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© 2000 American Society for Clinical Oncology Phase I Study of Paclitaxel in Combination With a Multidrug Resistance Modulator, PSC 833 (Valspodar), in Refractory MalignanciesFrom the Department of Medicine, Washington University School of Medicine, St Louis, MO; Marlene and Stewart Greenebaum Cancer Center and Department of Medicine, University of Maryland School of Medicine, Baltimore, and Cancer Therapy Evaluation Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD; and Novartis Pharmaceuticals Corporation, East Hanover, NJ. Address reprint requests to Paula M. Fracasso, MD, PhD, Washington University School of Medicine, Box 8056, 660 South Euclid Ave, St Louis, MO 63110; email pfracass{at}imgate.wustl.edu
PURPOSE: To determine the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), and pharmacokinetics of paclitaxel when given with PSC 833 (valspodar) to patients with refractory solid tumors. PATIENTS AND METHODS: Patients were initially treated with paclitaxel 175 mg/m2 continuous intravenous infusion (CIVI) over 3 hours. Subsequently, 29 hours of treatment with CIVI PSC 833 was started 2 hours before paclitaxel treatment was initiated. In this combination, the starting dose of paclitaxel was 52.5 mg/m2. Paclitaxel doses were escalated by 17.5 mg/m2 increments for four subsequent cohorts. Each cohort consisted of three patients with the exception of the last cohort, which consisted of six patients. Data for the pharmacokinetics of paclitaxel with and without concurrent PSC 833 administration were obtained. RESULTS: All 18 patients completed at least one course of concurrent treatment (median, two courses; range, one to six) and were evaluable for toxicity. The MTD for paclitaxel with PSC 833 was 122.5 mg/m2. Neutropenia was the DLT. All patients had PSC 833 blood concentrations greater than 1,000 ng/mL before, during, and 24 hours after the paclitaxel infusion. PSC 833 produced small increases in the paclitaxel peak plasma concentrations and areas under the concentration-time curve. However, PSC 833 greatly prolonged the terminal phase of paclitaxel, resulting in plasma paclitaxel concentrations of more than 0.05 µmol/L for much longer than expected. As a result, myelosuppression was comparable to that produced by full-dose paclitaxel given without PSC 833. Of the 16 patients who were assessable for response, one patient experienced a partial response and an additional nine patients experienced disease stabilization after paclitaxel treatment alone. CONCLUSION: Treatment with paclitaxel 122.5 mg/m2 as a 3-hour CIVI concurrent with a 29-hour CIVI of PSC 833 results in acceptable toxicity. The addition of PSC 833 alters the pharmacokinetics of paclitaxel, which explains the enhanced neutropenia experienced by patients treated with this drug combination.
THE DEVELOPMENT OF resistance to antineoplastic agents by tumor cells presents a formidable obstacle to the successful treatment of human malignancies. The phenomenon of multidrug resistance (MDR), whereby tumor cells in vitro and animal models in vivo develop simultaneous cross-resistance to multiple unrelated agents, has been well-described and attributed, at least in part, to the expression of the MDR-1 gene by tumor cells.1 MDR-1 encodes a 170-kd membrane glycoprotein (P-glycoprotein), which is expressed in a wide variety of human malignancies and normal tissues. P-glycoprotein is believed to function as a transmembrane efflux pump that prevents the intracellular accumulation of natural product–derived cytotoxic agents, such as anthracyclines, epidophyllotoxins, vinca alkaloids, and taxanes.1,2 High P-glycoprotein levels are often observed at diagnosis in tumors such as gastrointestinal, renal cell, hepatocellular, and adrenal carcinomas.1 In contrast, elevated P-glycoprotein expression is typically not observed in other tumors, such as breast and ovarian carcinomas and hematopoietic malignancies, until such tumors recur after treatment with chemotherapeutic agents.2 P-glycoprotein expression has also been demonstrated in normal tissues, including secretory epithelial cells of the gastrointestinal tract and kidney and vascular endothelial cells of the placenta, testis, and CNS, where it is believed to function by purging cells of potentially toxic substances. Because of the potential clinical importance of P-glycoprotein–mediated drug resistance in vivo, there has been considerable interest in developing pharmacologic strategies for MDR reversal. A variety of agents—verapamil, tamoxifen, toremifene, quinidine, trifluoperazine, and cyclosporine A—have been shown to block P-glycoprotein–mediated drug efflux, but the concentrations required for MDR inhibition by these agents in vitro are sufficient to cause unacceptable toxicities in vivo.3 PSC 833, a nonimmunosuppressive, nonnephrotoxic cyclosporine D analog, is a 10-fold more potent MDR inhibitor in vitro than cyclosporine A.4-8 In vivo, PSC 833 administered to MDR tumor-bearing mice reversed vinca alkaloid and anthracycline resistance, with considerably less renal, hepatic, and neurologic toxicity than that observed with cyclosporine A.7-9 Previously, PSC 833 has been shown to be well-tolerated when given as a 2 mg/kg intravenous (IV) loading dose and up to 10 mg/kg/d continuous IV infusion (CIVI) over 5 days and combined with etoposide at 75 mg/m2/d. Dose-limiting ataxia was observed at higher dose levels of PSC 833.10 A phase I trial combining oral PSC 833 with IV paclitaxel demonstrated a PSC 833 maximum-tolerated dose (MTD) of 20 mg/kg/d administered in four divided doses and a paclitaxel MTD of 70 mg/m2 CIVI over 3 hours.11,12 At the doses studied, oral PSC 833 was associated with reversible cerebellar ataxia in most patients. The study presented here was designed as a single-arm, dose-escalation, phase I clinical trial to (1) determine the MTD and dose-limiting toxicity (DLT) of paclitaxel given in combination with CIVI PSC 833 at its previously determined MTD, (2) investigate the effect of IV PSC 833 on the pharmacokinetics of paclitaxel, and (3) evaluate the toxicities of paclitaxel and PSC 833 given in combination intravenously. Treatment response was also observed and documented but was not a primary end point of the study.
Patient Selection Patients were eligible for enrollment onto the study if they had a histologically confirmed diagnosis of malignancy that was refractory to standard therapy. Patients were required to be at least 18 years old and have measurable or evaluable disease; a performance status of 0 to 2, as defined by the National Cancer Institute Common Toxicity Criteria; and a life expectancy of at least 2 months. Laboratory exclusion criteria were a creatinine level greater than 2.0 mg/dL, absolute neutrophil count (ANC) less than 1,500/µL, platelet count less than 100,000/µL, hemoglobin level less than 9.0 g/dL, bilirubin level greater than 1.5 times the institutional upper limit of normal, and AST or ALT greater than twice the institutional upper limit of normal. No chemotherapy or radiotherapy was permitted within the 3 weeks before entry onto the study; nitrosoureas or mitomycin were not permitted within the 6 weeks before entry onto the study. Patients who had had other malignancies within the previous 5 years (with the exception of nonmelanoma skin cancers or in situ cervical carcinoma) were ineligible. Patients who had significant comorbid conditions (including congestive heart failure, angina pectoris, cardiac arrythmias requiring medical therapy, history of major gastrointestinal tract resection, active hepatitis, cirrhosis, and renal failure) or brain metastases were ineligible. Medications known to alter cyclosporine A pharmacokinetics, including calcium channel blockers, imidazole antifungal agents, macrolide antibiotics, glucocorticoids (except as premedication before the paclitaxel infusion), allopurinol, bromocriptine, danazol, metoclopramide, nafcillin, rifampin, carbamazepine, phenobarbital, phenytoin, octreotide, and ticlopidine, were not allowed. This protocol was approved by the National Cancer Institute, Division of Cancer Treatment and Diagnosis, Cancer Therapy Evaluation Program (T93-0034) and the Washington University Human Studies Committee. All patients provided their signed informed consent before entry onto the study.
Study Design and Treatment Plan Patients were eligible to continue treatment until there was evidence of progressive disease, as defined below. Dose escalation for each successive three-patient cohort was not allowed until the entire cohort treated at the previous dose level had completed the second course. For individual patients within a cohort, paclitaxel dose escalation by 17.5 mg/m2 was permitted after patients had completed the second course if the ANC and platelet nadirs in the previous course were 1,000/µL or greater and 100,000/µL or greater, respectively. Paclitaxel doses were reduced by 35 mg/m2 (20% of 175 mg/m2) in subsequent courses if the ANC nadir in the previous course was less than 500/µL for greater than 7 days, if the platelet nadir was less than 50,000/µL, if febrile neutropenia occurred, or if neutrophil recovery to an ANC of 1,500/µL or greater was not observed by day 1 of the next course. Use of granulocyte colony-stimulating factors (G-CSFs; 5 µg/kg/d, days 3 through 17 or until the ANC was 1,500/µL or greater) was permitted in lieu of dose reduction in the event of asymptomatic grade 4 neutropenia and was required together with dose reduction for the neutropenia indications listed above. PSC 833 doses were reduced by 25% in the event of grade 3 or 4 cerebellar dysfunction, as defined below. The definition of DLT was determined on the basis of the toxicity observed with the first course of treatment with paclitaxel in combination with PSC 833. DLT was defined as either an ANC less than 500/µL for more than 3 days and/or febrile neutropenia; failure of neutrophil recovery to an ANC of 1,500/µL or greater or platelet recovery to 100,000/µL or greater by day 28; grade 3 or 4 nonhematologic toxicity (with the exception of alopecia, nausea, vomiting, fever, malaise, anorexia, stomatitis, and esophagitis/dysphagia); or grade 3 stomatitis/esophagitis/dysphagia lasting more than 3 days. In addition, recurrent grade 3 or 4 cerebellar toxicity after a 25% PSC 833 dose reduction was considered to be dose-limiting. The MTD was determined as follows: if DLT was experienced by one of three patients at a given dose level, an additional three patients were enrolled at the same dose level. If no DLT was observed in these patients, that dose was considered to be the MTD. If DLT was observed in one of three of these additional patients, however, the MTD would the dose at the previous level. If two of three patients experienced DLT at a given level, accrual at that level would be stopped, and the previous dose level would be declared the MTD, after a total of six patients were treated at that level to ensure tolerability. Response criteria were as follows: a complete response was defined as disappearance of all measurable disease by physical examination and/or radiographic criteria for a duration of at least 4 weeks. A partial response was defined as a reduction of 50% or greater in the sum of the products of the perpendicular diameters of all index lesions for at least 4 weeks and no appearance of new lesions. Stable disease was defined as a 50% reduction or a 25% or smaller increase in the sum of the perpendicular diameter products and no appearance of new lesions. Disease progression or relapse was defined as more than a 25% increase in the sums of the perpendicular diameter products of the index lesions, compared with best response, or the appearance of new areas of malignant disease.
Pharmacokinetic Monitoring
Paclitaxel plasma concentrations were determined with a previously described high-performance liquid chromatography method.13 Paclitaxel plasma concentration versus time data were analyzed by compartmental methods. Plasma concentrations of paclitaxel were fit using the ADAPT II program14 with a previously described three-compartment, nonlinear model.15 In these analyses, the model was fit to the data by use of Bayesian estimation, with previously described population means and variances as prior information for each pharmacokinetic parameter estimated by the model.16 Patient-specific estimates of individual pharmacokinetic parameters were then used to simulate complete concentration versus time profiles by using the simulation module of ADAPT II. From these simulations, peak paclitaxel concentrations, areas under the concentration versus time curve (AUCs), and durations of time for which the concentration of paclitaxel was 0.05 µmol/L or greater were extracted. Apparent clearance of paclitaxel was calculated from the definition
PSC 833 blood concentrations were determined by H. Thomas Smith, of Novartis Pharmaceuticals Corporation, using the ANAWA Whole Blood Radioimmunoassay Kit (ANAWA Laboratories AG, ANAWA Biomedical Services and Products, Zurich, Switzerland, for Novartis Pharma Ltd). This kit provided reagents and instructions for the quantitative analysis of blood PSC 833 concentrations by radioimmunoassay. The procedure specified in the ANAWA radioimmunoassay kit instruction manual was followed without exception. Novartis-prepared standards, quality-control samples, pooled blank normal human whole blood, and unknown samples were assayed with the patient samples on each day of analysis. Using the results from the seven standard concentrations (37.5 to 1,800 ng/mL) and a RIAPROG program, a linear standard curve was constructed by plotting percent binding (%B) over Bo versus the standard concentration (Logit-Log Plot). The mean value of each set of replicate values was reported for all unknown and quality-control samples. Concentrations were reported in ng/mL, and for sample volumes of 50 µL, a lower limit of quantitation of 75 ng/mL was established for each day of analysis. Using a sample volume of 100 µL, a lower limit of quantitation of 37.5 ng/mL was established.
Patient Characteristics The characteristics of the 18 patients enrolled in the study over a 15-month period are summarized in Table 1. The high percentage of female patients reflected the number of patients with breast and ovarian carcinomas who were enrolled, although a variety of other common tumor types were also represented. The performance status of patients at the time of entry onto the study was high, with the majority (61%) having a performance status of 0 and the rest having a performance status of 1. Consistent with the treatment-refractory nature of this patient group, 16 of 18 patients had been treated with at least two prior chemotherapy regimens. Only one patient was chemotherapy-naïve and was considered to be eligible for enrollment because of the absence of a proven effective therapy for his disease (mesothelioma). The majority of patients (56%) had been treated previously with paclitaxel and ultimately their disease progressed on this treatment. One patient each at dose levels 1, 2, and 4 (Table 2) began treatment while taking allopurinol, diltiazem, and phenytoin, respectively. These medications should have been discontinued before the patients’ entry onto the study, as they were believed to have the potential to alter PSC 833 pharmacokinetics. This potential interaction was suggested on the basis of observations that cyclosporine A concentrations increased with concurrent allopurinol and diltiazem treatment and decreased with concurrent phenytoin treatment.17 The protocol was subsequently amended to allow the use of allopurinol, because this drug has not been shown to produce an appreciable effect on cyclosporine A pharmacokinetics.18 The patients taking allopurinol and diltiazem remained on those drugs throughout the study, without adverse outcome. The patient treated at paclitaxel dose level 4 while taking phenytoin discontinued her phenytoin 14 days before the fourth course, and pharmacokinetic studies with paclitaxel and PSC 833 were repeated in that fourth course. All patients were included in the pharmacokinetic and toxicity analyses.
Treatment All 18 patients enrolled completed at least one course of combined paclitaxel and PSC 833 treatment while participating in the study (Table 2) and were evaluable for toxicity and response. A total of 46 combined paclitaxel and PSC 833 treatment courses were administered, with a median of two courses per patient (range, one to six courses). Eighty-five percent of the combined paclitaxel and PSC 833 courses were administered on schedule. Two courses were postponed for 7 days because of patients’ delayed neutrophil recovery. One course was postponed for 2 weeks because of an exacerbation in one patient’s anxiety and depressive symptoms. One patient enrolled at paclitaxel dose level 1 and two patients enrolled at dose level 2 were subsequently escalated by one dose level each, for a total of two and three courses, respectively. Two patients enrolled at dose level 5 were subsequently dose-reduced by two dose levels. The dose of paclitaxel given with PSC 833 was escalated to 122.5 mg/m2 (dose level 5) before dose-limiting neutropenia was observed in one of three patients. An additional three patients were enrolled at that level, and, because no further DLT was observed, 122.5 mg/m2 was considered to be the MTD. No patients received G-CSF during the first or second courses of treatment. However, two patients (one at dose level 3 and another initially treated at dose level 5) received G-CSF for a total of seven courses. At the time of treatment with G-CSF, both patients were receiving paclitaxel at 87.5 mg/m2 in combination with PSC 833. All patients were withdrawn from the study because of eventual disease progression, and one patient died of progressive disease while on the study.
Toxicity A variety of nonhematologic toxicities, although possibly related to treatment, did not seem to be dose-related and were observed in less than 10% of all courses. Grade 3 paresthesias were observed in two patients, at the 87.5 and 122.5 mg/m2 levels, but were not considered dose-limiting because of their presence at the grade 1 and 2 levels before treatment and because of their improvement to baseline before retreatment. Similarly, grade 3 anxiety and depression, which developed in one patient during treatment, was not felt to represent a dose-limiting, treatment-related toxicity because of that patient’s prior history of depression. One patient was hospitalized for presumed pneumonia with fever, pleuritic chest pain, and pulmonary infiltrates 1 day after going off the study because of progressive disease. Although these conditions were reported to be a possible treatment-related infection, it was believed that the patient’s signs and symptoms, in the setting of negative cultures and a new, cytologically proven, malignant pleural effusion, were more likely due to progression of her disease. One patient was hospitalized 17 days after combined paclitaxel and PSC 833 treatment. This patient required fluid resuscitation because of orthostatic hypotension that occurred after several days of nausea, vomiting, anorexia, and a possible urinary tract infection. Cerebellar ataxia was not observed. There were no treatment-related deaths.
Response
Pharmacokinetics
At the time that the PSC 833 2 mg/kg bolus infusion was completed, PSC 833 blood concentrations were greater than 1,000 ng/mL, the concentration known to reverse P-glycoprotein–mediated resistance in vitro in all patients (Fig 4). The blood concentrations of PSC 833 remained in the therapeutic range until the completion of the PSC 833 10 mg/kg/24 h CIVI 27 hours later. Within 24 hours after the completion of the infusion, the PSC 833 blood concentrations fell to below 1,000 ng/mL in all but two of the 18 patients (Fig 4).
The pharmacokinetics of paclitaxel treatment with and without PSC 833 were obtained from a patient while she was taking phenytoin and after she discontinued phenytoin (Table 4). This patient had a distant history of seizures and had been on oral phenytoin 200 mg twice daily for many years. Fourteen days before the fourth course of treatment, a phenytoin level was obtained from her and was found to be 7.4 µg/mL (therapeutic level range, 10 to 20 µg/mL); her phenytoin was then discontinued. Pharmacokinetics were performed during her first course of treatment with paclitaxel alone and during her second and fourth courses of treatment with paclitaxel 105 mg/m2 in combination with PSC 833. While she was taking phenytoin, her paclitaxel peak concentration, AUC, clearance, time of plasma paclitaxel concentration at or above 0.05 µmol/L, and her PSC 833 blood concentrations were lower than they were after she discontinued the drug (Table 4). As would be expected, the degree of myelosuppression was lower while she was taking the phenytoin, and marked myelosuppression was noted after she discontinued the phenytoin. These data confirm that PSC 833 pharmacokinetics, like cyclosporine A pharmacokinetics, are affected by phenytoin.
Because of the potential importance of P-glycoprotein in clinical drug resistance and the discovery that MDR can be reversed both in vitro and in vivo by several resistance-modifying agents, multiple small-phase I and II clinical trials have been undertaken with several agents, including verapamil, tamoxifen, toremifene, quinidine, trifluoperazine, and cyclosporine A (reviewed in22,23). However, the serious toxicities that accompanied the concentrations of these agents that were needed to modulate MDR effectively led to the development of second-generation agents with a more favorable therapeutic index. Because cyclosporine seemed to be one of the most promising early MDR modulators, the screening of nonimmunosuppressive cyclosporine analogs was done at the Sandoz Research Institute to define the most potent resistance-modifying agents.4 The most promising analog that emerged from this screening was SDZ PSC 833 or [3'-keto-Bmt1]-[Val2]-cyclosporine. In comparison with cyclosporine A, PSC 833 was noted to be more potent, reversing MDR in vitro at concentrations between 1,000 and 2,000 ng/mL,5-8 and less nephrotoxic, hepatotoxic, and neurotoxic.9 In a phase I study of etoposide with increasing doses of PSC 833 given as a CIVI, the DLT was cerebellar ataxia.10 The recommended dose of PSC 833 for further trials was a loading dose of 2 mg/kg and a continuous infusion of 10 mg/kg/d. The loading dose of PSC 833 was selected to give an initially high blood concentration that could be maintained by the continuous infusion. Although overshoot of the target concentration was occasionally noted after the loading dose, all patients who received a continuous infusion of 6.6 mg/kg/d or more had a PSC 833 concentration or more than 1,000 ng/mL. The study presented here involved a higher than expected number of women for a typical phase I trial. This reflects the 10 patients with a previous history of breast or ovarian malignancies. All these women had had previous paclitaxel therapy and their disease had progressed either while on treatment (nine women) or within 6 months of treatment (one woman). Nine patients (four with ovarian cancer and two with breast cancer) experienced stabilization of previously progressive disease for a mean duration of 13 weeks while undergoing treatment. Hematologic toxicity was the major DLT of this trial. Equivalent myelosuppression was noted when approximately 40% (70 mg/m2) of the single-agent paclitaxel dose was given in combination with IV PSC 833. However, patients were still able to continue dose escalation until paclitaxel was given at 70% (122.5 mg/m2) of the single-agent paclitaxel dose. At that dose, one of six patients had dose-limiting neutropenia. This enhanced myelosuppresion noted with the combination of an antineoplastic agent and a cyclosporine analog has been well-documented in other phase I solid-tumor trials with cyclosporine24-27 and with PSC 833.10,28 Notably, this enhanced myelosuppression was described with paclitaxel and oral PSC 833.11,12 In contrast to the study presented here with paclitaxel and IV PSC 833, the maximum-tolerated dose was 40% (70 mg/m2) of the single-agent paclitaxel dose when given over 3 hours in combination with oral PSC 833. Whether the higher MTD in this phase I study, as compared with the phase I study with paclitaxel and oral PSC 833, is due to selection bias or pharmacokinetic parameters is presently being determined. Other nonhematologic toxicities were modest and, although possibly related to the study drug, were not dose-limiting. Paresthesias in the hands and feet were present in some patients before the start of protocol treatment and worsened during protocol treatment. Whether this worsening was secondary to paclitaxel alone or exacerbated by the combination of paclitaxel and PSC 833 is unknown. Cerebellar ataxia, a potential toxicity of PSC 833, was not observed in this study, although it was noted in the phase I study of paclitaxel and oral PSC 833.12 This toxicity is related to the higher peak levels of PSC 833 obtained after oral administration of this drug. Asymptomatic reversible hyperbilirubinemia has been noted to occur 48 hours after treatment with PSC 833 commenced, decrease after PSC 833 treatment was stopped, and return to normal within 7 days after the end of treatment.10 In this study, bilirubin concentrations were measured on days 1 and 10 of each course of treatment. Only one patient had an elevated bilirubin concentration, which was minimal, occurred on day 10, and normalized by day 1 of the next course. The enhanced myelosuppression noted with the combination of paclitaxel and PSC 833 prevented administration of the full dose of paclitaxel and was accounted for by the pharmacokinetic interaction between these two drugs. Although PSC 833 produced small increases in the peak plasma paclitaxel concentration and AUC, compared with historical controls treated with the same dose of paclitaxel, PSC 833 greatly prolonged the terminal phase of decline in the paclitaxel concentration. As a result, at the paclitaxel dose of 70 mg/m2, the time plasma paclitaxel concentration remained at or above 0.05 µmol/L was similar to that observed when full-dose paclitaxel was given without PSC 833. The time that plasma paclitaxel concentration remains at or above 0.05 µmol/L, and not the AUC, has been reported as the pharmacokinetic parameter most relevant to relate to the neutropenia produced by paclitaxel therapy. Therefore, it is not surprising that full doses of paclitaxel could not be given in combination with PSC 833, despite the fact that PSC 833 had little effect on the apparent clearance of paclitaxel and, as a consequence, on the paclitaxel AUC. The fact that there was no obvious enhanced pharmacodynamic response to the paclitaxel exposure when paclitaxel was given with PSC 833 implies that the majority of the enhanced neutropenia encountered with that combination is primarily the result of a pharmacokinetic drug-drug interaction rather than a pharmacodynamic sensitization of myeloid stem cells by PSC 833. Although the PSC 833 dose was not escalated in this study, its pharmacokinetics were studied before, during, and 48 hours after paclitaxel administration. The mean concentrations after the PSC 833 loading dose (just before the paclitaxel infusion) and continuing throughout the 24 hours after the paclitaxel infusion were more than 1,000 ng/mL, thereby demonstrating that the concentrations of PSC 833 needed to reverse MDR in vitro were obtained. One patient had the pharmacokinetics of paclitaxel and PSC 833 studied while she was taking phenytoin and again 14 days after she discontinued treatment with the phenytoin. These pharmacokinetic studies clearly demonstrate the interaction between paclitaxel in combination with PSC 833 and myelosuppression. While the patient was taking phenytoin, the paclitaxel and PSC 833 concentrations and the time that plasma paclitaxel concentrations were at or above 0.05 µmol/L were lower than when she was not taking phenytoin. These pharmacokinetic differences correlated with the absence or occurrence, respectively, of clinically significant myelosuppression. In conclusion, we performed a phase I study of paclitaxel in combination with the multidrug reversing agent PSC 833. The MTD of paclitaxel is 122.5 mg/m2 given as a 3-hour continuous infusion with IV PSC 833. The pharmacokinetic interaction of PSC 833 and paclitaxel explains the enhanced myelosuppression produced by doses of paclitaxel that, by themselves, would not be myelosuppressive and provides a rationale for why dose-reduction of paclitaxel is necessary when it is given in combination with PSC 833. This study complements the phase I study of paclitaxel and oral PSC 833. The difference noted in the MTD of paclitaxel in these two studies is presently being investigated. Although taxane resistance has been attributed to several mechanisms, including P-glycoprotein–mediated drug resistance, tubulin changes, and alterations in the pathways leading to apoptosis, the contribution of these mechanisms to clinical taxane resistance is unknown.29 Recent studies will clarify the role of P-glycoprotein in ovarian cancer. Two phase II trials using paclitaxel and PSC 833 in recurrent and refractory ovarian cancer have been completed.30 More importantly, the role of P-glycoprotein is presently being examined in the ongoing phase III study comparing the combination of paclitaxel, carboplatin, and PSC 833 to paclitaxel and carboplatin without PSC 833 in women with suboptimally debulked stage III or stage IV ovarian carcinoma.
Supported by National Institutes of Health (Bethesda, MD) grant no. M01 RR00036 (General Clinical Research Center, Washington University School of Medicine, St Louis, MO), Clinical Oncology Career Development Award CDA-96-27 from the American Cancer Society (Atlanta, GA) (to P.M.F.), and Novartis Pharmaceuticals Corporation (East Hanover, NJ). We acknowledge Michaele C. Christian, MD, and S. Percy Ivy, MD, of the Cancer Therapy Evaluation Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, for their helpful discussions; Teresa J. Vietti, MD, for her editorial assistance, and Professor J. Philip Miller, for his biostatistical analyses of the PSC 833 blood concentrations.
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INTRODUCTION
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