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© 2001 American Society for Clinical Oncology Phase I and Pharmacokinetic Study of the Novel MDR1 and MRP1 Inhibitor Biricodar Administered Alone and in Combination With DoxorubicinFrom the Vincent T. Lombardi Cancer Research Center and Department of Nuclear Medicine, Georgetown University, Washington, DC, and Vertex Pharmaceuticals Incorporated, Cambridge, MA. Address reprint requests to Matthew Harding, PhD, Vertex Pharmaceuticals Incorporated, 130 Waverly St, Cambridge, MA 02139; email: matthew_harding{at}vpharm.com
PURPOSE: To evaluate the safety, tolerability, and pharmacokinetics of biricodar (VX-710), an inhibitor of P-glycoprotein (P-gp) and multidrug resistance–associated protein (MRP1), alone and with doxorubicin in patients with advanced malignancies. The effect of VX-710 on the tissue distribution of 99mTc-sestamibi, a P-gp and MRP1 substrate, was also evaluated. PATIENTS AND METHODS: Patients with solid malignancies refractory to standard therapy first received a 96-hour infusion of VX-710 alone at 20 to 160 mg/m2/h. After a 3-day washout, a second infusion of VX-710 was begun, on the second day of which doxorubicin 45 mg/m2 was administered. Cycles were repeated every 21 to 28 days. 99mTc-sestamibi scans were performed before and during administration of VX-710 alone. RESULTS: Of the 28 patients who enrolled, 25 patients were eligible for analysis. No dose-limiting toxicity (DLT) was observed in the nine assessable patients who received 120 mg/m2/h or less. Among seven patients receiving VX-710 160 mg/m2/h, two DLTs were seen: reversible CNS toxicity and febrile neutropenia. All other adverse events were mild to moderate and reversible. Plasma concentrations of VX-710 in patients who received at 120 and 160 mg/m2/h were two- to fourfold higher than concentrations required to fully reverse drug resistance in vitro. VX-710 exhibited linear pharmacokinetics with a harmonic mean half-life of 1.1 hours. VX-710 enhanced hepatic uptake and retention of 99mTc-sestamibi in all patients. CONCLUSION: A 96-hour infusion of VX-710 at 120 mg/m2/h plus doxorubicin 45 mg/m2 has acceptable toxicity in patients with refractory malignancies. The safety and pharmacokinetics of VX-710 plus doxorubicin warrant efficacy trials in malignancies expressing P-gp and/or MRP1.
AN IMPORTANT goal of cancer research has been to define the molecular basis for multidrug resistance (MDR) to chemotherapy. Of the many mechanisms that have been elucidated to date, MDR associated with overexpression of the MDR1 and MRP1 genes are among the best characterized. MDR1 encodes a 170-kd transmembrane protein, P-glycoprotein (P-gp), which causes the efflux of antineoplastic agents from tumor cells via an adenosine triphosphate–dependent process. Expression of P-gp confers resistance to a broad spectrum of the most commonly used chemotherapeutic agents including the anthracyclines, taxanes, epipodophyllotoxins, vinca alkaloids, and dactinomycin, all of which are natural products (or synthetic derivatives of natural products) and amphiphilic in charge.1-3 P-gp is intrinsically overexpressed in many neoplasms, including the majority of carcinomas arising in the colon, rectum, pancreas, liver, and kidneys.4-6 P-gp is also frequently detected in more chemoresponsive diseases, such as acute leukemia, lymphoma, myeloma, small-cell lung cancer, breast cancer, and ovarian cancer, when patients have become refractory to therapy.4-8 Another important mediator of MDR seems to be the multidrug resistance–associated protein (MRP1). MRP1, like P-gp, is a 190-kd member of the adenosine triphosphate–binding cassette family of membrane transport proteins. MRP1 seems to confer resistance to anthracyclines, vinca alkaloids, epipodophylotoxins, and mitoxantrone, but probably not taxanes, by causing the efflux of glutathione-conjugated natural product agents.9-11 MRP1 mRNA and MRP1 protein seem to be expressed in epithelial cells of most normal tissues, including hematopoietic cells, the digestive, urogenital, and respiratory tracts, and endocrine glands.12 Elevated levels of MRP1 have been observed in relapsed acute myelogenous leukemia, chronic lymphatic leukemia, small-cell and non–small-cell lung cancer, and neuroblastoma.13-15 Since Tsuruo et al16 first reported that the calcium channel blocker verapamil can reverse P-gp–mediated resistance in vitro, a variety of P-gp modulators have been identified and characterized in vitro.17,18 Several of these first-generation MDR inhibitors have been evaluated in patients with advanced or refractory cancers. However, results to date have been largely disappointing.19-23 The lack of benefit seen thus far in patients with solid tumors may in part be a reflection of the properties of the first-generation MDR modulators (eg, verapamil, cyclosporine, and quinidine) that were studied in the 1980s and early 1990s. Some agents had low potencies, and others had significant intrinsic toxicities that prevented sustaining the plasma concentrations necessary to reverse P-gp in vitro.19-23 In addition, many of the agents reversed only P-gp–mediated resistance; therefore, overlapping mechanisms of resistance such as MRP1 expression may be another explanation for the disappointing results from these early studies.3 There are now several new agents that can achieve plasma levels consistently above those required to fully reverse P-gp mediated drug resistance in vitro. Of these, only VX-710 (biricodar) (Incel; Vertex Pharmaceuticals, Cambridge, MA) has been shown to reverse both P-gp– and MRP1-mediated resistance. A common feature of many MDR modulators is their pharmacokinetic interaction with chemotherapeutic drugs. For example, the addition of cyclosporine to doxorubicin resulted in a 55% and 350% increase in the dose adjusted areas under the plasma concentration time curve (AUCs) of doxorubicin and its active metabolite doxorubicin, respectively, and that the doxorubicin dose had to be decreased by 40% to achieve the same degree of myelosuppression.24 In a phase I trial of etoposide plus the cyclosporine analog PSC-833, the terminal half-life of etoposide was increased by 89%, and etoposide clearance was reduced by 45% as a consequence of PSC-833 administration.25 Several other clinical trials have confirmed the influence of cyclosporine, PSC-833, verapamil, and other MDR modulators on the pharmacokinetics of antineoplastic agents.18,26-29 Recent studies have shown that 99mTc-sestamibi, a commercially available radionuclide used in functional cardiac imaging, is a transport substrate for both P-gp and MRP1,30-33 which makes it possibly useful as a noninvasive method for assessing the expression of the MDR proteins in normal tissues and tumor lesions.30-32 Several studies have shown that patients with tumors that rapidly efflux 99mTc-sestamibi and express P-gp, MRP1, or both as determined by immunohistochemical staining have a poorer response to therapy compared with patients whose tumors retain 99mTc-sestamibi. Results of these studies provide further indirect evidence that expression of MDR proteins is correlated with a poor prognosis.34-36 VX-710 (Fig 1) is a novel MDR modulating agent that reverses P-gp– and MRP1-mediated drug resistance. In vitro, VX-710 sensitizes P-gp– and MRP1-expressing cells to doxorubicin at concentrations of 0.6 to 1.5 µg/mL and 1.0 to 3.0 µg/mL, respectively.37,38 Furthermore, preclinical pharmacokinetic studies of VX-710 in beagle dogs and Sprague-Dawley rats showed that VX-710 has no effect on the clearance of doxorubicin after intravenous bolus administration.39
We conducted a phase I trial of VX-710 in combination with doxorubicin for the following reasons: (1) to determine the toxicity profile and establish the maximum-tolerated dose (MTD) of VX-710 in combination with doxorubicin 45 mg/m2; (2) to evaluate the pharmacokinetics of VX-710 administered alone and in combination with doxorubicin; (3) to evaluate potential effects of VX-710 on doxorubicin pharmacokinetics; and (4) to assess the effect of VX-710 on the distribution of 99mTc-sestamibi in normal tissues and tumor lesions.
Eligibility Patients with histologically documented assessable or measurable tumors who previously failed to respond to or were not candidates for standard therapy were eligible for this study. In addition, subjects were required to be 18 years of age or older; to have a confirmed diagnosis of incurable malignancy; a Karnofsky performance status score of 70% or more; to have adequate hepatic, renal, and hematologic function; to have left ventricular ejection fraction within the normal range; to have no significant laboratory abnormalities; and to have a life expectancy of at least 12 weeks. Patients who had received prior therapy were required to have recovered from reversible toxicities associated with that therapy. Patients were not considered eligible who had had treatment under another investigational protocol within 28 days; who had significant EEG abnormalities or history of seizures; who had active concomitant malignancies; or who had other serious comorbid illness. Subjects may have had prior doxorubicin therapy but must not have received cumulative exposure of more than 325 mg/m2. Pregnant or lactating women were not eligible. Patients were required to provide written informed consent. Concomitant use of other drugs known to inhibit P-gp was not allowed.
Study Design, Dosage, and Drug Administration VX-710 was administered via a central venous catheter with a CADD-1 ambulatory pump (SIMS Deltec, St Paul, MN) for all but two patients. During the first cycle, treatment was given in an inpatient clinical research unit. In subsequent cycles, only combination treatment was given on an outpatient basis. Patients who had not progressed and had recovered from any toxicities from the previous cycle were eligible for retreatment every 21 to 28 days. A minimum of three patients were treated at each of the VX-710 dose levels (20, 40, 80, 120, and 160 mg/m2/h), with additional patients added when dose-limiting toxicity was observed or to confirm the MTD. Toxicities were evaluated according to the National Cancer Institute common toxicity criteria. The MTD was defined as one dose level less than the dose that induced dose-limiting toxicity in one of three or a maximum of two of six patients. Dose-limiting toxicity was defined as any grade 3 or 4 toxicity excluding nausea, vomiting, and hematologic toxicities. Nausea and vomiting were dose limiting at grade 4. Dose-limiting myelosuppression was defined as grade 4 toxicity (absolute neutrophil count < 500 cells/µL; hemoglobin < 6.5 g/dL; platelet count < 25,000 cells/µL) of at least 5 days’ duration or grade 4 of any duration associated with fever, documented infection, or both. VX-710 was provided by Vertex Pharmaceuticals in vials containing 3 g of VX-710 as a dicitrate salt in 6 mL of sterile water for injection (500 mg/mL VX-710, which is 300 mg base equivalent). At the time of use, the concentrated drug solution was aseptically mixed with 0.9% normal saline or 5% dextrose for administration with a 250-mL polyvinylchloride infusion set.
Pretreatment and Follow-Up Studies
Pharmacokinetic Sampling and Assays The analytic methods used for extraction of VX-710 or doxorubicin were as follows. VX-710 was recovered from whole blood or urine samples via a double liquid-liquid extraction procedure with methyl-tert-butyl ether. Subsequently, the extract was subjected to an isocratic reverse-phase high-performance liquid chromatography separation with a Selectosil 5 CN column (Phenomenex, Torrance, CA) (250 x 4.6 mm, 5 µm) with ultraviolet detection at 305 nm for the determination of VX-710 concentration. The linear range was 0.2 to 12.42 and 0.3 to 4.88 µg/mL for blood and urine assays, respectively. The assay precision and accuracy were 2.6 to 13.2% and more than 90%, respectively, for the VX-710 whole-blood assay, and 4% to 10% and more than 89%, respectively, for VX-710 urine assay. These assays were determined to be selective and specific after the analysis of six independent blood samples and six independent urine samples. Doxorubicin was recovered from plasma and urine samples with ethyl acetate extraction. Subsequently, the extract was subjected to isocratic reverse phase high-performance liquid chromatography separation with a Phenomenex Selectosil C-18 column (250 x 4.6 mm, 5 µm) with fluorescence detection (excitation wave length of 470 nm and emission wave length of 550 nm) for the quantitation of doxorubicin concentration. The linear range for the plasma and the urine assays were 5 to 2,000 and 50 to 10,000 ng/mL, respectively. The assay precision and accuracy were 2.4% to 28% and more than 98%, respectively, for the plasma assay and 1% to 12% and 88%, respectively, for the urine assay. The assays were determined to be selective and specific after the analysis of six independent samples for plasma and urine. Concurrent monitoring of plasma concentrations of doxorubicinol, the major metabolite of doxorubicin, was not completely in accordance with the principles of good laboratory practice because of the limited availability of a reference standard. Briefly, a calibration curve was generated with the limited amount of doxorubicinol reference standard and subsequently used to quantitate the doxorubicinol concentrations in all plasma samples from this study.
Pharmacokinetic Analysis
Response Criteria
99mTc-Sestamibi Scintigraphy
where AOI was the uptake within the area of interest (liver or tumor) and heart indicates the uptake within the heart.
General From February 1995 to December 1996, 28 patients were entered onto this trial. A total of 91 cycles (26 cycles of VX-710 alone and 65 combination cycles) of study treatment were administered to patients at five VX-710 dose levels. Characteristics of patients enrolled in this study are summarized in Table 1. Table 2 summarizes the number of patients enrolled at each dose level and number of patients who received a cycle of VX-710 alone and subsequent VX-710–doxorubicin combination treatment cycles. Three patients, all entered at the 120-mg/m2/h dose level, were not assessable for toxicity. One patient was diagnosed with a perforated duodenal ulcer (considered unrelated to study treatment) during the first week of treatment and was immediately removed from the study. The second patient was removed from the study before the second week of treatment because of a significant decrease in performance status attributed to disease progression. The third patient developed obstructive jaundice during the second week of treatment secondary to a biliary obstruction attributable to extensive hepatic metastases.
Toxicity In general, VX-710 administered alone and in combination with doxorubicin was well tolerated. All toxicities were reversible, mild to moderate in severity, and manageable. Table 3 summarizes the median and range for cycle 1 absolute neutrophil counts and platelet counts for patients treated at each VX-710 dose level in combination with doxorubicin 45 mg/m2. The combination regimen was not associated with significant myelosuppression. Dose-limiting neutropenia was observed in one patient at the 160-mg/m2/h dose level (absolute neutrophil count nadir of 154 cells/µL) whose absolute neutrophil count remained below 500 cells/µL for 6 days during the first cycle of combination therapy. Prophylactic granulocyte-macrophage colony-stimulating factor was given starting on day 3 for subsequent cycles. Neutrophil nadirs during cycles 2, 3, and 4 were 867, 546, and 98 cells/µL, respectively. The patient developed febrile neutropenia during the fourth cycle, and further treatment was discontinued because of disease progression. Overall, grade 4 neutropenia was observed in five (17%) of 29 and four (30%) of 13 of cycles for patients receiving VX-710 120 and 160 mg/m2/h with doxorubicin 45 mg/m2. No patients treated with VX-710 80 mg/m2/h or less experienced significant neutropenia. Mild thrombocytopenia was observed infrequently, with platelet nadirs of less than 100,000 cells/µL occurring in only five patients during cycle 1, with the lowest nadir at 92,000 cells/µL.
The predominant nonhematologic toxicities observed during the administration of VX-710 alone or the first cycle of combination therapy are summarized by dose group in Tables 4 and 5. Nausea or emesis during administration of VX-710 alone or with combination therapy was adequately controlled with a combination of metoclopramide and ondansetron or granisetron. One patient also required a short tapering schedule of oral dexamethasone. Bilirubinemia (without increases in AST or ALT) was observed in four patients treated with VX-710 120 or 160 mg/m2/h alone and in 12 patients during combination treatment (Tables 4 and 5). A two- to threefold increase in serum bilirubin was typically observed on day 4 or 5, but returned to normal levels within 72 hours of discontinuing VX-710. One patient with Gilbert’s disease had an increase in total bilirubin from a normal baseline value to 6.6 mg/dL that was probably related to both study treatment and the patient’s Gilbert’s disease history. Headaches, occurring during administration of VX-710 alone and combination treatment, were not clearly dose related and were adequately controlled with orally administered analgesics. Asymptomatic grade 1 and 2 orthostatic hypotension during VX-710 administration occurred in 21 patients during administration of VX-710 alone and in 10 patients during combination treatment. Two patients required short-term administration of intravenous fluids and had immediate restoration of their blood pressure. The hypotension was also independent of VX-710 dosage. MUGA scans obtained after alternating cycles of VX-710 and doxorubicin showed no significant change in left ventricular function in all but one patient who had received prior mediastinal radiation. His left ventricle ejection fraction fell from 60% to 45% after two cycles, and study treatment was discontinued.
A local irritant effect was noted in six patients who received VX-710 through a peripheral intravenous catheter. Redness, swelling, and pain were noted within 24 to 48 hours; however, symptoms resolved within 7 days with supportive care. Five patients developed subclavian vein thrombosis associated with their indwelling central venous catheters (Table 5). This diagnosis was made during the first cycle of combination VX-710–doxorubicin treatment in three patients and during cycles 3 and 4 in the other two patients. Neurocortical toxicity was observed in two patients treated at the 160-mg/m2/h dose level. One patient developed fleeting visual hallucinations that could be attributed, at least in part, to concomitant narcotic analgesics. The second patient experienced dose-limiting mental status changes characterized by somnolence and disorientation starting within 24 hours of beginning infusion of VX-710 alone. The patient fully recovered within 24 hours of discontinuing VX-710. None of the other patients treated in the 160-mg/m2/h dose group or in the lower-dose cohorts experienced similar neurologic events in association with VX-710 administered alone or in combination with doxorubicin.
MTD As described above, two of seven patients at the 160-mg/m2/h VX-710 dose level experienced dose-limiting toxicities: one patient developed grade 4 neutropenia of more than 5 days’ duration during combination therapy, and the other patient developed grade 3 neurocortical toxicity during administration of VX-710 alone. None of the nine assessable patients treated with VX-710 120 mg/m2/h alone or in combination with doxorubicin 45 mg/m2 developed dose-limiting toxicity, confirming 120 mg/m2/h as the MTD of VX-710.
Whole-Body 99mTc-Sestamibi Scintigraphy
Pharmacokinetics There were no differences in VX-710 pharmacokinetic parameter values between the VX-710 single-agent infusion cycle and the combination therapy cycle (VX-710–doxorubicin), as shown in Fig 3, where selected pharmacokinetic parameters of VX-710 from all patients were plotted by cohorts. VX-710 has linear pharmacokinetics as indicated by the lack of dose dependence in CLs and Vss. In lieu of the observed linear pharmacokinetics, Table 6 summarizes the pharmacokinetic parameters of VX-710 for the combined data from all dose groups and both treatment phases, except for Css, which was proportional to dose and hence summarized by dose cohorts. The median (mean ± SD) Css achieved at doses of 20, 80, 120, and 160 mg/m2/h were 0.35 (0.45 ± 0.26), 2.13 (2.12 ± 0.53), 6.5 (7.37 ± 5.98), and 8.3 (9.37 ± 5.77) µg/mL, respectively. The median (mean ± SD) values of CLs and Vss for VX-710 were 0.46 (0.52 ± 0.36) L/h/kg and 1.15 (1.34 ± 1.15) L/kg, respectively, and the harmonic mean half-life value was 1.1 hour. An accurate measurement of urinary excretion for VX-710 was not possible in all patients because of the existence of chromatographic interference in some study samples. However, on the basis of data from a small number of patients, urinary excretion of VX-710 accounted for less than 0.5% of dose administered.
Four pharmacokinetic parameters of doxorubicin (AUC, CLs, Vss, and plasma AUC ratio of doxorubicinol to doxorubicin) derived from a single intravenous injection of doxorubicin 45 mg/m2 administered in combination with VX-710 were plotted by VX-710 dose cohorts in Fig 4 and summarized in Table 7. Regression analyses on all four parameters as a function of VX-710 dose resulted in coefficient of determination (r2) values ranging from 0.03 to 0.18, indicating that the parameters were not influenced by the increase in VX-710 dose from 20 to 160 mg/m2/h. Consequently, data from all cohorts were combined for further analysis. The resulting median (mean ± SD) AUC, CLs, and Vss of doxorubicin were 3.23 (3.187 ± 1.176) µg/h/mL, 0.38 (0.45 ± 0.21) L/h/kg, and 6.8 (8.9 ± 6.0) L/kg, respectively. The harmonic mean value and the median value for doxorubicin half-life were 19.1 and 31.2 hours, respectively. The median (mean ± SD) renal clearance derived from urinary data was 41.0 (51.5 ± 37.8) mL/h/kg, indicating that urinary excretion of doxorubicin accounted for approximately 11% of the administered dose. The ratio of plasma doxorubicinol AUC to plasma doxorubicin AUC was determined to have the median and mean ± SD values of 0.77 and 1.5 ± 3.2, respectively.
Tumor Response A 49-year-old man with extensive stage small-cell carcinoma of the lung treated at the 120-mg/m2/h dose level achieved a partial response, with an 80% reduction in his measurable lesions after five cycles of VX-710–doxorubicin therapy. His previous treatment included two platinum-based regimens as well as palliative radiation. This response was maintained for at least 1 month. The expression of P-gp or MRP1 by his tumor was unknown. Three patients had stable disease for at least four cycles of therapy, and two of these three patients received a total of six cycles.
P-gp and MRP1 confer resistance against a broad range of important antineoplastic agents and each can independently confer resistance to doxorubicin.3,9 Both proteins are commonly expressed in a large number of drug-resistant malignancies. VX-710, unlike most other P-gp modulators, is a potent inhibitor of both P-gp– and MRP1-mediated drug efflux.37,38 This phase I study demonstrated that a 96-hour continuous infusion of VX-710 administered alone and in combination with doxorubicin 45 mg/m2 was well tolerated by patients with advanced solid malignancies. Hematologic and nonhematologic toxicities were reversible, and most were mild to moderate in severity. The MTD for the 96-hour infusion of VX-710–doxorubicin was 120 mg/m2/h. No dose-limiting toxicities were observed in any of the nine assessable patients treated at the MTD. Furthermore, VX-710 steady-state plasma concentrations at this dose (mean and median of 7.37 and 6.53 µg/mL, respectively; Table 6) were severalfold above concentrations required to fully restore drug sensitivity to P-gp– and MRP1-expressing cells in vitro (0.6 to 1.5 µg/mL and 1.0 to 3.0 µg/mL, respectively). Thus, VX-710 plasma concentrations achieved at the 120-mg/m2/h dose level are sufficiently high to restore cytotoxic drug accumulation in tumors expressing P-gp or MRP1. VX-710–doxorubicin was not associated with significant myelosuppression. The overall incidence of grade 4 neutropenia in patients treated at the 120- and 160-mg/m2/h dose levels was 17% and 30%, respectively. Nonhematologic adverse events were similar in incidence and severity to those observed with single-agent doxorubicin therapy; however, bilirubinemia, headaches, transient asymptomatic hypotension, and a local irritant effect may be attributable solely to VX-710 administration. Transient bilirubinemia, a frequent observation in trials with other MDR modulators,20,21 was also observed in this study. P-gp and MRP1 are expressed by biliary canaliculi cells, and both seem to have a role in the transport of bile acids, glutathione, and glucuronate conjugates.9,10,40-43 Because increased total bilirubin was noted only at VX-710 Css concentrations of more than 7 µg/mL (predominantly at the 120- and 160-mg/m2/h dose levels; Tables 4 and 5), inhibition of biliary transport functions of P-gp, MRP1, or related proteins by VX-710 may be associated with the transient increase in bilirubin observed during VX-710 infusion.
Headaches were frequently reported by patients, but they were not dose related and proved manageable with orally administered analgesics. Mild to moderate hypotension, although observed in this study, was not observed in a study involving a 24-hour infusion of VX-710 120 mg/m2/h in combination with paclitaxel.44 Because a local irritant effect was observed in the first patients who received VX-710 by peripheral intravenous catheter, administration to all subsequent patients was performed by means of an indwelling central venous catheter. No significant irritant or vesicant activity was observed in preclinical studies with VX-710 infusions of up to 14 days. Thus, the basis for the irritant effect is unknown, but it may be attributable to the low pH ( Characterization of VX-710 and doxorubicin pharmacokinetics was an important objective of the study. VX-710 showed linear pharmacokinetics in the intravenous infusion dose range of 20 to 160 mg/m2/h, and the pharmacokinetics of VX-710 did not change when doxorubicin was coadministered at 45 mg/m2. Doxorubicin pharmacokinetics (at the 45-mg/m2 dose) were not significantly affected by the increase in VX-710 dosage from 20 to 160 mg/m2/h, as the median VX-710 Css increased from 0.35 to 8.31 µg/mL. Additionally, the overall median value of the plasma AUC ratio of doxorubicinol to doxorubicin was 0.77, falling within the range of 0.3 to 0.9 for doxorubicin alone.48-51 Although results of this study suggest that VX-710 does not affect doxorubicin pharmacokinetics, a second study in which patients are administered doxorubicin 60 mg/m2 alone followed by doxorubicin 60 mg/m2 plus VX-710 120 mg/m2/h will further evaluate minor effects of VX-710 on doxorubicin pharmacokinetics. The apparent lack of a significant pharmacokinetic interaction with doxorubicin is an advantage for VX-710 as an MDR modulator. This study also included an evaluation of the effects of VX-710 on the distribution of 99mTc-sestamibi. 99mTc-sestamibi has been demonstrated to be a transport substrate for both P-gp and MRP1,30-32 and exposure of P-gp–positive cell lines to MDR modulators has also been shown to augment cellular 99mTc-sestamibi accumulation and retention.30-32,52 Clinical studies have shown that P-gp expression is associated with decreased accumulation and retention of 99mTc-sestamibi within tumor tissue.33,52 Several studies have now shown an inverse correlation between 99mTc-sestamibi uptake within tumors, expression of P-gp, and response to chemotherapy in patients with breast cancer,53-56 small-cell lung cancer,57-59 and renal carcinoma.60 Accordingly, we used 99mTc-sestamibi imaging as a noninvasive surrogate marker to measure the inhibition of P-gp and MRP1 transport function in vivo. VX-710 administration enhanced hepatic 99mTc-sestamibi uptake and retention in all patients evaluated, with a maximum enhancement index (3.86 ± 2.58) observed at the VX-710 MTD of 120 mg/m2/h, consistent with inhibition of P-gp and MRP1 transport functions in normal liver in vivo. Unfortunately, the limited number of patients (nine) with imageable tumors (most lesions were abdominal and obscured by normal 99mTc-sestamibi distribution in the kidneys, gastrointestinal tract, and bladder) did not allow for a meaningful assessment. Those tumors with enhanced 99mTc-sestamibi uptake and retention during VX-710 administration had lower enhancement indexes compared with enhancement indexes for normal liver. Potential explanations include pooling of 99mTc-sestamibi in the liver in the presence of an MDR modulator, or it may relate to VX-710 drug distribution. Because P-gp and MRP1 expression were not measured in this study, it is possible that some of the tumors did not express either P-gp or MRP1. Further studies will be necessary to better define the role of 99mTc-sestamibi scintigraphy as a surrogate indicator of in vivo MDR modulation within tumors. In conclusion, VX-710 has an acceptable tolerability profile when administered with doxorubicin to cancer patients and VX-710 does not seem to affect doxorubicin pharmacokinetics. When given at the recommended phase II dose of 120 mg/m2/h, VX-710 achieves serum concentrations that are greater than those needed to reverse P-gp and MRP1 in vitro. VX-710 consistently promoted uptake and retention of the P-gp–MRP1 substrate 99mTc-sestamibi within normal liver. Phase II studies with VX-710 in combination with multiple cytotoxic agents are now under way in various malignancies known to express P-gp and MRP1.
1. Bellamy WT, Dalton WS: Multidrug resistance in the laboratory and clinic. Adv Clin Chem 31: 1-61, 1994[Medline] 2. Bradley G, Ling V: P-glycoprotein, multidrug resistance and tumor progression. Cancer Metastasis Rev 13: 223-233, 1994[Medline] 3. Ling V: Multidrug resistance: Molecular mechanisms and clinical relevance. Cancer Chemother Pharmacol 40: S3-S8, 1997 (suppl) 4. Patel NH, Rothenberg ML: Multidrug resistance in cancer chemotherapy. Invest New Drugs 12: 1-13, 1994[Medline] 5. Leighton JC Jr, Goldstein LJ: P-glycoprotein in adult solid tumors: Expression and prognostic significance. Hematol Oncol Clin North Am 9: 251-273, 1995[Medline] 6. Goldstein LJ: MDR1 gene expression in solid tumours. Eur J Cancer 32A: 1039-1050, 1996 7. Marie JP: P-glycoprotein in adult hematologic malignancies. Hematol Oncol Clin North Am 9: 239-249, 1995[Medline] 8. Nooter K, Sonneveld P: Clinical relevance of P-glycoprotein expression in haematological malignancies. Leuk Res 18: 233-243, 1994[Medline] 9. Loe DW, Deeley RG, Cole SP: Biology of the multidrug resistance–associated protein MRP. Eur J Cancer 32A: 945-957, 1996 10. Keppler D, Leier I, Jedlitschky G, et al: The function of the multidrug resistance proteins (MRP and cMRP) in drug conjugate transport and hepatobiliary excretion. Adv Enzyme Regul 36: 17-29, 1996[Medline]
11.
Zaman GJ, Lankelma J, van Tellingen O, et al: Role of glutathione in the export of compounds from cells by the multidrug-resistance-associated protein. Proc Natl Acad Sci U S A 92: 7690-7694, 1995 12. Flens MJ, Zaman GJR, van der Valk P, et al: Tissue distribution of the multidrug resistance protein. Am J Pathol 148: 1237-1247, 1996[Abstract] 13. Nooter K, Westerman A, Flens M, et al: Expression of the multidrug resistance–associated protein (MRP) gene in human cancers. Clin Cancer Res 1: 1301-10, 1995[Abstract] 14. Kruh G, Gaughan K, Godwin A, et al: Expression pattern of MRP in human tissues and adult solid tumor cell lines. Proc Natl Cancer Inst 87: 1256-1258, 1995
15.
Norris M, Bordow SB, Marshall GM, et al: Expression of the gene for multi-drug resistance–associated protein and outcome in patients with neuroblastoma. N Engl J Med 334: 231-238, 1996
16.
Tsuruo T, Iida H, Tsukagoshi S, et al: Overcoming of vincristine resistance in P388 leukemia in vivo and in vitro through enhanced cytotoxicity of vincristine and vinblastine by verapamil. Cancer Res 41: 1967-1972, 1981 17. Ford JM: Experimental reversal of P-glycoprotein–mediated multidrug resistance by pharmacological chemosensitisers. Eur J Cancer 32A: 991-1001, 1996 18. Sikic BI, Fisher GA, Lum BL, et al: Modulation and prevention of multidrug resistance by inhibitors of P-glycoprotein. Cancer Chemother Pharmacol 40: S13-S19, 1997 (suppl) 19. Naito M, Tsuruo T: Therapeutic approach to drug resistant tumors. Ther Drug Monit 20: 577-580, 1998[Medline] 20. Ferry DR, Traunecker H, Kerr DJ: Clinical trials of P-glycoprotein reversal in solid tumours. Eur J Cancer 32A: 1070-1081, 1996 21. Bradshaw DM, Arceci RJ: Clinical relevance of transmembrane drug efflux as a mechanism of multidrug resistance. J Clin Oncol 16: 3674-3690, 1998[Abstract] 22. Raderer M, Scheithauer W: Clinical trials of agents that reverse multidrug resistance: A literature review. Cancer 72: 3553-3563, 1993[Medline] 23. Fisher GA, Sikic BI: Clinical studies with modulators of multidrug resistance. Hematol Oncol Clin North Am 9: 363-382, 1995[Medline] 24. Bartlett NL, Lum BL, Fisher GA, et al: Phase I trial of doxorubicin with cyclosporine as a modulator of multidrug resistance. J Clin Oncol 12: 835-842, 1994[Abstract]
25.
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
26.
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
27.
Lee EJ, George SL, Caligiuri M, et al: Parallel phase I studies of daunorubicin given with cytarabine and etoposide with or without the multidrug resistance modulator PSC-833 in previously untreated patients 60 years of age or older with acute myeloid leukemia: Results of Cancer and Leukemia Group B Study 9420. J Clin Oncol 17: 2831-2839, 1999 28. Rushing DA, Raber SR, Rodvold KA, et al: The effects of cyclosporine on the pharmacokinetics of doxorubicin in patients with small cell lung cancer. Cancer 74: 834-841, 1994[Medline]
29.
Tolcher AW, Cowan KH, Solomon D, et al: Phase I crossover study of paclitaxel with r-verapamil in patients with metastatic breast cancer. J Clin Oncol 14: 1173-1184, 1996
30.
Piwnica-Worms D, Chiu ML, Budding M, et al: Functional imaging of multidrug-resistant P-glycoprotein with an organotechnetium complex. Cancer Res 53: 977-984, 1993 31. Crankshaw C, Piwnica-Worms D: Tc-99m-sestamibi may be a transport substrate of the human multidrug resistance–associated protein (MRP). J Nucl Med 37: 247P, 1996 (suppl, abstr) 32. Hendrikse NH, Franssen EJ, van der Graaf WT, et al: 99mTc-sestamibi is a substrate for P-glycoprotein and the multidrug resistance–associated protein. Br J Cancer 77: 353-358, 1998[Medline]
33.
Luker GD, Fracasso PM, Dobkin J, et al: Modulation of the multidrug resistance P-glycoprotein: Detection with technetium-99m-sestabmibi in vivo. J Nucl Med 38: 369-372, 1997 34. Del Vecchio S, Ciarmiello A, Salvatore M: Clinical imaging of multidrug resistance in cancer. Q J Nucl Med 43: 125-131, 1999[Medline]
35.
Cordobes MD, Starzec A, Delmon-Moingeon L, et al: Technetium-99m-sestamibi uptake by human benign and malignant breast tumor cells: Correlation with mdr gene expression. J Nucl Med 37: 286-289, 1996
36.
Kostakoglu L, Elahi N, Kiratli P, et al: Clinical validation of the influence of P-glycoprotein on technetium-99m-sestamibi uptake in malignant tumors. J Nucl Med 38: 1003-1008, 1997 37. Germann UA, Ford PJ, Shlyakhter D, et al: Chemosensitization and drug accumulation effects of VX-710, verapamil, cyclosporin A, MS-209 and GF120918 in multidrug resistant HL60/ADR cells expressing the multidrug resistance–associated protein MRP. Anticancer Drugs 8: 141-155, 1997[Medline] 38. Germann UA, Shlyakhter D, Mason VS, et al: Cellular and biochemical characterization of VX-710 as a chemosensitizer: Reversal of P-glycoprotein–mediated multidrug resistance in vitro. Anticancer Drugs 8: 125-140, 1997[Medline] 39. Chaturvedi P, Harding MW, Decker C, et al: Evaluation of the pharmacokinetic interactions of VX-710 with doxorubicin and paclitaxel in beagle dogs. Proc Am Assoc Cancer Res 37: 373, 1996 (abstr)
40.
Buchler M, Konig J, Brom M, et al: cDNA cloning of the hepatocyte canalicular isoform of the multidrug resistance protein, cMRP, reveals a novel conjugate export pump deficient in hyperbilirubinemic mutant rats. J Biol Chem 271: 15091-15098, 1996 41. Mazzanti R, Fantappie O, Kamimoto Y, et al: Bile acid inhibition of P-glycoprotein–mediated transport in multidrug-resistant cells and rat liver canalicular membrane vesicles. Hepatology 20: 170-176, 1994[Medline] 42. Oude Elferink RP, Groen AK: The role of mdr2 P-glycoprotein in biliary lipid secretion: Cross-talk between cancer research and biliary physiology. J Hepatol 23: 617-625, 1995[Medline]
43.
Hirohashi T, Suzuki H, Ito K, et al: Hepatic expression of multidrug resistance–associated protein-like proteins maintained in eisai hyperbilirubinemic rats. Mol Pharmacol 53: 1068-1075, 1998
44.
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 45. Bern MM, Lokich JJ, Wallach SR, et al: Very low doses of warfarin can prevent thrombosis in central venous catheters: A randomized prospective trial. Ann Intern Med 112: 423-428, 1990 46. Bramwell V, Morris D, Ernst S, et al: Phase I/II study with the MDR inhibitor INCELTM (biricodar, VX-710) + doxorubicin in anthracycline resistant advanced soft tissue sarcoma. Proc Am Soc Clin Oncol 18: 542a, 1999 (abstr 2094) 47. Rago RP, Einstein AB, Lush RM, et al: A Phase II study of the safety pharmacokinetics and efficacy of Incel (biricodar, VX-710) in combination with mitoxantrone (M) and prednisone (P) in hormone refractory prostate cancer (HRPC). Proc Am Soc Clin Oncol 19: 180a, 2000 (abstr 699) 48. Speth PA, van Hoesel QG, Haanen C: Clinical pharmacokinetics of doxorubicin. Clin Pharmacokinet 15: 15-31, 1988[Medline] 49. Camaggi CM, Comparsi R, Strocchi E, et al: Epirubicin and doxorubicin comparative metabolism and pharmacokinetics: A crossover study. Cancer Chemother Pharmacol 21: 221-228, 1988[Medline] 50. Mross K, Maessen P, van der Vijgh WJF, et al: Pharmacokinetics and metabolism of epidoxorubicin and doxorubicin in humans. J Clin Oncol 6: 517-526, 1988[Abstract] 51. Preiss R, Sohr R, Kittelmann B, et al: Investigations on the dose-dependent pharmacokinetics of adriamycin and its metabolites. Int J Clin Pharmacol Ther Toxicol 27: 156-164, 1989[Medline] 52. Ballinger JR, Hua HA, Berry BW, et al: 99-Tcm-sestamibi as an agent for imaging P-glycoprotein–mediated multi-drug resistance: In vitro and in vivo studies in a rat breast tumour cell line and its doxorubicin-resistant variant. Nucl Med Commun 16: 253-257, 1995[Medline] 53. Del Vecchio S, Ciarmiello A, Potena MI, et al: In vivo detection of multidrug-resistant (MDR1) phenotype by technetium-99m sestamibi scan in untreated breast cancer patients. Eur J Nucl Med 24: 150-159, 1997[Medline] 54. Ciarmiello A, Del Vecchio S, Silvestro P, et al: Tumor clearance of technetium 99m-sestamibi as a predictor of response to neoadjuvant chemotherapy for locally advanced breast cancer. J Clin Oncol 16: 1677-1683, 1998[Abstract] 55. Moretti J-L, Azaloux H, Boisseron D, et al: Primary breast cancer imaging with technetium-99m sestamibi and its relation with P-glycoprotein overexpression. Eur J Nucl Med 23: 980-986, 1996[Medline]
56.
Del Vecchio S, Ciarmiello A, Pace L, et al: Fractional retention of technetium-99m-sestamibi as an index of P-glycoprotein expression in untreated breast cancer patients. J Nucl Med 38: 1348-1351, 1997 57. Ceriani L, Giovanella L, Bandera M, et al: Semi-quantitative assessment of 99Tcm-sestamibi uptake in lung cancer: Relationship with clinical response to chemotherapy. Nucl Med Commun 18: 1087-1097, 1997[Medline] 58. Kao CH, Chang Lai SP, Chieng PU, et al: Technetium-99m methoxyisobutylisonitrile chest imaging of small cell lung carcinoma. Cancer 83: 64-68, 1998[Medline]
59.
Bom H-S, Kim Y-C, Song H-C, et al: Technetium-99m-MIBI uptake in small cell lung cancer. J Nucl Med 39: 91-94, 1998 60. Chen CC, Meadows B, Regis J, et al: Detection of in vivo P-glycoprotein inhibition by PSC 833 using Tc-99m sestamibi. Clin Cancer Res 3: 545-552, 1997[Abstract] Submitted August 25, 2000; accepted March 6, 2001.
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Copyright © 2001 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
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3.5) of the VX-710 infusion preparation in the case of localized catheter leakage. Catheter-associated thrombi occurred in 18% of patients. Patients in this study were not routinely given prophylactic anticoagulation therapy, and the incidence of thrombosis observed was lower than the 37% incidence observed in the control arm of a randomized trial of low-dose coumadin in cancer patients with indwelling catheters.
