dose. In total, 17 patients were treated at the 100 mg/m2 dose. This dose level was generally well tolerated, although three patients experienced severe but reversible toxicity during the first cycle, consisting of grade 3 neuropathy (n = 1), grade 4 neutropenia (n = 1), and grade 4 neutropenia combined with grade 3 diarrhea (n = 1). Other side effects were generally mild to moderate (Table 2). Gastrointestinal symptoms occurred in 28 of 38 patients some time during their treatment with BMS-275183, but were usually mild to moderate and short-lasting, and did not interfere with ingestion of the capsules. ECG monitoring revealed a grade 1 prolongation of the QTc interval in 1 of 38 patients treated at the 60 mg/m2 dose. This normalized on repeated ECGs and did not recur after the second dose, suggesting that BMS-275183 does not have clinically relevant effects on cardiac rhythm. Taken together, DLTs associated with twice weekly administration of BMS-275183 were neutropenia, neuropathy, fatigue, and diarrhea. Other grades 3 and 4 toxicities were not dose-limiting and consisted of increased urinary frequency and hematuria. The 100 mg/m2 dose level was identified as the recommended dose level for future phase II trials.

Peripheral neuropathy. Overall, 47% (18/38) of patients developed a new or worsening neuropathy event in this trial. These patients belonged to the following dose cohorts: one patient in the 60 mg/m2 cohort, four patients in the 80 mg/m2 cohort, seven patients in the 100 mg/m2 cohort, and six patients in the 120 mg/m2 cohort. In most patients (11/18; 61%), the neuropathy was mild and did not exceed grade 1, whereas only 1 of 18 patients (5.6%) experienced severe grade 3 neuropathy (both sensory and motor). Nerve conduction studies were done in this patient with severe neuropathy, and showed both sensory and motor axonal neuropathy.

Interestingly, neuropathy occurred less frequently in the twice weekly regimen than in the weekly schedule: overall incidence of 47% (18/38 patients) versus 65% (31/48 patients; ref. 10). Moreover, the neuropathy exceeded grade 1 in only 7 of 18 (39%) patients treated with the twice weekly schedule, compared with 25 of 31 (81%) patients in the weekly treatment regimen. In addition, the neuropathy induced by twice weekly administration of BMS-275183 developed more slowly than in the weekly treatment regimen. The median time to onset of any grade of new or worsening neuropathy was 2.7 months (95% confidence interval, 1.4-{infty}; Fig. 1 ) in patients treated with the twice weekly regimen compared with 1.2 months (95% confidence interval, 0.3-10.8 months) in patients treated with weekly administration. In 17 out of 18 patients, the neuropathic symptoms recovered to baseline with a median time to resolution of 3.5 months (95% confidence interval, 2.9-5.3 months). This recovery was remarkably faster than that observed in the weekly study protocol, in which the median time to resolution was 8.6 months (95% confidence interval, 5.8-17.5 months).


Figure 1
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  		Fig. 1. Time to onset of neuropathy (months). Analysis includes onset of any grade of new or worsening sensory, motor, or painful neuropathy in all patients treated with BMS-275183 (cohort pooled, n = 38). The curve estimates the time to onset if all patients would be treated until they develop neuropathy disregarding the other reasons for going off the study. {lozenge}, patients going off the study without having developed neuropathy (censored data).

 
We studied whether prior treatment with neurotoxic chemotherapy was a risk factor for the development of peripheral neuropathy upon treatment with BMS-275183. From the 18 patients who developed peripheral neuropathy during this trial, 10 (56%) patients received prior treatment with at least one cytotoxic compound known to be associated with the development of peripheral neuropathy (defined as platinum compounds, taxanes, Vinca alkaloids), and 8 (44%) patients were pretreated with a nonneurotoxic chemotherapeutic drug. In the group of 20 patients who did not experience any neurotoxic side effects from BMS-275183, 14 (74%) patients were pretreated with at least one neurotoxic drug, whereas 5 (26%) patients received prior treatment with a nonneurotoxic drug. One patient in the latter group did not receive any prior chemotherapeutic agents. Although the patient groups in this trial were small, these data suggest that prior treatment with neurotoxic agents does not predispose for the development of neuropathy on treatment with BMS-275183, confirming our previous findings (10). It is, however, noteworthy that patients with neuropathy higher than grade 1 resulting from prior therapies were excluded from participation in both trials, which might have confounded our results.

Pharmacokinetic analysis. Blood samples for pharmacokinetic analyses were available from 37 patients following the first dose (day 1), and from 32 patients following the fifth dose (day 15). Figure 2 depicts the plasma pharmacokinetic profiles of BMS-275183 on days 1 and 15 after twice weekly dosing of 60, 80, 100, and 120 mg/m2 BMS-275183. Table 3 presents the pharmacokinetic variables of BMS-275183 on days 1 and 15. For all dose levels (60-120 mg/m2), the compound was rapidly absorbed with a median Tmax ranging from 0.5 to 1.0 h, suggesting that the rate of absorption was comparable among the four dose levels. The mean T1/2 over all dose levels ranged from 25 to 35 h.


Figure 2
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  		Fig. 2. Plasma concentration versus time profiles of BMS-275183 on days 1 and 15 following oral administration in a twice weekly regimen. A, 60 mg/m2 (n = 3); B, 80 mg/m2 (n = 10 for day 1 and n = 8 for day 15); C, 100 mg/m2 (n = 17 for day 1 and n = 15 for day 15); and D, 120 mg/m2 (n = 7 for day 1 and n = 6 for day 15). Points, means of the observed concentrations; bars, SD.

 

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  		Table 3. Pharmacokinetic variables for BMS-275183

 
For increasing dose levels of 60, 80, 100, and 120 mg/m2, the median Cmax and AUCinf on day 1 changed in the ratio of 1:0.75:0.78:0.67 and 1:1.03:0.93:1.16, respectively. As summarized in Table 3, the systemic exposure to BMS-275183 was comparable between days 1 and 15 across the four dose levels. The interpatient variability (%CV) of the AUCinf in patients treated at the recommended dose level of 100 mg/m2 was 94% on day 1 (n = 17) and 93% on day 15 (n = 15). At other dose levels, the interpatient variability on days 1 and 15 was lower compared with the 100 mg/m2 dose cohort. One patient in the 100 mg/m2 dose level exhibited high exposure (AUCinf = 7639 ng h/mL, day 1), which may have contributed to the higher interpatient variability in this dose cohort. This patient experienced a DLT after the second dose, consisting of grade 3 peripheral neuropathy. Provided that this outlier patient's data were excluded, the interpatient variability in AUCinf for 100 mg/m2 (day 1) was 57%.

In general, patients in whom a DLT occurred had a higher exposure to BMS-275183 [mean AUCinf, 3,731 ng h/mL (n = 7)] compared with patients who did not experience a DLT [mean AUCinf, 1,488 ng h/mL (n = 30)]. We could not identify a common denominator predicting drug exposure and development of side effects. In particular, patients with tumor involvement of the liver did not have a lower drug clearance. Additionally, many potentially interacting concomitant medications were excluded by the protocol. However, the use of PPIs was only excluded from July 2005, as at that time an association between PPI use and elevated exposure to BMS-275183 was found in ongoing clinical trials, suggesting a potential drug-drug interaction (17). In this study, there were 11 patients using a PPI concomitantly with study medication. Of the seven patients experiencing a DLT, two patients (29%) were concomitantly using a PPI. Of the 30 patients who did not experience a DLT, 9 (30%) were reported to use a PPI during their treatment with BMS-275183, suggesting that concomitant use of PPIs was not an important risk factor for developing severe toxicity in this trial.

Tumor response. We observed four confirmed partial responses in 30 evaluable patients with measurable disease. The tumor types of responding patients included: NSCLC (2 of 10 response evaluable patients), prostate carcinoma (1 of 3 response evaluable patients), and melanoma (1 of 3 response evaluable patients). In addition, a long-lasting prostate-specific antigen response (baseline prostate-specific antigen level, 670 ng/mL, decreasing to 6.1 ng/mL with a response duration of 8 months) was seen in one patient with prostate carcinoma out of four patients with nonmeasurable disease. In total, four patients treated at the 80, 100, 120, and 140 mg/m2 dose levels went off the study in the first cycle and were not evaluable for response. Computed tomography scans of a responding patient with NSCLC, as well as a responding patient with prostate carcinoma, are shown in Fig. 3 . Confirmed partial responses were observed after a mean of two cycles. The response duration was 6.5 and 15 months for the two patients with NSCLC, 3.5 months for the patient with prostate carcinoma and 1.75 months for the patient with melanoma (mean response duration of 6.7 months). Interestingly, one additional patient with prostate carcinoma had a partial response (>50% reduction of lymph node and pulmonary metastases) after only two doses of BMS-275183 (100 mg/m2 dose level), but the response was not confirmed because he discontinued treatment due to the development of grade 3 neurotoxicity. Upon recovery and progression, he was retreated at a lower dose level of 60 mg/m2, resulting in a minor response. All confirmed responses occurred in patients who were not previously treated with taxanes or other microtubule-interacting agents. Interestingly, however, the one patient with prostate carcinoma with an unconfirmed response after only two doses of BMS-275183 was resistant to docetaxel, as he had shown clear progressive disease after three courses of docetaxel.


Figure 3
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  		Fig. 3. Computed tomography scans of two responding patients. A, computed tomography scan of a 56-year-old male with NSCLC, previously treated with cisplatin/gemcitabine and gefitinib. Confirmed partial response (after six cycles) of the primary tumor and intrapulmonary metastases. B, abdominal computed tomography scan of a chemotherapy-naïve 65-year-old male with prostate carcinoma. Confirmed partial response (after three cycles) of paraaortal lymph node metastases.

 

   Discussion
Top
 Abstract
 Patients and Methods
 Results
 Discussion
References
 
In the present clinical study, we have shown that BMS-275183 seems to be better tolerated in a twice weekly regimen than in a weekly schedule. In addition, we confirm that this drug has considerable antitumor activity. DLTs consisted of neutropenia, neuropathy, and diarrhea, and other severe toxicities comprised fatigue and hematuria/increased urinary frequency and occurred only after prolonged treatment with BMS-275183. Remarkably, peripheral neuropathy occurred less frequently and was less severe than in our previous study with a weekly dosing schedule. This observation confirms our hypothesis that adapting the dosing regimen from once weekly to twice weekly dosing, and thereby spreading the systemic exposure over a longer period of time, would reduce the neurotoxic side effects of BMS-275183. Interestingly, we observed a similar incidence of myelosuppression after twice weekly administration of BMS-275183 compared with the weekly dosing regimen. Although we did not use prophylactic medication against anaphylaxis, we did not observe any hypersensitivity reactions, confirming the results of our previous trial with this compound (10).

In this study, the systemic exposure to BMS-275183 on day 15 was comparable to the exposure on day 1 for all dose levels, suggesting that twice weekly dosing does not result in the accumulation of BMS-275183. No clinically relevant accumulation is expected based on the observed T1/2 and the twice weekly dosing interval. The fact that no proportional increase in systemic exposure was seen in increasing dose levels might be due to the saturation of absorption of BMS-275183 after oral dosing. We identified 100 mg/m2 twice weekly as the MTD. With this dose, we achieved a similar dose intensity as compared with the trial in which we studied weekly administration of BMS-275183 (MTD of 200 mg/m2). The dose of 100 mg/m2 given in a twice weekly regimen was generally well tolerated with 3 of 17 patients experiencing (reversible) grade 3 or 4 toxicity in the first cycle. Patients with a relatively high exposure to the drug were more prone to develop severe side effects. This relationship between drug exposure and adverse events is not unprecedented and has also been reported for other taxanes (18). Neither in our former study, nor in this trial, could we identify a common denominator predicting drug exposure and development of side effects upon treatment with BMS-275183 (10). However, concomitant use of PPIs was not excluded from the start of the study, and a clinical study to explore the interaction between BMS-275183 and PPIs is ongoing.

In the 100 mg/m2 dose cohort, one patient experienced a very high exposure (and a DLT), which may contribute to the high interpatient variability of 94% in this dose cohort. In our previous trial, we observed an interpatient variability of 53%, which is consistent with the average interpatient variability throughout all dose cohorts in this study. This variability is approximately 2-fold higher than for i.v. paclitaxel (historical data; ref. 19). Variations in absorption of the drug combined with individual differences in metabolism due to CYP3A4 polymorphism (20, 21) may explain the observed high interpatient variability in systemic exposure to the drug. In the present study, concomitant use of CYP3A4-modifying drugs were prohibited and no violations of the protocol were made in this respect. However, no studies were undertaken to investigate the effect of CYP3A4 polymorphisms on the metabolism of BMS-275183, and future trials may elaborate on this important issue. The high interpatient variability may be of concern for the use of BMS-275183 in large-scale phase II or III trials. Care should be taken to delay and reduce dosing upon the first signs of development of severe toxicity, in order to give the drug safely to those patients with an unexpected high exposure to the drug.

The response rate of 13% in the heavily pretreated patient group of this trial confirms our previous finding that BMS-275183 is a potent new taxane analogue. As expected, based on our previous trial and preclinical studies (1, 4), most responses in this trial were observed in patients with NSCLC and prostate carcinoma. In preclinical studies, antitumor activity was observed in taxane-resistant tumor models, including those harboring tubulin mutations or overexpressing P-glycoprotein (4). Our previous study indicated that BMS-275183 was active after prior taxane treatment, but no conclusion could be drawn on its activity in taxane-resistant tumors. In this study, all responses were in taxane-naïve patients, but interestingly, there were clear hints of activity in a taxane-resistant patient with prostate carcinoma.

In summary, BMS-275183 is a potent taxane analogue that is generally well tolerated at its MTD of 100 mg/m2 in a twice weekly dosing schedule. A twice weekly regimen is preferred over a once weekly administration schedule because of a considerably lower incidence of neuropathic side effects. BMS-275183 has antitumor activity in NSCLC and prostate carcinoma, and is currently being investigated in a phase II trial of patients with NSCLC.


   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.

Note: This study was presented in part at the American Society of Clinical Oncology Conference 2005 (abstract no. 2040) and the European Organization for Research and Treatment of Cancer/National Cancer Institute/AACR Conference on Molecular Targets and Cancer Therapeutics 2006 (abstract no. 644).

6 Unpublished data. Back

Received 12/ 5/06; revised 3/ 8/07; accepted 4/ 9/07.


   References
Top
 Abstract
 Patients and Methods
 Results
 Discussion
 References
 

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