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Journal of Clinical Oncology, Vol 19, Issue 3 (February), 2001: 832-842
© 2001 American Society for Clinical Oncology

Phase I Study of Infusional Paclitaxel in Combination With the P-Glycoprotein Antagonist PSC 833

By Isagani Chico, Min H. Kang, Raymond Bergan, Jame Abraham, Susan Bakke, Beverly Meadows, Ann Rutt, Rob Robey, Peter Choyke, Maria Merino, Barry Goldspiel, Tom Smith, Seth Steinberg, William D. Figg, Tito Fojo, Susan Bates

From the Medicine Branch and Department of Pathology, Division of Clinical Sciences, and Biostatistics and Data Management Section, National Cancer Institute; Clinical Center Pharmacy and Department of Radiology, Clinical Center, National Institutes of Health, Bethesda, MD; Northwestern University Medical School, Chicago, IL; and Novartis Pharmaceuticals Corporation, East Hanover, NJ.

Address reprint requests to Susan Bates, MD, Medicine Branch, National Cancer Institute, National Institutes of Health, Bldg 10, Rm 12N226, 9000 Rockville Pike, Bethesda, MD 20892; email: sebates{at}helix.nih.gov


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
PURPOSE: PSC 833 (valspodar) is a second-generation P-glycoprotein (Pgp) antagonist developed to reverse multidrug resistance. We conducted a phase I study of a 7-day oral administration of PSC 833 in combination with paclitaxel, administered as a 96-hour continuous infusion.

PATIENTS AND METHODS: Fifty patients with advanced cancer were enrolled onto the trial. PSC 833 was administered orally for 7 days, beginning 72 hours before the start of the paclitaxel infusion. Paclitaxel dose reductions were planned because of the pharmacokinetic interactions known to occur with PSC 833.

RESULTS: In combination with PSC 833, maximum-tolerated doses were defined as paclitaxel 13.1 mg/m2/d continuous intravenous infusion (CIVI) for 4 days without filgrastim, and paclitaxel 17.5 mg/m2/d CIVI for 4 days with filgrastim support. Dose-limiting toxicity for the combination was neutropenia. Statistical analysis of cohorts revealed similar mean steady-state concentrations (Cpss) and areas under the concentration-versus-time curve (AUCs) when patients received paclitaxel doses of 13.1 or 17.5 mg/m2/d for 4 days with PSC 833, as when they received a paclitaxel dose of 35 mg/m2/d for 4 days without PSC 833. However, the effect of PSC 833 on paclitaxel pharmacokinetics varied greatly among individual patients, although a surrogate assay using CD56+ cells suggested inhibition of Pgp was complete or nearly complete at low concentrations of PSC 833. Responses occurred in three of four patients with non–small-cell lung cancer, and clinical benefit occurred in five of 10 patients with ovarian carcinoma.

CONCLUSION: PSC 833 in combination with paclitaxel can be administered safely to patients provided the paclitaxel dose is reduced to compensate for the pharmacokinetic interaction. Surrogate studies with CD56+ cells indicate that the maximum-tolerated dose for PSC 833 gives serum levels much higher than those required to block Pgp. The variability in paclitaxel pharmacokinetics, despite complete inhibition of Pgp in the surrogate assay, suggests that other mechanisms, most likely related to P450, contribute to the pharmacokinetic interaction. Future development of combinations such as this should include strategies to predict pharmacokinetics of the chemotherapeutic agent. This in turn will facilitate dosing to achieve comparable CPss and AUCs.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
THE EDUCTION OF intracellular drug concentrations by energy-dependent transport has been identified as a common mechanism of anticancer drug resistance in in vitro models. Although an increasing number of putative drug transporters have been identified, transport mediated by P-glycoprotein (Pgp), encoded by the MDR-1 gene, has been most extensively studied.1 Clinical interest in Pgp was stimulated by the discovery that resistance reversal could be achieved by the addition of other Pgp substrates.2 First-generation reversal agents, such as verapamil, had limited success in the clinic. This limited success was most likely the result of the inability to achieve serum concentrations sufficient to reverse drug resistance. Subsequently, second-generation agents have been developed that offer both greater potency and specificity.3 PSC 833 (valspodar), a second-generation agent, is a cyclosporine D derivative that is nonnephrotoxic and nonimmunosuppressive.4

First-generation studies demonstrated that Pgp antagonists can reduce the clearance of anticancer drugs.5 Among the first-generation agents, pharmacokinetic interactions were reported most frequently with cyclosporine A. Cyclosporine A not only inhibits Pgp but also can interfere with the metabolism of compounds that are substrates for the 3A4 isoenzyme of cytochrome P450; thus, it seems likely that both of these properties contribute to the pharmacokinetic interaction.6,7 Numerous anticancer agents, including paclitaxel, are substrates for this isoform of P450. Consequently, cyclosporine, and likewise the cyclosporine derivative PSC 833, would be expected to affect the clearance of paclitaxel by inhibiting both Pgp and the 3A4 isoenzyme of cytochrome P450. However, the relative contribution of each has not been delineated.

The phase I study described herein was designed to determine the maximum-tolerated dose (MTD) of PSC 833 in combination with paclitaxel and to ascertain how PSC 833 affects the pharmacokinetics of paclitaxel administered as a 96-hour continuous intravenous infusion (CIVI). Paclitaxel was chosen as the antineoplastic agent based on extensive in vitro data demonstrating that overexpression of Pgp confers resistance to paclitaxel. An infusional schedule was selected because previous studies had shown that continuous exposure could reduce the relative resistance of cancer cells with high levels of Pgp overexpression.8 Because previous studies had demonstrated pharmacologic interactions between Pgp antagonists and chemotherapeutic agents, the current combination study used a sequential dose-escalation schema. The primary goal was to maximize the dose of PSC 833 while de-escalating the dose of paclitaxel, so as to limit the toxicity of the combination while maintaining cytotoxic activity.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patient Selection
Patients were required to meet standard phase I selection criteria. Fifty patients were enrolled onto the trial, which had been reviewed and approved by the National Cancer Institute’s institutional review board. Verbal and written informed consent was obtained from all patients. Patients were treated at the Warren Magnusen Clinical Center in Bethesda, MD. Enrollment criteria included age older than 18 years, a Karnofsky performance status score of 70 or better, and a life expectancy of more than 3 months. A patient was ineligible if he or she had received chemotherapy, immunotherapy, or radiation therapy in the 4 weeks before study entry. Patients who had received prior bone marrow transplantation or extensive radiation resulting in compromised bone marrow reserve were not eligible. Patients were required to have AST and ALT levels <= twice the upper limit of normal, creatinine clearance >= 50 mL/min, WBC count >= 3,000/mm3, absolute neutrophil count >= 1,000/mm3, and platelet count >= 100,000/mm3. While on study, patients were not allowed to take agents known to be metabolized by P450 nor drugs known to interact with cyclosporine A. Forty-one of the 50 patients received at least the second cycle (first combined cycle). Five patients did not complete the first cycle (due to progressive disease while receiving paclitaxel, diagnosis of brain metastases requiring radiation, severe neutropenia and stomatitis before PSC 833, progressive disease with superior vena cava syndrome, and patient refusal) and four patients completed the first cycle but did not receive cycle 2 (due to rapidly progressive disease, diagnosis of brain metastases requiring radiation, severe neutropenia and stomatitis in first cycle, and patient refusal). Thus, in only 41 patients was it possible to evaluate the toxicity of the paclitaxel/PSC 833 combination.

Drug Supply and Treatment Schema
PSC 833 (supplied by Novartis Pharmaceuticals Corporation, East Hanover, NJ) and paclitaxel (Taxol; Bristol Myers Squibb Oncology, Princeton, NJ) were distributed through Cancer Therapy Evaluation Program, National Cancer Institute. Filgrastim was obtained from commercial sources. In the formulation used in this study, PSC 833 was suspended as a microemulsion composed of polyoxyl 40 hydrogenated castor oil, ethanol, D-L-alpha tocopherol, propylene glycol, and maize oil (labrifil). PSC 833 was administered orally at intervals of 8 or 6 hours. For paclitaxel, a 24-hour supply prepared in an Excel (McGaw, Inc, Irvine, CA) container was infused via nonplasticized tubing with an in-line filter by using a portable infusion pump. Filgrastim was administered subcutaneously.

Patients were treated according to the schema in Fig 1. The study was designed so that patients received paclitaxel and PSC 833 separately in the first cycle and together in all subsequent cycles. This design was chosen to allow paclitaxel pharmacokinetics to be determined alone and in combination with PSC 833. In the first cycle, the 96-hour paclitaxel infusion was begun on day 1 and the 7-day PSC 833 administration was begun 48 hours after completion of the paclitaxel infusion. After the first 32 patients were treated, the interval between the end of the paclitaxel infusion and the start of PSC 833 administration was extended to 96 hours. Cycle 2 began on day 22. In cycle 2, oral PSC 833 was started 72 hours before the initiation of the paclitaxel infusion and was administered for an additional 96 hours together with paclitaxel (a total of 7 days PSC 833), after which time the paclitaxel infusion and the PSC 833 ingestion were terminated simultaneously. After cycle 2, patients were treated at 3-week intervals, or at 4-week intervals, if required for adequate bone marrow recovery. The design called for escalating the dose of PSC 833 while decreasing paclitaxel as required. Dose-limiting toxicity (DLT) of a given paclitaxel/PSC 833 dose was defined as either grade 3 or 4 nonhematologic toxicity (excluding hyperbilirubinemia), fever with neutropenia, or an ANC less than 500/mm3 for more than 4 days. However, even if DLT was encountered, further dose escalations of PSC 833, up to a maximum of 5 mg/kg every 6 hours for 7 days, were allowed provided the paclitaxel dose was reduced. The PSC 833 dose of 5 mg/kg every 6 hours for 7 days was established as the MTD in ongoing clinical trials, and thus a further dose escalation was not attempted (M. Litchman, personal communication). For all but the first three patients, the paclitaxel dose in the first cycle was 35 mg/m2/d by CIVI for 4 days. The starting dose of paclitaxel in cycle 2 was 25 mg/m2/d by CIVI for 4 days, but this was subsequently reduced to 17.5 mg/m2/d by CIVI for 4 days, because dose reductions of 50% had been required in previous studies with PSC 833 and other agents.9-11 After the MTD for paclitaxel in combination with PSC 833 5 mg/kg every 6 hours was established, further paclitaxel dose escalations were performed with filgrastim support in cycle 2 and subsequent cycles. The dose of filgrastim was 5 mg/kg/d beginning 48 hours after cessation of the paclitaxel infusion. Patients were continued on-study until disease progression was documented or when it was considered in the patient’s best interest to be removed from the study. On completion of the study, tumor measurements from radiographic studies of patients considered to have stable disease or a response were confirmed by a single radiologist (P.C.).



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  		Fig 1. Treatment schema showing the drug administration schedules for cycles 1 and 2. *The first cohort of three patients received 25 mg/m2/d for 4 days. #Some patients also received 13.1 or 21.3 mg/m2/d for 4 days to identify the MTD.

 
PSC 833 Radioimmunoassay
PSC 833 levels were measured during the first cycle when PSC 833 was administered alone. PSC 833 concentrations in whole-blood samples were determined by the Bioanalytics and Pharmacokinetics Section, Drug Metabolism and Pharmacokinetics Department, Novartis Pharmaceuticals Corporation. Blood PSC 833 concentrations were determined with the SDZ PSC 833 radioimmunoassay kit (ANAWA Laboratories, Zurich, Switzerland). On each analysis day, the PSC 833 standard stock solution (12 ± 0.2 µg/mL) provided in the kit was diluted with human blood (with EDTA anticoagulant) to produce seven standard concentrations according to the dilution scheme outlined in the PSC 833 kit instructions. The blood standard concentrations were 37.5, 75.0, 150, 300, 600, 1,200, and 1,800 ng/mL. Briefly, standards, quality control (QC) samples, pooled blank normal human whole blood, and patient blood samples were pipetted into prelabeled 16 x 75-mm glass tubes. Each blood sample was analyzed in duplicate. To each sample, 1 mL of methanol was dispensed, and the sample was vortex-mixed and centrifuged at 3,000 rpm at 40°C for 10 minutes. The supernatant from each tube was decanted into clean prelabeled 16 x 75-mm glass tubes and evaporated to dryness using a vortex evaporator set at 54°C. To each tube, appropriate volumes of buffer and normal human plasma were added and vortex-mixed to redissolve all of the sample residue. To each sample tube, tracer (3H-Dihydro-PSC 833) and antibody-specific cyclosporine monoclonal antibody were added and vortex-mixed briefly. The tubes were covered and then incubated overnight at 4°C. The next morning, the samples were placed in an ice-water bath, then a volume of prechilled charcoal suspension was added to each sample and the samples were vortex-mixed and incubated at 40°C for 10 minutes. Each tube was centrifuged at 800 x g at 4°C for 7 minutes. The supernatant from each sample tube was decanted into 10 mL of Picofluor contained in a separate scintillation vial. Each vial was capped, thoroughly mixed, placed in a beta counter, and counted for 5 minutes. Each assay run included the seven blood standard concentrations, B0 samples, totals and nonspecific binding samples, blood samples from patients, and six QC sample concentrations. The QC sample concentrations ranged from 70 ng/mL to 4,520 ng/mL. Using the internal RIAPROG program, a linear standard curve was constructed by plotting percentage B (binding) over B0 versus the standard concentration (Logit-Log). For sample and QC sample concentrations higher than the calibration standard concentrations, dilution with blank blood was performed before an aliquot was taken for analysis. The appropriate volume correction factor was applied to the concentration observed for diluted samples. The mean concentration of each set of replicate values was reported for all unknowns and QC samples, and the blood PSC 833 concentrations were reported in nanograms per milliliter.

Paclitaxel Measurements and Pharmacokinetics
Blood samples were drawn in heparinized tubes before paclitaxel treatment and 24, 48, 72, and 96 hours after the start of the paclitaxel infusion from all patients in the first and second cycles. Data obtained beyond 96 hours were not included because in the second cycle both the PSC 833 administration and the paclitaxel infusion finished at the 96th hour, precluding an accurate assessment of the effect of PSC 833 on the terminal paclitaxel kinetics. Samples were centrifuged immediately, and the plasma was collected and stored at -80°C until analysis. The concentration of paclitaxel in plasma was determined using high-performance liquid chromatography (HPLC) with ultraviolet detection. A Hewlett-Packard 1090 Series II liquid chromatograph (Agilent Technologies, Wilmington, DE) equipped with a photodiode-array detector was used. The paclitaxel concentration, after extraction of 0.6 mL of the patient plasma or paclitaxel-spiked plasma standard solutions containing harmine 0.2 µg/mL as the internal standard, was measured using the following procedure. Solid-phase extraction was performed using C18 elution columns. The columns were equilibrated with 2 mL of methanol followed by 2 mL of NH4Ac 10 mmol/L (pH 5.0). After 0.6 mL of ammonium acetate 0.2 M was added to the plasma, the plasma-buffer mixtures were loaded onto the columns and washed with 2 mL of NH4Ac 10 mmol/L followed by 2 mL of 20% methanol in NH4Ac 10 mmol/L and 1 mL of n-hexane. The columns were dried and eluted with 2 x 1 mL of 0.1% triethylamine in acetonitrile. The eluents were dried and reconstituted in 200 µL of acetonitrile, methanol, and water (4:1:5 v/v/v) containing NH4Ac 0.01 M. The reconstituted sample, 170 µL, was injected onto a Waters Nova-Pak C18 (3.9 x 300-mm) column (Waters Co., Milford, MD). The mobile phase (25% acetonitrile, 5% methanol, 70% water, and NH4Ac 10 mmol/L) with gradient was used at a flow rate of 1.0 mL/min at room temperature. Ultraviolet detection was at 242 nm (bandwidth 35 nm). Average retention times were 13.3 and 9.7 minutes for paclitaxel and the internal standard, harmine, respectively. The lower limit of quantification for paclitaxel was 25 ng/mL. The intra-assay and interassay coefficients of variation were less than 10% between 25 ng/mL and 100 ng/mL. The steady-state concentration (Cpss) was calculated as the mean of the 48-, 72-, and 96-hour time points. The area under the concentration-versus-time curve (AUC) for the duration of the 96-hour infusion was calculated by using the trapezoidal rule. Calculations of AUC to infinity for paclitaxel could not be made, because sufficient data were not obtained. Samples were not collected after the 96-hour infusion because the protocol design called for discontinuing PSC 833 and paclitaxel simultaneously; as a result, the decreasing PSC 833 levels precluded an accurate assessment of the effect of PSC 833 on terminal paclitaxel kinetics. The clearance of paclitaxel was calculated from the following formula: clearance = infusion rate/CPss.

Rhodamine Accumulation in CD56+ T Cells
Whole blood was obtained from each patient in a heparinized syringe. Rhodamine 123 (Sigma, St Louis, MO) with or without PSC 833 was added to aliquots of whole blood to achieve a final rhodamine concentration of 0.5 µg/mL. PSC 833 was added to control aliquots to a final concentration of 3 µg/mL. The blood was incubated for 30 minutes at 37°C in 5% CO2. After the accumulation period, the blood was layered onto lymphocyte separation medium and centrifuged at 2,000 rpm for 5 minutes. The mononuclear cell layer from each tube was transferred to a separate tube, washed with cold Dulbecco’s phosphate-buffered saline (DPBS), resuspended in 200 µL of cold DPBS with 2% fetal calf serum (DPBS/FCS), and held at 4°C for later staining. Cells that were to be subjected to an efflux period were then resuspended in rhodamine-free complete media (phenol-red–free improved modified Eagle’s medium with 10% FCS) with or without PSC 833 3 µg/mL and incubated another 60 minutes at 37°C in 5% CO2. After the efflux period, cells were sedimented and washed twice with cold DPBS/FCS. After the washings, the cells were resuspended in 200 µL cold DPBS/FCS. The cells were then stained with phycoerythrin (PE)-labeled CD56 antibody (Becton Dickinson, San Jose, CA) or PE-labeled mouse immunoglobulin G1 (Becton Dickinson) as a negative control. After staining, the cells were washed twice and then resuspended in DPBS and kept on ice in the dark until analyzed. A FACSort flow cytometer (Becton Dickinson) with a 488-nm argon laser was used to analyze the samples. Rhodamine fluorescence was collected after a 520-nm bandpass filter, and PE fluorescence was collected after a 585-nm bandpass filter. A minimum of 5,000 events were collected per sample, and the samples were gated on forward scatter versus side scatter to exclude clumps and debris. Dead cells were excluded based on propidium iodide staining.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Patient Characteristics
Table 1 summarizes the diagnosis, performance status, age, and prior therapy of patients enrolled onto the trial. Because paclitaxel is known to have a wide spectrum of activity, enrollment was not confined to patients whose tumors might be expected to express Pgp. Thus, 26 of the 50 patients had tumors with a low likelihood of Pgp expression (10 ovarian cancer, five lung cancer, three melanoma, two mesothelioma, and six other). All patients had a Karnofsky score of 70 or higher. Forty-five of the 50 patients had received at least one prior therapy, including 19 patients who had received prior taxane therapy.


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  		Table 1. Clinical Characteristics of Patients Enrolling Onto the Study
 
Paclitaxel/PSC 833 Dose Escalation
Table 2 lists the dose escalation schedule for PSC 833 and paclitaxel. The chief adverse reaction from the PSC 833/paclitaxel combination was neutropenia. The initial three patients received a paclitaxel dose of only 25 mg/m2/d by CIVI for 4 days, and two of the three received the same dose in combination with PSC 833. However, it was decided that a dose of paclitaxel of 25 mg/m2/d for 4 days was too low if administered without PSC 833, and this was increased to 35 mg/m2/d by CIVI for 4 days. This dose was then administered in the first cycle to all subsequent patients with the exception of two patients who had extensive liver metastases, but normal liver function tests, for whom the dose was reduced to 26.25 mg/m2/d by CIVI for 4 days, as previously recommended.12 In addition, in anticipation of a greater pharmacokinetic interaction, the dose of paclitaxel administered in combination with PSC 833 was further reduced to 17.5 mg/m2/d by CIVI for 4 days. This dose was administered in combination with 7 days of PSC 833 at doses of 1.25 mg/kg every 8 hours, 2.5 mg/kg every 8 hours, 2.5 mg/kg every 6 hours, and 4 mg/kg every 6 hours without encountering DLT. However, when the PSC 833 dose was escalated to 5 mg/kg every 6 hours for 7 days, DLT (grade 4 neutropenia > 4 days) was encountered and the paclitaxel dose was reduced to 13.1 mg/m2/d for 4 days. This established a paclitaxel dose of 13.1 mg/m2/d by CIVI for 4 days in combination with PSC 833 at 5 mg/kg every 6 hours as the MTD. Filgrastim was then added to the regimen to support an advance of the paclitaxel dose. With filgrastim, a paclitaxel dose of 17.5 mg/m2/d by CIVI for 4 days in combination with a PSC 833 dose of 5 mg/kg every 6 hours for 7 days was identified as the MTD, after demonstrating DLT (grade 4 neutropenia) with a paclitaxel dose of 21.3 mg/m2/d by CIVI for 4 days in either the second or the third cycle. Thus the MTD of the combination was 5 mg/kg PSC 833 orally every 6 hours for 7 days with paclitaxel 13.1 mg/m2/d by CIVI for 4 days in patients not receiving filgrastim and 17.5 mg/m2/d by CIVI for 4 days in patients receiving filgrastim support.


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  		Table 2. Dose Escalation
 
Toxicities of the Combination
Forty-one of 50 patients received at a minimum both the first and second cycles, with the second cycle the first combined cycle. Thus in only 41 patients was it possible to evaluate the toxicity of the paclitaxel/PSC 833 combination. The initial cohort of three patients received a paclitaxel dose of 25 mg/m2/d for 4 days, but this dose was decreased to 17.5 mg/m2/d for 4 days because 50% reduction of other antineoplastic agents had been required in concurrent studies using PSC 833.9-11 Myelosuppression (grade 4 neutropenia) was the DLT. Grade 3 or 4 hyperbilirubinemia was observed in 13 patients. However, hyperbilirubinemia, which has been previously observed with cyclosporine A, was not considered a DLT.13,14 Other toxicities included grade 3 stomatitis in two patients and ataxia (defined as a grade 3 gait disturbance) in three patients. The former was considered a toxicity of paclitaxel, whereas the latter was thought to be a PSC 833 toxicity. Ataxia had been shown in earlier trials to be related to peak levels,11,15 and its occurrence was reduced in this study by administering PSC 833 every 6 hours. There was no evidence of a cumulative dose effect on ataxia. The PSC 833 dose was reduced to 4 or 3 mg/kg every 6 hours in the second or subsequent cycles in five patients because of ataxia (three patients), bloating (one patient), and headache and fatigue (one patient).

Paclitaxel Pharmacokinetics
Paclitaxel plasma concentrations were measured both in the first cycle, when paclitaxel was administered alone, and in the second cycle, when reduced doses of paclitaxel were administered in combination with PSC 833. Figures 2A and 2B present the data from 21 patients. These patients all received 35 mg/m2/d for 4 days paclitaxel in the first cycle and paclitaxel in combination with 5 mg/kg PSC 833 every 6 hours in the second cycle. Patients receiving lower doses of PSC 833 were not included in this analysis because DLTs occurred at PSC 833 doses of 5 mg/kg; and because pharmacokinetic interactions would be expected to vary across a PSC 833 concentration range. Figure 2A presents a comparison of paclitaxel Cpss; Fig 2B presents the same comparison for the paclitaxel AUCs. Table 3 summarizes the Cpss, AUCs, and clearance and shows the unadjusted P values for the Wilcoxon signed rank test. For Cpss and AUCs, none of the differences tested between cycle 1 and cycle 2 were significantly different from zero in the group of patients who received either paclitaxel 13.1 or 17.5 mg/m2/d CIVI for 4 days with PSC 833 5 mg/kg for 7 days in cycle 2 and a paclitaxel dose of 35 mg/m2/d for 4 days in cycle 1. However, filgrastim support was required to administer 17.5 mg/m2/d. Table 3 also shows a significant reduction (of 50% or more) in paclitaxel clearance in the presence of PSC 833.



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  		Fig 2. Comparison of paclitaxel Cpss (A) and AUCs (B) without concomitant administration of PSC 833 (paclitaxel dose, 35 mg/m2/d by CIVI for 4 days) and when paclitaxel was administered in combination with PSC 833 5 mg/kg every 6 hours for 7 days (paclitaxel doses, 13.1, 17.5, or 21.3 mg/m2/d by CIVI for 4 days). Statistical analysis failed to demonstrate significant differences among the various groups (see Table 3). Symbols: dashed line, the mean; solid line, the median; boxes, the 25th to the 75th percentile; error bars, the 10th to 90th percentile. Statistical analysis failed to demonstrate significant differences among the various groups (see Table 3).

 

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  		Table 3. Paclitaxel Pharmacokinetics{dagger}
 
Although statistical differences could not be demonstrated when the data from the patient groups were examined, Fig 3 shows that substantial variability could be observed in results from a given patient. Figure 3 depicts the results in the 14 patients who received paclitaxel 35 mg/m2/d by CIVI for 4 days in cycle 1 and paclitaxel 17.5 mg/m2/d by CIVI for 4 days in cycle 2. The upper panels, which show a comparison of Cpss and AUCs in cycles 1 and 2, demonstrate the marked variability. In five of the 14 patients, Cpss in cycle 2 were 36%, 62%, 65%, 69%, and 72% of the Cpss in cycle 1, indicating that a substantial reduction in concentrations had occurred as a result of the reduced paclitaxel dose administered (50% would be the level expected if no pharmacokinetic interaction occurred, with 100% desired). In contrast, five patients had increased Cpss levels in cycle 2, and four had minimal changes. The variability among patients is underscored by the results shown in the bottom panels, which demonstrate the measured levels in three of these patients over the 96-hour period (patients identified by asterisks in the top left panel). A marked decrease, a marked increase, or no significant change in paclitaxel levels can be seen when the results in cycle 1 (paclitaxel 35 mg/m2/d for 4 days) are compared with the results in cycle 2 (paclitaxel 17.5 mg/m2/d for 4 days with PSC 833 5 mg/kg every 6 hours for 7 days). It should be stressed that the patients with substantial decreases in paclitaxel levels had PSC 833 levels comparable to those of the group as a whole (peak 2,410 to 4,900 ng/mL and trough 1,290 to 2,700 ng/mL) and complete inhibition of rhodamine efflux from CD56+ cells in the surrogate assay described below. It should also be stressed that these five patients went on to receive a third cycle, and in four of those patients, the dose of paclitaxel was increased in accordance with the protocol, whereas in the fifth patient the dose was held at the level administered in cycle 2. These increases were administered without knowledge of paclitaxel levels, which were not available during treatment. Thus, the clinical impression that these patients had tolerated the combination of paclitaxel and PSC 833 such that the dose of paclitaxel could be increased, paralleled the paclitaxel pharmacokinetics eventually obtained.



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  		Fig 3. (Top panels) Differences in paclitaxel Cpss and AUCs in each individual patient. All 13 patients depicted received paclitaxel doses of 35 mg/m2/d by CIVI for 4 days without PSC 833 in the first cycle and 17.5 mg/m2/d by CIVI for 4 days with PSC 833 5 mg/kg every 6 hours for 7 days in the second cycle. (Bottom panels) Paclitaxel concentrations as a function of time in three individual patients. The three patients whose results are depicted in the bottom panels are identified in the top left panel by one, two, or three asterisks. Symbols in the bottom panels: •, results in cycle 1 without PSC 833; |b, results in cycle 2 with PSC 833.

 
Response Evaluation
Responses were evaluated by taking bidimensional measurements of lesions; where numerous lesions were present, measurements of as many as four to six index lesions were obtained. Among the 50 patients enrolled onto the study, 41 of whom completed at least the first combined paclitaxel/PSC 833 cycle, we observed one complete response (non–small-cell lung cancer [NSCLC]), three partial responses (NSCLC, NSCLC, and breast cancer), and three minor responses (leiomyosarcoma [41% decrease], mesothelioma [39% decrease], and renal cell cancer [25% decrease]). Responses were observed in two patients with NSCLC who had progressive disease after receiving prior paclitaxel alone (eight cycles) or paclitaxel in combination with cisplatin (one cycle). None of the other responders had been previously treated with a taxane. Although not meeting classical response criteria, clinical improvement and/or reduction in CA125 was observed in five of 10 ovarian cancer patients. These patients had received two or three prior regimens, had received prior paclitaxel, and had progressive disease on study entry. As a result of clinical improvement, these patients remained on therapy from 6 to 13 months.

Surrogate Assay to Measure Inhibition of Pgp by Using CD56+ Cells
Inhibition of rhodamine efflux from CD56+ cells was used as a surrogate marker for Pgp inhibition. The results in 16 of the patients enrolled onto the trial at a PSC 833 dose of 5 mg/kg every 6 hours are shown in Fig 4. This assay was performed by incubating mononuclear cells in rhodamine and determining rhodamine accumulation by measuring fluorescence. A sample obtained from a patient was divided into two. One sample was directly incubated with rhodamine; the extent of accumulation reflects the extent of Pgp inhibition by the PSC 833 bathing circulating cells. The other sample was incubated in rhodamine with exogenous PSC 833 added to a final concentration of 3 µg/mL. This final concentration of PSC 833 resulted in complete inhibition of Pgp-mediated efflux and maximal rhodamine accumulation. In this assay, the greater the inhibition by the circulating PSC 833, the smaller the difference between the mean fluorescence obtained with and without the addition of exogenous PSC 833. Conversely, the lower the inhibition by the circulating PSC 833, the greater the difference between the result without added PSC 833 and the result after the addition of PSC 833. This difference in rhodamine fluorescence quantitated as channel numbers was plotted on the y axis, and the PSC 833 concentration was plotted on the x axis. For each patient, samples were obtained at various time points after the ingestion of PSC 833, and for each sample, PSC 833 concentration and rhodamine accumulation were measured. Thus, for each patient, rhodamine accumulations over a range of PSC 833 concentrations are available. As shown by the data in Fig 4, complete (100%) or near-complete inhibition of Pgp was achieved in all patients, usually at low circulating concentrations of PSC 833. Indeed, 93% of patients had more than 90% inhibition at a PSC 833 concentration of 500 ng/mL or less, and 79% had more than 95% inhibition at this concentration, whereas all patients had more than 90% inhibition at a concentration of 1,000 ng/mL or less, with 93% demonstrating more than 95% inhibition in this range. The inset depicts the results using the same rhodamine accumulation assay and samples obtained at the peak (2 hours after dose) and trough (just before next dose) after PSC 833 administration. Nineteen patients are presented in this analysis, including 12 of the above 16. Inhibition approximating that obtained with exogenously added PSC 833 is demonstrated again by the low values for the differences in rhodamine accumulation. As shown, at both the peak (mean ± SD PSC 833 in 19 patients, 3,537 ± 1,015 ng/mL) and trough (mean ± SD PSC 833 in 19 patients, 2,332 ± 753 ng/mL), effective inhibition of Pgp was achieved, with more than 90% inhibition in all but one sample. Thus the data indicate that inhibition of Pgp in this surrogate assay was achieved with concentrations much lower than those eventually reached in these patients and that this effect was sustained.



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  		Fig 4. Surrogate assay measuring accumulation of rhodamine in CD56+ cells. Differences in channel number are plotted on the y axis. Larger differences represent less inhibition of Pgp by endogenous PSC 833. (Inset) Results of the same assay and samples obtained 2 hours after the administration of PSC 833 (peak) and samples obtained just before the next dose of PSC 833 (trough).

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
This study presents the results of a phase I study of PSC 833 in combination with a 4-day paclitaxel infusion. The MTD of the final combination was PSC 833 5 mg/kg every 6 hours for 7 days in combination with paclitaxel 13.1 mg/m2/d administered by CIVI for 4 days (day 4 to day 7). With the addition of filgrastim, the MTD was PSC 833 5 mg/kg every 6 hours for 7 days with paclitaxel 17.5 mg/m2/d administered by CIVI for 4 days. The DLT of the combination was neutropenia. Although the pharmacokinetic analysis of the group as a whole suggested that adjusting the administered paclitaxel dose resulted in comparable Cpss and AUCs, individual patients demonstrated quite different results.

Delays in drug clearance have been observed previously with Pgp antagonists, most notably cyclosporine and PSC 833, but have also been noted with other second-generation Pgp antagonists such as VX 710.16 In humans, the interaction with etoposide required a 25% dose reduction,15 as did the interaction with doxorubicin.10,11 Larger etoposide reductions were required when PSC 833 was added to a combined regimen consisting of mitoxantrone plus etoposide or mitoxantrone plus etoposide and cytarabine, so that the tolerable dose was a 66% reduction, compared with the MTD without PSC 833.9,17 PSC 833 has also been shown to delay paclitaxel clearance in humans, increasing half-life two-fold, and requiring a dose reduction.18,19 In the present study, dose reductions were required because of reduced clearance when paclitaxel was administered in combination with PSC 833. MTDs of 13.1 mg/m2/d by CIVI for 4 days (37.4%) and 17.5 mg/m2/d by CIVI for 4 days (50%) without and with filgrastim support, respectively, were determined. These reductions are similar to those reported in a recent phase I study in which paclitaxel was administered for 3 hours.19 Although the MTD for paclitaxel in the study by Fracasso et al19 was determined to be 122.5 mg/m2, the observation that in the majority of patients the paclitaxel dose was reduced to 87.5 mg/m2 in the ensuing cycle, together with the need to use filgrastim, indicates that the MTD dose was probably not sustainable. A dose of 87.5 mg/m2 represents a 50% reduction compared with the 175 mg/m2 administered without PSC 833.

Reductions in the dose of paclitaxel are required because the Cpss and AUCs are increased in some but not all patients after the addition of PSC 833. The mechanisms of this pharmacokinetic interaction are unknown but potentially relate to both inhibition of cytochrome P450 (the principal pathway of PSC 833 metabolism) and/or inhibition of Pgp-mediated drug transport in the normal liver and kidney.20 PSC 833 is like many other compounds that are known to be both substrates for Pgp and also substrates for metabolism by the P450 pathway.7 Pgp-interacting compounds, such as the cyclosporines, anthracyclines, vinca alkaloids, epipodophyllotoxins, taxanes, and dihydropyridines, have all been shown to interact with P450. However, studies in mice in which the mouse homologs for MDR-1 have been deleted have shown a decrease in drug clearance and an increase in drug accumulation particularly in the brain, indicating that Pgp inhibition alone is sufficient to alter pharmacokinetics.20-22 Although the data in the present study cannot quantitate the relative contribution of these two mechanisms, two observations suggest that P450 makes a substantive contribution: (1) the DLT of the PSC 833/paclitaxel combination was not reached until the PSC 833 dose was increased from 4 mg/kg to 5 mg/kg every 6 hours, although at low PSC concentrations, marked Pgp inhibition was observed in the surrogate assay, and (2) variability was observed in paclitaxel Cpss and AUCs in individual patients at the MTD, despite complete or nearly complete inhibition of Pgp in the surrogate assay. The variability in paclitaxel Cpss and AUCs was seen when comparing cycle 1 when paclitaxel 35 mg/m2/d was administered by CIVI for 4 days without PSC 833 with cycle 2 when paclitaxel 17.5 mg/m2/d was given by CIVI for 4 days in combination with PSC 833 (Fig 3 and Table 3). This dissociation between the extent of Pgp inhibition and paclitaxel levels and clinical effects supports the existence of a secondary mechanism(s) (likely P450) affecting paclitaxel clearance after the administration of PSC 833. This mechanism seems most important at higher PSC 833 concentrations. Variability among patients may be due to differences in the extent of drug interaction, presumably at the level of P450. Interpatient variations in P450 interactions are well-known, and assays have been developed to quantitate these differences.23,24 Indeed, clearance mediated by P450 has been reported to vary 10-fold among patients.25 In the future, it may be possible to predict differences in P450 interactions and thus improve drug dosing.

The need to significantly reduce the dose of paclitaxel administered in combination with PSC 833 raises concerns as to the comparability of Cpss in patients receiving the combination compared with those receiving paclitaxel alone. It could be argued that both groups are statistically similar and thus identical. However, examination of the data on individual patients demonstrates that in a proportion of patients the expectation that a dose of paclitaxel 17.5 mg/m2/d by CIVI for 4 days would be sufficient when combined with PSC 833 was incorrect, because these patients had much lower paclitaxel levels when the latter was administered with PSC 833. Similarly, some patients had much higher paclitaxel levels when a dose of 17.5 mg/m2/d was administered by CIVI for 4 days with PSC 833, a result that, although potentially beneficial in terms of antitumor effect, could be detrimental in terms of normal tissue toxicity. This variability and unpredictability underscore the need to better forecast this interaction or attempt to avoid it. The latter could potentially be achieved by reducing the dose of PSC 833, because the results indicate that much lower concentrations of PSC 833 than are currently administered can achieve complete or nearly complete inhibition of Pgp function. This is clearly demonstrated by the results with the CD56+ cells, a surrogate that has higher levels of Pgp than those found in the majority of tumors.

The surrogate assay in this study used CD56+ cells to detect the extent of in vivo Pgp inhibition. In this assay, the patient’s mononuclear cells, obtained before and after treatment with PSC 833, are incubated ex vivo with the Pgp substrate rhodamine 123.26,27 Efflux of rhodamine 123 is blocked by PSC 833, resulting in higher levels of fluorescence in patients’ cells after treatment. The degree of inhibition of efflux can be correlated with the PSC 833 level in a patient’s plasma. Patients receiving PSC 833 5 mg/kg every 6 hours demonstrated inhibition of rhodamine efflux from their CD56+ cells, which indicates in vivo inhibition of Pgp. Similar results were reported for patients receiving the second-generation antagonist GF120918.26 The rhodamine efflux studies suggested a plateau in the inhibition of rhodamine efflux at the PSC 833 dose of approximately 500 to 1,000 ng/mL. At the MTD dose of PSC 833 5 mg/kg every 6 hours, the peak (3,537 ± 1,015 ng/mL) and trough (2,332 ± 753 ng/mL) concentrations greatly exceeded this concentration. This suggests that the dose of PSC 833 at the MTD exceeded the dose needed to achieve its biologic effect. A caveat regarding this interpretation is that there is no confirmation to date that measurement of efflux from CD56+ cells accurately reflects the level of efflux occurring in a tumor. Although the levels of Pgp in CD56+ cells exceed those in most tumors, as circulating cells, they are exposed to optimal blood concentrations of PSC 833.28,29

In the present study, among 41 assessable patients with a variety of cancers, one complete response, three partial responses, and three minimal responses were observed. Responses were observed in two patients with NSCLC who had previously received paclitaxel; and clinical benefit was seen in five patients with ovarian cancer who had also received prior paclitaxel therapy. Possible explanations for this include (1) modulation of Pgp in the patient’s tumors, a possibility that cannot be substantiated because biopsies were not required for enrollment onto this phase I study, (2) enhanced paclitaxel activity when administered as an infusion, a possibility for which there is some supporting data,12,30,31 and (3) enhanced activity as a result of the altered paclitaxel pharmacokinetics after the administration of PSC 833. The latter two possibilities could have a significant impact in patients with NSCLC, given the available data which suggest that response to paclitaxel in NSCLC correlates with time above a given serum concentration of paclitaxel.32 Efficacy of the 96-hour schedule alone could confound interpretation of a phase II study with this combination. Thus, a randomized study would be required to discriminate among these possibilities.

Clinical trials with MDR reversal agents have traditionally used the MTD of the blocking agent. An alternative strategy may be to use clinically relevant surrogates to establish an optimal blocking dose. This dose may be lower than that determined using an MTD strategy and could minimize the reduction in clearance of the anticancer compound. This in turn may reduce the variability in pharmacokinetic interaction among individual patients, facilitate dosing, and allow one to optimize combination treatments. This study demonstrates that a potent Pgp antagonist can be combined safely with an infusional chemotherapy regimen and indicates that this can be potentially accomplished without significantly altering the pharmacokinetic profile. The latter may be achievable with either lower doses of some Pgp antagonists (including PSC 833), the use of surrogate assays to predict individual differences, or the development of Pgp antagonists without significant pharmacokinetic effects.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
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15. Boote DJ, Dennis IF, Twentyman PR, et al: Phase I study of etoposide with SDZ PSC 833 as a modulator of multidrug resistance in patients with cancer. J Clin Oncol 14: 610-618, 1996[Abstract/Free Full Text]

16. Rowinsky EK, Smith L, Wang YM, et al: Phase I and pharmacokinetic study of paclitaxel in combination with biricodar, a novel agent that reverses multidrug resistance conferred by overexpression of both MDR1 and MRP. J Clin Oncol 16: 2964-2976, 1998[Abstract/Free Full Text]

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19. Fracasso PM, Westerveldt P, Fears CA, et al: Phase I study of paclitaxel in combination with a multidrug resistance modulator: PSC 833 (valspodar) in refractory malignancies. J Clin Oncol 18: 1124-1134, 2000[Abstract/Free Full Text]

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27. Robey R, Bakke S, Stein W, et al: Efflux of rhodamine from CD56+ cells as a surrogate marker for reversal of P-glycoprotein-mediated drug efflux by PSC 833. Blood 93: 306-314, 1999[Abstract/Free Full Text]

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Submitted March 29, 2000; accepted September 28, 2000.




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