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Journal of Clinical Oncology, Vol 20, Issue 23 (December), 2002: 4508-4516
© 2002 American Society for Clinical Oncology

Phase II and Pharmacologic Study of Weekly Oral Paclitaxel Plus Cyclosporine in Patients With Advanced Non–Small-Cell Lung Cancer

By C.M.F. Kruijtzer, J.H.M. Schellens, J. Mezger, M.E. Scheulen, U. Keilholz, J.H. Beijnen, H. Rosing, R.A.A. Mathôt, S. Marcus, H. van Tinteren, P. Baas

From the Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, and Slotervaart Hospital, Amsterdam, the Netherlands; St Vincentius-Kliniken, Karlsruhe, Universitätsklinikum, Essen, and Universitätsklinik Benjamin Franklin, Berlin, Germany; and IVAX Research, Inc, Miami, FL.

Address reprint requests to P. Baas, MD, PhD, Department of Medical Oncology, the Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands; email: p.baas{at}nki.nl


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
PURPOSE: A phase II study was performed to assess the efficacy and toxicity of oral cyclosporine (CsA) plus paclitaxel in advanced non–small-cell lung cancer (NSCLC).

PATIENTS AND METHODS: Chemotherapy-naive or previously treated patients (one regimen) with measurable disease and World Health Organization performance status <= 2 were eligible. Oral paclitaxel was given weekly in a dose of 90 mg/m2 bid. CsA (10 mg/kg) was given 30 minutes before each dose of oral paclitaxel.

RESULTS: Twenty-six patients with a median age of 54 years (range, 32 to 77 years) were entered onto this study. Eighteen patients (69%) had received one prior chemotherapy regimen. The most frequently recorded toxicities were as follows: National Cancer Institute common toxicity criteria grade 3 neutropenia, eight patients (31%); grade 4, six patients (23%); grade 4 febrile neutropenia, three patients (12%); grade 2/3 neurotoxicity, three patients (12%); and grade 2 nail changes, four patients (15%). The overall response rate (ORR) of the 23 assessable patients was 26% (95% confidence interval [CI], 10% to 48%). In the intention-to-treat population, the ORR was 23% (95% CI, 9% to 44%). The median time to progression was 3.5 months (95% CI, 1.2 to 3.9 months), and median overall survival was 6.0 months (95% CI, 2.3 months to not available). Pharmacokinetics revealed that the mean area under the concentration-time curve (AUC) of oral paclitaxel was 5.0 ± 2.3 µmol/L/h in week 1 and 4.6 ± 2.0 µmol/L/h in week 2, with interpatient variabilities (coefficient of variation [%CV]) of 45% and 42%, respectively. The intrapatient variability (%CV) of the AUC was 14.5%.

CONCLUSION: Oral paclitaxel plus CsA is active and safe in advanced NSCLC, including in patients previously treated with chemotherapy.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
PATIENTS WITH extensive non–small-cell lung cancer (NSCLC) have a poor prognosis, as the disease is incurable with currently available therapy. The results of a meta-analysis revealed that cisplatin-based chemotherapy significantly increased median survival by 1 to 2 months and induced objective response rates between 15% and 30%.1-3 Several single agents such as vinorelbine,4 gemcitabine,5 irinotecan,6 and the taxanes7,8 have shown response rates between 8% and 40%, and median overall survival ranged from 6 to 11 months. The taxanes are also used in combination chemotherapy with carboplatin9 or gemcitabine.10 A recently published phase III study investigated paclitaxel as first-line treatment plus supportive care versus best supportive care in patients with advanced NSCLC and showed that the addition of paclitaxel significantly improved both time to progression (3.9 v 0.5 months) and overall survival (6.8 v 4.8 months).11 Another phase III study evaluated docetaxel 75 or 100 mg/m2 versus vinorelbine or ifosfamide as second-line treatment in patients with advanced NSCLC and has shown a significantly improved 1-year survival rate for the docetaxel arm.12 The overall response rates in both studies were low (16% and 10%, respectively), but the benefit was largely because of disease stabilization.11,12 In an attempt to increase the drug exposure over time, weekly schedules of intravenous paclitaxel were initiated and showed promising activity and manageable toxicity in several tumor types.13,14 When paclitaxel was administered as a single agent weekly for 6 weeks every 8 weeks, a dose of 150 to 175 mg/m2 intravenously can be used safely as first-line treatment and a dose of 80 mg/m2 was feasible as second-line treatment in patients with advanced NSCLC. Response rates of approximately 35% to 40% and 6%, respectively, were observed.14-16 Limited data are available thus far regarding activity and toxicity of weekly schedules as second-line treatment.

The development of an oral formulation of paclitaxel is attractive, because oral administration is convenient and practical for patients and may enable development of chronic treatment schedules resulting in sustained plasma concentrations above a pharmacologically relevant threshold level. Our preclinical studies have shown that the oral bioavailability of paclitaxel is low because of its affinity for the membrane-bound drug efflux pump P-glycoprotein (P-gp) in the gastrointestinal tract. In addition, presystemic extraction in the liver by the cytochrome P-450 system may also play an important role.17 Preclinical studies at our institute have shown that coadministration of oral cyclosporine (CsA), an efficacious inhibitor of P-gp and cytochrome P-450 3A4–mediated drug metabolism, results in an approximately eight-fold increase of the systemic exposure of oral paclitaxel.18,19 The apparent bioavailability of oral paclitaxel, which did not account for the effect of CsA on systemic clearance, increased from 4% without to approximately 47% with CsA.19 Of note, no systemic exposure to the vehicle Cremophor EL was seen, which is responsible for the severe hypersensitivity reactions.19 Another study showed that P-gp inhibition by CsA was maximal at a single dose between 10 and 15 mg/kg.20 Prolongation of the time period of drug exposure of paclitaxel seemed to be more important for the activity of paclitaxel than an increase in the plasma concentration.21,22 For that reason, a bid dosing schedule of oral paclitaxel was investigated in a phase I study, and results revealed that at the dose level of 2 x 90 mg/m2, the highest systemic exposure of paclitaxel was reached with a good safety profile.23

The aim of this phase II study was to assess the activity and toxicity of the combination of oral paclitaxel and oral CsA given bid on a weekly basis in patients with advanced NSCLC who were chemotherapy-naive or previously treated with one chemotherapy line. We also determined the time to progression and overall survival of these patients. In addition, we evaluated the pharmacokinetics of this combination.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Eligibility Criteria
Patients with histologically or cytologically confirmed stage IIIB/IV NSCLC were eligible for this study. Prior taxane therapy was not allowed. At entry, patients were required to have measurable disease according to the response evaluation criteria in solid tumors (RECIST).24 They had to have adequate hematologic, renal, and hepatic functions (absolute neutrophil count [ANC] > 1.5 x 109/L, platelets > 100 x 109/L, bilirubin <= 1.5 times upper limit of normal, AST and/or ALT <= 2.0 upper limit of normal, unless liver metastases were present, then <= 5 times upper limit of normal, and serum creatinine <= 2 times upper normal limit). All patients had to have a World Health Organization performance status of <= 2. Exclusion criteria were concomitant use of known P-gp inhibitors and chronic use of H2-receptor antagonists or proton pump inhibitors; known history of cerebral or leptomeningeal metastases or neurologic disease; history of prior malignancy except completely excised carcinoma in situ of the cervix or nonmelanoma skin cancer; bowel obstruction or motility disorders that may influence the absorption of drugs; concurrent treatment with other experimental drugs; allergy to CsA; concomitant medication that has been reported to increase the metabolism of CsA; unresolved toxicities of previous treatment (>= grade 2); intercurrent disease (active infections); and serious heart disease. The study protocol was approved by the medical ethics committees of all participating institutes, and all patients gave written informed consent.

Treatment Plan
On day 1 of each week, oral paclitaxel (Paxoral; IVAX Research, Inc, Miami, FL) was dosed bid (90 mg/m2) with at least 7 but not more than 12 hours between doses. CsA in a dose of 10 mg/kg was given 30 minutes before each dose of oral paclitaxel. CsA was supplied as capsules of 50 mg and 100 mg. Oral paclitaxel was supplied as a solution in a bottle. The solution contained paclitaxel 12 mg/mL. The pharmacist used a syringe to deliver the appropriate number of milliliters of the oral paclitaxel solution into a plastic cup for dispensing as a drinking solution. Oral paclitaxel was added to at least 50 mL of tap water or juice (not grapefruit) into the plastic cup and was shaken gently for about 1 minute and had to be ingested within 2 hours of preparation. The treatment was administered weekly until disease progression or unacceptable toxicity developed. Patients were advised to have a "light" meal consisting of one cracker and a cup of tea before intake of the drugs, and they started eating 1 hour after dosing. No antiallergic (dexamethasone, clemastine, and ranitidine) premedications were taken, because our previous phase I studies had revealed that this can be omitted.19,25 Oral granisetron in a dose of 1 mg was given 1 hour before intake of the chemotherapy to prevent nausea and vomiting.

Evaluation of Response and Toxicity
Hematology and blood chemistries were checked before treatment and subsequently weekly. All toxicities were graded according to the National Cancer Institute common toxicity criteria.26 All patients who received at least one weekly cycle of therapy were assessable for toxicity. Two dose reductions were allowed, first to 70 mg/m2 (bid) and then to 55 mg/m2 (bid), and patients who required further dose reductions were withdrawn from the study. Dose reduction of one dose level was mandated for patients who experienced common toxicity criteria grade 3 or 4 nonhematologic toxicity (except alopecia), or hematologic toxicity consisting of ANC less than 0.5 x 109/L, or neutropenic fever or thrombocytopenia less than 25 x 109/L. For patients who required dose reductions, the dosage was not re-escalated in subsequent cycles. The CsA dose of 10 mg/kg remained constant despite dose reductions. Treatment was postponed until recovery of thrombocytes more than 100 x 109/L and ANC more than 1.5 x 109/L. When treatment delay was more than 2 weeks because of hematologic toxicity, the patient was treated at the next lower dose level. Standard clinical measurements and radiologic examination were used to ensure bidimensionally measurable disease according to the RECIST criteria24 for response evaluation. Radiologic responses were confirmed by independent review. Patients who completed eight weekly cycles were considered assessable for response. The primary end point of the study was the response rate. We also determined the duration of response as the number of days between the onset of response and the date of last progression-free evaluation. For patients whose disease had not progressed, the date of last progression-free evaluation was censored. In addition, we determined the time to progression as the number of days between the date of first treatment and the date of progression or death. Survival was defined as the number of days from the date of the first dose to the date of death.

Sample Collection and Analysis
Pharmacokinetic monitoring was performed in every patient during week 1 and week 2. For paclitaxel, blood samples of 5 mL each were collected in heparinized tubes before dosing, and at 30 and 60 minutes and 2, 3, 4, 6, 7, 7.5, 8, 10, 12, 24, and 30 hours after ingestion of oral paclitaxel. For the centers outside the Netherlands, blood samples of 5 mL each were collected before dosing, and 1, 3, and 4 hours after paclitaxel intake. Blood samples were centrifuged, and plasma was separated and stored at -20°C until analysis. Paclitaxel concentrations in plasma were determined using a validated high-performance liquid chromatography assay.27 For CsA monitoring, only blood sampling was performed in the patients at the Dutch hospital at the same sampling times as for paclitaxel. Whole blood samples were stored at 4°C and analyzed within 1 week using a fluorescence polarization immunoassay (FPIA; Abbott Laboratories, Amstelveen, the Netherlands).28

Pharmacokinetic Analysis
A population pharmacokinetic model was developed for paclitaxel by using the nonlinear mixed-effect modeling program NONMEM (double precision; version v, level 1.1, University of California, San Francisco, CA).29 The first-order conditional estimation method was applied. A two-compartment structural kinetic model with first-order absorption and elimination and saturable transport between central and peripheral compartment was used to describe the time profiles of paclitaxel plasma concentration (Fig 1). The pharmacokinetics of paclitaxel were parameterized in terms of absorption rate constant (Ka), volume of distribution of the central compartment (V), clearance from the central compartment (CL), maximal transport capacity from the central to the peripheral compartment (Tmax), the concentration at which the transport is half maximal (Tm), and rate constant for transport from the peripheral to the central compartment (K21). Interpatient variability of the pharmacokinetic parameters was estimated using a proportional error model. For instance, interindividual variability in CL was estimated using



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  		Fig 1. The pharmacokinetics of paclitaxel were parameterized in terms of absorption rate constant (Ka), volume of distribution (V), clearance (CL), maximal transport capacity (Tmax), concentration at which the transport is half maximal (Tm), and rate constant for transport from the peripheral to the central compartment (K21).

 
equation


in which i represents the number of the individual, CLi is the CL of individual i, CLpop is the population value, and {eta} is the interindividual random effect with mean 0 and variance {omega}2. The difference between the observed concentration (Cobs) and its respective prediction (Cpred) was modeled with a proportional error model:

equation


where {epsilon} is an independent random variable with mean 0 and SD {varsigma}. Because plasma concentration-versus-time profiles were assessed during two courses, interoccasion ("between-course") variability was estimated. The following expression was used for CL:

equation


in which j represents the number of the course (1 or 2), CLij is the CL of individual i at occasion j, CLpop is the population value, and {eta} and {kappa} are the interindividual and interoccasion random effects with mean 0 and variances {omega}2 and {pi}2, respectively.

Individual pharmacokinetic parameters were generated by Bayesian analysis. On the basis of these parameters, individual plasma concentration-time profiles were generated for assessment of the area under the plasma concentration-time curve (AUC), the maximal plasma concentration (Cmax), the time to maximal plasma concentration (tmax), and the time above the previously defined threshold concentrations of 0.1 µmol/L (T > 0.1 µmol/L) and 0.05 µmol/L (T > 0.05 µmol/L) of paclitaxel. For CsA, the parameters AUC, Cmax, and tmax were determined directly from the experimental data.

Statistical Analysis
Patients were accrued according to a two-stage study design30 aiming at 25 eligible patients. Analyses of response rate and time to progression and overall survival were performed on all assessable patients. The response rate was also analyzed on the total population on an intention-to-treat basis. Confidence intervals were calculated using binomial confidence intervals.

The time to progression and overall survival curves were estimated using the Kaplan-Meier method. We calculated the interpatient variability (coefficient of variation [%CV]) in the paclitaxel AUC by dividing the SD by the mean measured values and multiplying by 100. The intrapatient variability (%CV) in the AUC was defined as the AUC value in week 1 minus the AUC value in week 2 divided by the AUC value in week 1 and multiplied by 100. All the individual values were summed and divided by the number of patients.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Patient Characteristics
A total of 26 patients from five hospitals in Europe were entered onto the study between August 2000 and November 2000. Median age of the patients was 54 years (range, 32 to 77 years) (Table 1). Most patients were in a good general condition when they entered the study. Eighteen patients (69%) had received prior chemotherapy.


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  		Table 1. Patient Characteristics at Baseline
 
Dose-Intensity and Dose Reduction
A total of 228 weekly administrations (consisting of the two doses taken on 1 day) of CsA/oral paclitaxel were administered, with a median of eight weekly administrations per patient (range, one to 23) (Table 2). The median dose-intensity was 172 mg/m2/wk (range, 100 to 180 mg/m2/wk). Thirteen patients had a total of 48 weeks’ delay of treatment, which was mainly a result of insufficient recovery of the neutrophils (> 1.5 x 109/L) not allowing retreatment. One patient changed from a weekly to an every-2-weeks administration schedule after the seventh administration on the patient’s request, and two patients underwent a dose reduction from 90 mg/m2 bid to 70 mg/m2 bid because of neutropenic fever.


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  		Table 2. Extent of Exposure in All Patients
 
Treatment Duration
As of October 2001, all patients had discontinued treatment. Eighteen patients (69%) discontinued treatment as a result of disease progression. Seven patients died during study treatment, all but one as a result of disease progression. One patient died after an episode of grade 4 febrile neutropenia resulting in septic shock. Two patients stopped treatment as a result of toxicity, one for grade 3 neurotoxicity and one for grade 3 neutropenia.

Response
The response rates are listed in Table 3. Three patients were not assessable for response, one of whom died as a result of toxicity after two administrations, and two patients refused treatment after five and three administrations, respectively. One of them had problems with swallowing the drug and one patient experienced grade 3 nausea and vomiting.


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  		Table 3. Best Response (RECIST criteria) to Weekly Oral Paclitaxel (bid) in Combination With CsA
 
Partial responses were reported in six patients, resulting in an overall response rate of 26% in the 23 assessable patients (95% confidence interval [CI], 10% to 48%). The median duration of response was 16 weeks (range, 8 to 30 weeks). Furthermore, eight patients (35% of the assessable population) showed stabilization of the disease as best response for the median duration of 17 weeks (range, 8 to 34 weeks). In the intention-to-treat population, the overall response rate (ORR) was 23% (95% CI, 9% to 44%). Nine patients (39%) had progressive disease and went off study.

The characteristics of the six patients who showed a partial response are listed in Table 4. Five patients had received prior chemotherapy, and all responding patients had a relatively long time to progression and overall survival.


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  		Table 4. Characteristics of Responding Patients (n = 6)
 
Time to Progression and Overall Survival
As of November 2001, median time to progression of the assessable patients was 3.5 months (95% CI, 1.2 to 3.9 months), and eight of the 23 patients (35%) were still alive. The median overall survival was 6.0 months (95% CI, 2.33 months to not available). The Kaplan-Meier curves of the time to progression and overall survival of the assessable patients are shown in Figs 2 and 3.



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  		Fig 2. Kaplan-Meier curve of time to progression of the 23 assessable patients.

 


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  		Fig 3. Kaplan-Meier curve of the overall survival of the 23 assessable patients.

 
Toxicity
The hematologic toxicities observed in this study are listed in Table 5. The principal hematologic toxicity was neutropenia, with 54% of patients experiencing severe (grade 3 or 4) neutropenia. Three patients (12%) experienced grade 4 febrile neutropenia. One patient died after an episode of grade 4 febrile neutropenia. In the past, this patient had undergone a splenectomy. After an episode of grade 2 leukopenia, treatment was continued the following week, but after this administration, the patient experienced grade 4 febrile neutropenia and died the following day because of septic shock.


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  		Table 5. Hematologic Toxicities, by Patient
 
Of the nonhematologic toxicities (Table 6), gastrointestinal toxicity and neurotoxicity were the most frequently reported. The gastrointestinal toxicities included nausea/vomiting and diarrhea, which reached grade 3 nausea/vomiting and grade 3 diarrhea in 8% of patients. Neurotoxicity was prevalent, being reported in eight patients (31%), one of whom experienced grade 3. Most patients experienced grade 1 neurotoxicity after a median treatment duration of 11 weeks. Four patients (15%) reported grade 2 nail changes, which generally developed after a median treatment duration of 16 weeks and resolved completely when treatment was stopped.


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  		Table 6. Nonhematologic Toxicities, by Patient
 
Pharmacokinetics
All patients were considered assessable for pharmacokinetic analysis in week 1 and week 2. A total of 379 plasma levels were available for population pharmacokinetic analyses. Several pharmacokinetic-compartment models were applied to the data including two- and three-compartment models with linear and/or saturable distribution and/or elimination. The data were adequately described by a two-compartment model with first-order absorption, linear elimination, and a saturable pathway to the peripheral compartment (Fig 1). Population parameters are listed in Table 7. Structural parameters of the model were estimated with adequate precision (%CV, 8% to 25%). Interindividual variability could only be estimated for V, CL and Tm. This should not be interpreted as an absence of variability for the parameters Ka, Tmax, and K21, but simply that the data do not contain enough information to quantify these parameters. Interoccasion variability could be quantified for CL and Tm. The model-based and Bayesian-predicted concentrations were symmetrically distributed around the line of identity, indicating the adequacy of the population model (data not shown). On the basis of individual Bayesian estimates, secondary pharmacokinetic parameters of bid dosing of oral paclitaxel were derived and are listed in Table 8. The mean AUC of orally administered paclitaxel was 5.0 ± 2.3 µmol/L/h in week 1 and 4.6 ± 2.0 µmol/L/h in week 2. The calculated interpatient variability (%CV) of the AUC of paclitaxel was 45% and 42% in weeks 1 and 2, respectively. The intrapatient variability (%CV) of the AUC was 14.5%. An important pharmacokinetic parameter of paclitaxel is the time period of exposure above a certain threshold level (T > 0.1 µmol/L). The mean T more than 0.1 µmol/L values were 10.7 ± 5.6 hours in week 1 and 9.7 ± 5.1 hours in week 2. The mean T more than 0.05 µmol/L were 20.0 ± 10.8 hours in week 1 and 18.0 ± 10.0 hours in week 2. The mean Cmax values after the first and second dose were comparable in week 1 and week 2, but a small increase of the Cmax value was noted after the second dose. Figure 4 shows plots of all observed paclitaxel concentrations over time and the mean Bayesian-predicted plasma concentration-time profile in week 1 and week 2. The pharmacokinetic parameters of CsA are listed in Table 9.


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  		Table 7. Population Pharmacokinetic Parameters of Paclitaxel After Oral Administration of 90 mg/m2 bid
 

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  		Table 8. Pharmacokinetic Parameters of bid Dosing of Oral Paclitaxel in 26 Patients (data are listed as mean ± SD)
 


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  		Fig 4. Plots of all observed paclitaxel concentrations over time and the mean Bayesian-predicted plasma concentration time profile in week 1 (A) and week 2 (B).

 

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  		Table 9. Pharmacokinetic Parameters of CsA in 11 Patients (data are listed as mean ± SD)*
 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The results of this phase II study performed in patients with advanced NSCLC treated with oral paclitaxel in combination with CsA are encouraging and show an ORR of 26% in 23 assessable patients (intention-to-treat, 23%). This is higher in comparison with other drugs used in a single-agent setting (eg, irinotecan, gemcitabine, and vinorelbine).6,31,32 Data from 10 phase II studies in which patients with advanced NSCLC were treated with paclitaxel intravenously every 3 weeks as first-line therapy or as second-line therapy have shown an ORR of 26%.33 Only limited data are available for the activity of weekly schedules of paclitaxel in NSCLC. In general, the response rates of weekly schedules14,15 are at least comparable to the 3-weekly schedules,34-37 but responses of weekly schedules in the second-line treatment have been disappointing until now.16 It is noteworthy in our study that partial responses during paclitaxel treatment were observed in five pretreated patients with stage IIIB/IV disease. The median time to progression of 3.5 months and median overall survival of 6.0 months are in accordance with previously published studies.11,37

In general, the safety profile of this bid weekly regimen is good. In the current study, grade 3 and 4 neutropenia was the most prevalent hematologic toxicity (54%), and the incidence was comparable with the standard 3-weekly intravenous schedule.34,36,37 Neurotoxicity was reported in 31% of the patients, only one of whom experienced grade 3 neurotoxicity. The occurrence of the neurotoxicity was lower compared with the standard 3-weekly schedule.36,37 The lower peak plasma concentrations after bid dosing of oral paclitaxel might explain the reduced severity of the neurotoxicity. Lower severity of neurotoxicity was also observed in patients with ovarian cancer who received a 24-hour infusion compared with a 3-hour infusion of paclitaxel.38

The schedule used in this study allows greater dose-intensity than would be achieved with the standard 3-weekly intravenous schedule, and this may result in higher efficacy. The median dose-intensity after oral administration of paclitaxel was 172 mg/m2/wk. The apparent bioavailability of oral paclitaxel when coadministered with CsA increased to approximately 47%, when not taking into account the effect of CsA on clearance.19 This may be compared with an average dose-intensity of 80 mg/m2/wk (40 mg/m2/wk bid) when paclitaxel would be administered intravenously. Direct comparison of pharmacokinetic values and doses for oral versus intravenous paclitaxel must be made with great caution because Cremophor EL is responsible for the nonlinear pharmacokinetic behavior of intravenous paclitaxel.25 Because half of the patients experienced treatment delay, treatment with a slightly lower dose might be an alternative in future phase III studies.

Pharmacokinetics revealed that the mean AUC of oral paclitaxel administered weekly (bid) was 5.0 ± 2.3 µmol/L/h in week 1 and 4.6 ± 2.0 µmol/L/h in week 2. These data indicate good reproducibility of pharmacokinetic parameters of orally administered paclitaxel. The interpatient variability of the AUC after oral administration of paclitaxel was moderate and higher comparing the 3-weekly schedule. We demonstrated an interpatient variability of 45% and 42% in week 1 and week 2, respectively, and this was higher in comparison with intravenous data that showed values of 16% and 22%, respectively.39,40 The intrapatient variability (%CV) of the AUC in our study was low (14.5%) and indicates limited variation in absorption and elimination processes in every patient. Earlier data indicate a positive relationship between duration of the paclitaxel plasma concentration above a certain threshold level and pharmacologic activity.21,22 In our study, the high T more than 0.1 µmol/L and T more than 0.05 µmol/L per time period may therefore be a beneficial characteristic of this schedule.

The weekly single oral dose of CsA could have been associated renal toxicity or infections caused by immunosuppression.41 However, in this study, we did not observe any toxicity related to CsA. This can most likely be attributed to the weekly bid administration of the drug, whereas in the transplantation setting CsA is ingested on a chronic daily basis. We have also demonstrated in a clinical study that weekly administration of CsA plus docetaxel has no effect on immunologic parameters (Kruijtzer et al, manuscript submitted for publication).

The use of oral paclitaxel in combination with CsA may have significant advantages over the "classic" method of intravenous treatment. It enables treatment on an outpatient basis, which may increase the quality of life of the patients. Weekly bid treatment results in longer time periods of cytotoxic plasma levels. The disadvantages of the oral formulation of the cytotoxic drug are the possible interaction with food or comedication and unpredictable changes in uptake caused by vomiting or diarrhea. However, oral paclitaxel is not emetogenic, and mild nausea and vomiting were observed, especially 24 hours after intake of oral paclitaxel. This will not affect absorption of paclitaxel, which is maximum on average 1 to 2 hours after oral intake. Furthermore, the absence of Cremophor EL in this oral paclitaxel formulation offers substantial advantages. It circumvents the use of antiallergic medications, which are necessary to prevent hypersensitivity reactions.

In conclusion, in this small multicenter phase II study, promising activity was seen (ORR, 26%) in mostly pretreated patients with advanced NSCLC. Oral paclitaxel in combination with CsA is feasible and has a manageable toxicity profile. Exploration of the efficacy of the combination of oral paclitaxel with CsA in phase III studies in advanced NSCLC and other tumor types is of great interest and will be initiated.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
1. Chemotherapy in non-small cell lung cancer: A meta-analysis using updated data on individual patients from 52 randomised clinical trials—Non-Small Cell Lung Cancer Collaborative Group. BMJ 311:899-909, 1995

2. Stewart L, Pignon JP, Arriagada R, et al: A meta-analysis using individual patient data from randomized clinical trials (RCTS) of chemotherapy in non-small cell lung cancer (NSCLC): Survival in the surgical setting. Proc Am Soc Clin Oncol 13: 336, 1994 (abstr)

3. Marina P, Pampallona S, Preatoni A, et al: Chemotherapy versus supportive care in advanced non-small cell lung cancer: Results of a meta-analysis of the literature. Chest 106: 861-865, 1994[Abstract/Free Full Text]

4. Wozniak AJ: Single agent vinorelbine in the treatment of non-small cell lung cancer. Semin Oncol 26: 62-66, 1999[Medline]

5. Ten Bokkel Huinink WW, Bergman B, Chemaissanin A, et al: Single agent gemcitabine: An active and better tolerated alternative to standard cisplatin-based therapy in locally advanced or metastatic non-small cell lung cancer. Lung Cancer 26: 85-94, 1999[CrossRef][Medline]

6. Baker L, Khan R, Lynch T, et al: Phase II study of irinotecan in advanced non-small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol 16: 461a, 1997 (abstr 1658)

7. Socinski MA: Single agent paclitaxel in the treatment of advanced non-small cell lung cancer. Oncologist 4: 408-416, 1999[Abstract/Free Full Text]

8. Miller V, Kris M: Docetaxel as a single agent and in combination chemotherapy for the treatment of patients with advanced non-small cell lung cancer. Semin Oncol 27: 3-10, 2000[Medline]

9. Huizing MT, Giaccone G, Van Warmerdam LJC, et al: Pharmacokinetics of paclitaxel and carboplatin in a dose escalating and sequencing study in patients with non-small cell lung cancer. J Clin Oncol 15: 317-329, 1997[Abstract/Free Full Text]

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Submitted April 5, 2002; accepted August 6, 2002.


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