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© 2002 American Society for Clinical Oncology Phase I and Pharmacologic Study of Liposomal Lurtotecan, NX 211: Urinary Excretion Predicts Hematologic ToxicityByFrom the Department of Medical Oncology, Rotterdam Cancer Institute (Daniel den Hoed Kliniek) and University Hospital, Rotterdam, and Department of Medical Oncology, University Hospital Groningen, Groningen, the Netherlands; and Gilead Sciences Inc, Boulder, CO. Address reprint requests to Diederik Kehrer, MD, PhD, Department of Medical Oncology, Rotterdam Cancer Institute (Daniel den Hoed Kliniek) and University Hospital, Groene Hilledijk 301, 3075 EA Rotterdam, the Netherlands; email: diederikkehrer{at}hotmail.com
PURPOSE: To determine the maximum-tolerated and recommended dose, toxicity profile, and pharmacokinetics of the liposomal topoisomerase I inhibitor lurtotecan (NX 211) administered as a 30-minute intravenous infusion once every 3 weeks in cancer patients. PATIENTS AND METHODS: NX 211 was administered by peripheral infusion. Dose escalation decisions were based on all toxicities during the first cycle as well as pharmacokinetic parameters. Serial plasma, whole blood, and urine samples were collected for up to 96 hours after the end of infusion, and drug levels were determined by high-performance liquid chromatography. RESULTS: Twenty-nine patients (16 women; median age, 56 years; range, 39 to 74 years) received 77 courses of NX 211 at dose levels of 0.4 (n = 3), 0.8 (n = 6), 1.6 (n = 3), 3.2 (n = 6), 3.8 (n = 6), and 4.3 mg/m2 (n = 5). Neutropenia and thrombocytopenia were the dose-limiting toxicities and were not cumulative. Other toxicities were mild to moderate. Nine patients had stable disease while undergoing treatment. The systemic clearance of lurtotecan in plasma and whole blood was 0.82 ± 0.78 L/h/m2 and 1.15 ± 0.96 L/h/m2, respectively. Urinary recovery (Fu) of lurtotecan was 10.1% ± 4.05% (range, 4.9% to 18.9%). In contrast to systemic exposure measures, the dose excreted in urine (ie, dose x Fu) was significantly related to the percent decrease in neutrophil and platelet counts at nadir (P < .00001). CONCLUSION: The dose-limiting toxicities of NX 211 are neutropenia and thrombocytopenia. The recommended dose for phase II studies is 3.8 mg/m2 once every 3 weeks. Pharmacologic data suggest a relationship between exposure to lurtotecan and NX 211–induced clinical effects.
LURTOTECAN (7-(4-methylpiperazinomethylene)-10,11-ethylenedioxy-20(S)-camptothecin, also known as GI147211) (Fig 1) is a semisynthetic analog of camptothecin, a cytotoxic plant alkaloid that was first extracted from Camptotheca acuminata.1 Structurally, lurtotecan is unique among camptothecin drugs because of a dioxalane moiety on the A ring and a bulky 4-methyl-piperazinomethylene group on the C-7 position. These molecular modifications have resulted in enhanced aqueous solubility as compared with the original agent and increased affinity of the drug for DNA topoisomerase I, the cellular locus through which camptothecin analogs produce their antitumor activity. Its mechanism of action is based on stabilization of the cleavable complex formed by the intranuclear enzyme topoisomerase I and DNA and on induction of the single-stranded DNA breaks.2 The cytotoxicity of the topoisomerase I inhibitors is distinctly S-phase specific, and various preclinical studies with lurtotecan and other camptothecin drugs have suggested that prolonged exposure, achieved either by repeated doses or prolonged infusion, might be beneficial for efficacy profiles.3 Preclinical in vivo studies with lurtotecan as a single agent demonstrated that it is an effective inhibitor of mammalian DNA topoisomerase I, with at least similar potency as the related agent topotecan.1,4
Several clinical trials with lurtotecan have been performed to exploit the possible schedule dependence, focusing on intermittent (daily for 5 days every 3 weeks)5-8 or prolonged intravenous (IV) administration (72-hour infusion every 4 weeks, and 7-, 14-, or 21-day infusion schedules).9,10 These studies have demonstrated that the pharmacokinetic behavior of lurtotecan, in analogy to other topoisomerase I inhibitors, is significantly influenced by a chemical pH-dependent hydrolysis of the active lactone form to the ring-opened carboxylate form, which is devoid of biologic activity.11 On the basis of this knowledge, considerable effort has recently been put to the development of alternative pharmaceutical vehicles that would allow prolonged systemic exposure to the biologically active lactone form. Among various approaches, liposomal encapsulation of camptothecin analogs was demonstrated to effectively diminish lactone hydrolysis.12-18 Besides this, liposomal encapsulated anticancer drugs have been studied extensively both in the laboratory and in the clinic, with reports of prolonged plasma exposure, improved tumor delivery, decreased systemic toxicity, and increased efficacy for a variety of cytotoxic drugs.19 Increased antitumor activity by enhancement of tissue distribution and systemic drug availability of liposome-encapsulated topoisomerase I inhibitors has been found in rodent models, including improved therapeutic efficacy for a new stable unilamellar liposomal formulation of lurtotecan (NX 211) as compared with nonliposomal lurtotecan.20 In view of the above, a phase I open-label, dose-escalating trial was initiated to investigate the clinical utility of NX 211 administration. The objectives of this study were to assess the safety and toxicity profile of this lurtotecan formulation; to determine the dose-limiting toxicities (DLT), the maximum-tolerated dose (MTD), and the recommended dose for phase II studies with the drug given by IV administration once every 3 weeks; and to examine the disposition of this drug.
Eligibility Criteria Patients were eligible if they had a histologically confirmed diagnosis of advanced solid tumor refractory to standard chemotherapy or a malignancy for which there was no effective standard chemotherapeutic regimen. Additional criteria included the following: age  18 years; Eastern Cooperative Oncology Group status of 0 to 2; no previous treatment with antineoplastic agents for at least 3 weeks (4 weeks for carboplatin or an investigational drug and 6 weeks for nitrosoureas or mitomycin), or radiotherapy exceeding 25% of the bone marrow volume; adequate bone marrow function, defined as absolute neutrophil count (ANC) 1.5 x 109/L and platelets 100 x 109/L; adequate renal function as defined by a serum creatinine within normal limits; adequate liver function as defined by bilirubin within normal limits, and AST and ALT  2.5 times the upper limit of normal in the absence of liver metastasis and 5 with documented liver metastasis; and no known hypersensitivity to systemic liposomal formulations or any drug chemically related to lurtotecan. The current clinical protocol was approved by the ethics boards of the Rotterdam Cancer Institute and the University Hospital Groningen, and all patients provided written informed consent before study entry.
On-Study and Follow-up Investigations
Pharmaceutical Preparation and Drug Administration NX 211 was administered on day 1 of each 21-day course as a 30-minute IV infusion under complete light protection; both the syringe and the infusion line were totally wrapped in aluminum foil. All patients were admitted to the hospital for the first dose of the drug to facilitate pharmacokinetic sampling. Subsequent doses were provided in an outpatient setting. Chemotherapy was repeated every 3 weeks for at least two courses. No standard premedication was given in any course.
Study Design
Toxicity Evaluation
Response Evaluation
Pharmacokinetic Sample Collection and Preparation
Analytic Methods For the determination of lurtotecan in whole blood and feces, the assay for total plasma concentrations was modified as outlined below. The HPLC systems consisted of a ConstaMetric 3200 solvent delivery system (LDC Analytic, Riviera Beach, FL), a Waters 717plus autosampler (Waters, Milford, MA), an Inertsil-ODS 80A analytic column (150 mm x 4.6 mm inner diameter, 5-µm particle size; Alltech Applied Sciences, Breda, the Netherlands) maintained at 60°C by a model SpH99 column oven (Spark Holland, Meppel, the Netherlands), a Beam Boost photochemical reactor unit supplied with a coil of 25 m x 0.3 mm inner diameter (ICT-ASS-Chem, Bad Homburg, Germany), and a Jasco FP-920 fluorescence detector (Jasco, Maarssen, the Netherlands) operating at excitation and emission wavelengths of 378 and 420 nm (40 nm bandwidth), respectively. The mobile phases consisted of 1 M aqueous ammonium acetate-water-acetonitrile (100:725:175, vol/vol/vol), with the pH adjusted to 5.5 with acetic acid. The flow rates were set at 1.25 and 0.75 mL/min for the determination of total lurtotecan levels (ie, lurtotecan inside and outside the liposomes in blood and feces samples, respectively). Aliquots (50 µL) of heparinized whole blood were pretreated with 500 µL of 5% (wt/vol) aqueous perchloric acid-acetonitrile (5:1, vol/vol) in 1.5-mL polypropylene tubes (Eppendorf, Hamburg, Germany). The samples were vigorously vortex-mixed for 30 minutes on a multitube vortex mixer, then centrifuged for 5 minutes at 23,000 x g at ambient temperature. A volume of 250 µL of the clear supernatant was transferred to a low-volume insert of glass, from which 200 µL was injected into the HPLC system. The calibration curves were constructed in saline at concentrations of 0.25, 0.50, 1.00, 5.00, 10.0, and 25.0 ng/mL by serial dilutions of a lurtotecan working solution containing 0.10 mg/mL (expressed as free base). Three pools of quality-control samples were prepared in heparinized whole blood at concentrations of 0.40, 20.0, and 2,000 ng/mL, by addition of appropriate volumes of lurtotecan in saline to whole blood. In addition, to minimize potential differences with clinical samples, a lurtotecan recovery-control sample containing 7.50 ng/mL (as NX 211), was also analyzed simultaneously. The sample containing 2,000 ng/mL was diluted 100-fold in phosphate-buffered saline before extraction. Aliquots (100 µL) of feces homogenate were deproteinized and acidified with 1,000 µL of 5% (wt/vol) aqueous perchloric acid–acetonitrile (5:1, vol/vol) containing 6,7-dimethoxy-4-methylcoumarin at a concentration of 100 ng/mL (Sigma Chemical Co, St Louis, MO), which was used as the internal standard. Subsequently, the samples were vigorously vortex-mixed for 15 minutes on a multitube vortex mixer, then centrifuged at ambient temperature at 23,000 x g for 5 minutes. A 100-µL volume of supernatant was transferred to a limited volume insert of glass, from which 10 µL was injected onto the analytic column. Spiked homogenized feces samples used as calibration standards in concentrations of 10, 25, 50, 100, and 250 ng/mL were prepared by addition of 10 µL of serial dilutions in saline from the lurtotecan working solution to 240 µL of drug-free feces homogenates. Three pools of quality-control samples containing lurtotecan at 40, 200, and 2,000 ng/mL were prepared by addition of appropriate volumes of lurtotecan in saline to blank human feces homogenates. The sample containing 2,000 ng/mL was diluted 10-fold in a mixture of saline and the extraction solution (1:10, vol/vol) before injection. Validation of both assays included a set of calibration samples assayed in duplicate, with all samples in quintuplicate, and was performed on four separate occasions. Within-run and between-run precision, calculated by one-way analysis of variance for each concentration by means of the run day as classification variable, ranged between 2.9% to 13.2% and 3.9% to 12.4%, respectively; accuracy of both assays was between 94.9% and 106%. The mean extraction recoveries for lurtotecan in feces specimens and whole blood were between 97% and 103%.
Pharmacologic Data Analysis Relationships between various exposure measures (eg, plasma AUC) and hematologic toxicity were evaluated by sigmoid maximum-effect models by Siphar. Hematologic pharmacodynamics were evaluated by analysis of the absolute nadir values of blood cell counts or the relative hematologic toxicity—that is, the percentage decrease in blood cell count, which was defined as
For each patient, myelosuppression was described either by means of continuous variable, consisting of the percent decrease in WBC, ANC, and platelet count, or as a discrete variable in case of NCI-CTC myelotoxicity grade. Data were fitted to a sigmoid maximum-effect model on the basis of the modified Hill equation:
In this equation, E0 is the minimum reduction possible, Emax is the maximum response (fixed to a value of 100), KP is the pharmacokinetic parameter of interest, KP50 is the value of the pharmacokinetic parameter predicted to result in half of the maximum response, and
Statistical Analysis
Patients and Treatment Twenty-nine eligible patients with advanced carcinomas were enrolled onto the study. Patient demographic data are listed in Table 1. Two patients were not considered assessable for the response analysis, leaving 27 patients assessable for response, which included three patients who received only one dose of NX 211 because of early progressive disease.
Six dose levels of NX 211 (0.4, 0.8, 1.6, 3.2, 3.8, and 4.3 mg/m2, respectively) were explored during the trial. The 29 patients received a total of 77 courses of NX 211 (median, two courses; range, one to nine courses). Dose reduction was only required at the highest dose level, where one dose in a single patient was reduced from 4.3 to 3.2 mg/m2 because of febrile neutropenia in the preceding course. One patient died while on study as a result of progression of an endometrial sarcoma. There were no drug-related deaths. In four of 29 patients, scheduled doses had to be delayed for 1 week, one because of an intercurrent possible pulmonary embolism and three because of hematologic toxicity. Decisions on dose escalation were based on toxicity observed in course 1 only (Table 2). At the dose levels 0.4 and 0.8 mg/m2, no relevant toxicity was observed, except for one patient in the latter group, who experienced seizures. Because of a possible relationship to NX 211, this dose level was expanded to six patients. Retrospectively, however, this event was not considered related to the drug but was considered to be due to progression of disease to the brain. At the next two dose levels (1.6 and 3.2 mg/m2), hematologic toxicity never exceeded grade 2 without remarkable nonhematologic toxicity. The first two patients at the highest dose level (4.3 mg/m2) developed dose-limiting hematologic toxicity, consisting of grade 4 neutropenia and up to grade 3 thrombocytopenia. According to the protocol, the previous level (3.2 mg/m2) was expanded without remarkable toxicity observed.
It therefore was decided to add a new dose level of 3.8 mg/m2. At this dose level, six patients were included who received 18 courses (median, three courses; range, one to six courses) of NX 211; grade 1 thrombocytopenia was the most severe observed toxicity. Meanwhile, we could not find a pharmacokinetic-pharmacodynamic relationship or any other plausible explanation for the steep toxicity difference in dose levels, and discussion arose whether the observed toxicity in the two patients at the highest dose levels could be accidental. It was therefore decided to add further patients at the 4.3 mg/m2 dose level. One patient treated at this dose level developed grade 4 neutropenia with fever and grade 3 thrombocytopenia in the first course. In view of these data, it was definitely concluded that the 4.3 mg/m2 dose level was the MTD, and the recommended dose level for phase II studies was set at 3.8 mg/m2.
Toxicity Profiles
Nonhematologic toxicity in this study was not dose limiting, and although some grade 3 toxicities were observed, no cumulative nonhematologic toxicity was found (Table 4). Asthenia was the most common side effect observed, although no grade 3 or 4 nausea and vomiting were seen. One patient at the first cohort experienced chest tightness and a sensation like shortness of breath during the infusion, and there were three cases of flushing, symptoms commonly associated with a liposomal infusion–related reaction. After discontinuation of the infusion, the sensation disappeared spontaneously and quickly. Because no serious symptoms persisted, no medication such as antihistamines or corticosteroids needed to be administered. At rechallange, the infusion was started at half the previous rate; no recurrence of the reaction was noted. Other toxicities, as listed in Table 4, were observed sporadically. Overall, NX 211 was well tolerated by patients in this phase I study.
Antitumor Activity Objective responses were not observed, but nine patients (non–small-cell lung cancer [n = 3], ACUP [n = 2], cancer of the ovary [n = 1], cancer of the bladder [n = 1], biliary cancer [n = 1], and leiomyosarcoma [n = 1]) had stable disease (range, two to nine courses of therapy) while being treated with NX 211. There was no apparent relationship between the level of pretreatment and the chance of achieving SD. One patient with ACUP with stable disease who was treated at a dose level of 4.3 mg/m2 experienced a tumor regression of 49% after six courses with NX 211 but eventually developed progressive disease in the ninth course.
Plasma and Blood Disposition
Disappearance of lurtotecan from the central plasma compartment was characterized by elimination in an apparent monoexponential fashion, with a slow total body clearance of 0.82 ± 0.78 L/h/m2, typical of liposomal-formulated agents.19 The estimated terminal disposition half-life was relatively consistent in all patients, exhibiting a mean value of 6.24 ± 5.16 hours (CV = 82.7%) and was not dependent on the NX 211 dose (P = .42). As a result of the slow clearance, extended persistence of lurtotecan was apparent, with detectable levels of the compound even at 4 days after initial treatment in most patients. The volume of distribution of lurtotecan was extremely low and averaged 3.92 ± 4.43 L/m2, suggesting that distribution takes place mainly within the central compartment, with slow distribution to extravascular tissues. The concentration time course of lurtotecan in whole blood followed the same general pattern as in plasma, although concentrations were always well below corresponding plasma levels (Fig 2). The AUC ratio of lurtotecan in whole blood and plasma was 0.647 ± 0.134 (n = 27) and is indicative for liposomal encapsulation of lurtotecan in the plasma compartment, with no appreciable drug accumulation into erythrocytes (Table 6).
Urinary and Fecal Recovery Complete data on urinary excretion were available from 23 of 29 patients; data on fecal excretion were collected in nine patients. The time course of the cumulative urinary and fecal elimination of lurtotecan for a representative patient is depicted in Fig 3. The urinary excretion pattern was virtually identical in all patients, with approximately 10% (range, 4.90% to 18.7%) of the dose excreted in the first 72 hours and only a little after this time. The time course of the fecal excretion was more variable, with most of the compound excreted from 48 to 72 hours after the NX 211 infusion. Although samples were collected for only 96 hours after drug administration, the data imply that it is unlikely that the cumulative excretion in either urine or feces will change significantly after this time.
The total cumulative urinary excretion of lurtotecan accounted for 10.1% ± 4.05% of the dose in all patients and was independent of the NX 211 dose. Surprisingly, fecal excretion represented only 10.2% ± 9.28% (range, 3.28% to 31.4%) of the dose, leading to a total recovery of approximately 20% (range, 8.50% to 46.5%) of the dose. This suggests that lurtotecan is extensively metabolized into unknown degradation products. Analysis of the HPLC chromatograms from fecal extracts revealed two major additional peaks in all nine patients (absent in fecal extracts obtained before NX 211 treatment), which might represent lurtotecan metabolites (data not shown).
Hematologic Pharmacodynamics
Because the dose x Fu values obtained over the 96-hour time period were closely related to those obtained by means of the 0- to 12-hour (R = 0.77) or 0- to 24-hour urine collection interval (R = 0.93), we also evaluated whether hematologic toxicity could be predicted from excretion data obtained early after NX 211 administration. Unfortunately, these relationships, although still significant (P .012), were substantially weaker (R2 = 0.51 to 0.80; CV = 44.2% to 74.6%), thereby limiting the general applicability of the use of urine data to predict NX 211–mediated side effects in future clinical trials.
This study represents the results of a phase I trial of NX 211 in patients with solid tumors. Overall, this study demonstrates that NX 211 given every 3 weeks is well tolerated and that no unexpected toxicity was observed. The DLT of NX 211 given as a single drug administration as a 30-minute IV infusion repeated every 3 weeks consisted of a combination of neutropenia and thrombocytopenia. For hematologic toxicity, a remarkable contrast was noted between the 3.8 and 4.3 mg/m2 dose levels. Overall, the nonhematologic toxicity was relatively mild and consisted mainly of nausea, vomiting, and fatigue. These findings on toxicity seem similar to those of other schedules investigated with NX 21123 and also largely resemble side effects of other topoisomerase I inhibitors.3 The pharmacokinetic model currently presented accurately describes the plasma concentration versus time profile of lurtotecan after NX 211 administration and emphasizes the need to apply appropriate kinetic models with sufficient sampling time points—in this case, up to 96 hours—coupled with sensitive analytic procedures for the accurate estimation of kinetic parameters. In general, for topoisomerase I inhibitors, prolonged exposure has been associated with an increase in cytotoxicity.3 It is of particular note that the phase I data for free (ie, nonliposomal) lurtotecan suggest that antitumor activity may be enhanced with prolonged infusion regimens9,10 Therefore, the use of a liposomal formulation of lurtotecan may improve efficacy at optimally defined doses by increasing exposure to the drug. In our study, we have demonstrated that lurtotecan after NX 211 dosing delineates a linear and dose-independent pharmacokinetic behavior over the dose range studied (0.4 to 4.3 mg/m2), in agreement with other tested schedules of NX 211 administration.23 The disappearance of lurtotecan was characterized by a monoexponential decline with a terminal disposition half-life in plasma of approximately 6 hours. This is in contrast to the multiphasic elimination from plasma reported for nonliposomal lurtotecan, which displays a terminal half-life estimated as 9.6 ± 4.8 hours in a cohort of 14 patients.6 The basis for the longer elimination half-life of nonliposomal lurtotecan is most likely due to the slow elimination of the larger fraction of drug initially distributed to tissue. With NX 211, a prolonged association of lurtotecan within circulating intact liposomes in the plasma compartment would be assumed to release free drug over a period of time, quite possibly resulting in the same terminal half-life as lurtotecan, but with concentrations below the lower limit of quantitation of our HPLC assay.22 The prolonged association of lurtotecan with liposomes is thus likely to mask the true disposition half-life of the free drug, as has been observed previously with other agents, including liposomal daunorubicin (DaunoXome; Gilead Sciences, San Dimas, CA).24 The total lurtotecan plasma clearance from NX 211, on average 0.82 L/h/m2, is approximately 25-fold slower than the clearance of the free drug, which was established at 21.0 ± 9.6 L/h/m2.6 The observed steady-state volume of distribution of 3.92 ± 4.43 L/m2 and the blood-to-plasma AUC ratio of 0.647 ± 0.134 are indicative for prolonged encapsulation of lurtotecan in the liposomes, which are presumed to be localized in the plasma compartment. In this regard, the clinical pharmacokinetic behavior of NX 211 is similar to that observed in previous clinical trials with other liposome-encapsulated anticancer agents, including anthracyclines (eg, daunorubicin and doxorubicin) and vinca alkaloids (eg, vincristine).24-26 The observed variability in the pharmacokinetic behavior of lurtotecan after the administration of NX 211 is slightly higher than that reported for the free drug, with an interpatient variability in the plasma clearance of 95.4% for NX 211 versus 46% for free lurtotecan, whereas these values for the volume of distribution were 113% and 52%, respectively.6 Interestingly, after correction for the body-surface area of individual patients, the interpatient variability in clearance remained in a similar order of magnitude (95.4% v 98.8%), suggesting that body-surface area is not a significant predictor of lurtotecan clearance and that flat-dosing regimens might be applied in future studies without compromising overall safety profiles. The cumulative urinary excretion of unchanged lurtotecan of approximately 10% is consistent with data of previous studies in which nonliposomal lurtotecan was administered, indicating that renal clearance plays a minor role in drug elimination.5,6 The mean renal clearance of lurtotecan—that is, the product of the dose-fraction excreted in urine and the total body clearance—was estimated to be 0.074 ± 0.075 L/h/m2 (range, 0.008 to 0.313 L/h/m2). This value is much lower than the glomerular filtration rate in humans, presumably as a result of the association of the drug with the liposomes and binding of free drug to plasma proteins, and suggests that lurtotecan is neither reabsorbed nor actively secreted into the tubular lumen to any great extent. It also indicates that as much as 89.9% (range, 81.3% to 95.1%) of the overall clearance can be attributed to nonrenal processes, including hepatobiliary secretion of lurtotecan. Indeed, part of the nonrenal elimination was accounted for by fecal excretion of unchanged lurtotecan. However, because the total amount of lurtotecan in feces amounted to only 10% of the administered dose, leading to a total recovery of approximately 20%, lurtotecan is probably extensively metabolized. An important question that remains unanswered is whether monitoring of extraliposomal lurtotecan in the systemic circulation would aid in deriving exposure measures more closely linked to NX 211–induced side effects. The rationale for the measurement of free drug concentrations is founded on the basic pharmacologic tenet that agents associated with drug carrier systems or other macromolecules such as serum proteins are unable to cross cell membranes and interact with extravascular (active) sites. The current finding that various commonly applied exposure measures (eg, AUCs in plasma and whole blood) were not predictive for hematologic toxicity further substantiates this concept. We have previously demonstrated that the inherent instability of the current NX 211 formulation in aqueous solutions under laboratory light renders it extremely difficult to develop analytic methodologies that allow separation of free and liposomal lurtotecan.22,27 Because knowledge of the extent of binding of lurtotecan within the circulation was considered of crucial importance for a proper understanding of the clinical pharmacologic behavior of this drug, we set out to define a surrogate measure that could be linked to the DLT of NX 211. We hypothesized that a dose-corrected urinary-excretion fraction of unchanged drug within a certain time span would reflect systemic exposure to nonliposomal lurtotecan in each individual patient. The calculated parameter (ie, dose x Fu) was indeed clearly related to pharmacodynamic outcome of NX 211 treatment in terms of hematologic toxicity, and a sigmoid maximum-effect model was found most appropriate to fit the kinetic data to the observed myelosuppression. Considering this pharmacokinetic-pharmacodynamic relation, a target dose x Fu could be defined prospectively according to the grade of toxicity that is considered to be acceptable and applied in future studies to determine optimal dosing with NX 211 treatment in this schedule. The suitability of this relationship will be further explored in other dosing schedules with NX 211.23 In conclusion, in this phase I study with IV administration of NX 211 given once every 3 weeks, the DLT is a combination of neutropenia and thrombocytopenia. The recommended dose for phase II studies with NX 211 in this regimen is 3.8 mg/m2. Objective responses were not observed, but nine patients had stable disease; one of these patients experienced a tumor regression of 49%. We have found a pharmacokinetic-pharmacodynamic relationship for this liposomal encapsulated drug, calculated as the dose corrected urinary excretion in relation to hematologic toxicity. Moreover, we have demonstrated that administration of this formulation significantly reduces the plasma clearance of lurtotecan, which in turn might prove beneficial for pharmacodynamic outcome.
1. Luzzio MJ, Besterman JM, Emerson DL, et al: Synthesis and antitumor activity of novel water soluble derivatives of camptothecin as specific inhibitors of topoisomerase I. J Med Chem 38: 395-401, 1995[CrossRef][Medline] 2. Gerrits CJ, de Jonge MJ, Schellens JH, et al: Topoisomerase I inhibitors: The relevance of prolonged exposure for present clinical development. Br J Cancer 76: 952-962, 1997[Medline] 3. Kehrer DFS, Soepenberg O, Loos WJ, et al: Modulation of camptothecin analogues in the treatment of cancer: A review. Anticancer Drugs 12: 89-106, 2001[CrossRef][Medline]
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Sessa C, Wanders J, Roelvink M, et al: Second-line treatment of small-cell lung cancer with the camptothecin-derivative GI147211: A study of the EORTC Early Clinical Studies Group (ECSG). Ann Oncol 11: 207-210, 2000 9. Paz-Ares L, Kunka R, DeMaria D, et al: A phase I clinical and pharmacokinetic study of the new topoisomerase inhibitor GI147211 given as a 72-h continuous infusion. Br J Cancer 78: 1329-1336, 1998[Medline]
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Stevenson JP, DeMaria D, Sludden J, et al: Phase I/pharmacokinetic study of the topoisomerase I inhibitor GG211 administered as a 21-day continuous infusion. Ann Oncol 10: 339-344, 1999 11. Hertzberg RP, Caranfa MJ, Holden KG, et al: Modification of the hydroxy lactone ring of camptothecin: Inhibition of mammalian topoisomerase I and biological activity. J Med Chem 32: 715-720, 1989[CrossRef][Medline] 12. Burke TG, Gao X: Stabilization of topotecan in low pH liposomes composed of distearoylphosphatidylcholine. J Pharm Sci 83: 967-969, 1994[CrossRef][Medline] 13. Subramanian D, Muller MT: Liposomal encapsulation increases the activity of the topoisomerase I inhibitor topotecan. Oncol Res 7: 461-469, 1995[Medline] 14. Lundberg BB: Biologically active camptothecin derivatives for incorporation into liposome bilayers and lipid emulsions. Anticancer Drug Des 13: 453-461, 1998[Medline] 15. Sadzuka Y, Hirotsu S, Hirota S: Effect of liposomalization on the antitumor activity, side-effects and tissue distribution of CPT-11. Cancer Lett 127: 99-106, 1998[CrossRef][Medline] 16. Sadzuka Y, Hirotsu S, Hirota S: Effective irinotecan (CPT-11)–containing liposomes: Intraliposomal conversion to the active metabolite SN-38. Jpn J Cancer Res 90: 226-232, 1999[CrossRef][Medline] 17. Colbern GT, Dykes DJ, Engbers C, et al: Encapsulation of the topoisomerase I inhibitor GL147211C in pegylated (STEALTH) liposomes: Pharmacokinetics and antitumor activity in HT29 colon tumor xenografts. Clin Cancer Res 4: 3077-3082, 1998[Abstract]
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Tardi P, Choice E, Masin D, et al: Liposomal encapsulation of topotecan enhances anticancer efficacy in murine and human xenograft models. Cancer Res 60: 3389-3393, 2000 19. Mayer LD, Cullis PR, Bally MB: Designing therapeutically optimized liposomal anti-cancer delivery systems: Lessons from conventional liposomes, in Lassic D, Papahadjopoulos D (eds): Medical Applications of Liposomes. Amsterdam, the Netherlands, Elsevier Press, 1998, pp 231-256
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Emerson DL, Bendele R, Brown E, et al: Antitumor efficacy, pharmacokinetics, and biodistribution of NX 211: A low-clearance liposomal formulation of lurtotecan. Clin Cancer Res 6: 2903-2912, 2000 21. World Health Organization: WHO Handbook for Reporting Results of Cancer Treatment. Geneva, Switzerland, World Health Organization, 1979 22. Loos WJ, Kehrer DFS, Brouwer E, et al: Liposomal lurtotecan (NX 211): Determination of total drug levels in human plasma and urine by reversed-phase high-performance liquid chromatography. J Chromatogr B Biomed Sci Appl 738: 155-163, 2000[CrossRef][Medline] 23. Rothenberg ML, Gelmon KA, Eisenhauer E, et al: Phase I evaluation of liposomal topoisomerase I inhibitor, NX 211, given on days 1, 2, 3 or days 1, 8 every 3 weeks to patients (pts) with advanced solid tumors. Proc Am Soc Clin Oncol 19: 198a, 2000 (abstr 769) 24. Pea F, Russo D, Michieli M, et al: Liposomal daunorubicin plasmatic and renal disposition in patients with acute leukemia. Cancer Chemother Pharmacol 46: 279-286, 2000[CrossRef][Medline] 25. Rahman A, Treat J, Roh JK, et al: A phase I clinical trial and pharmacokinetic evaluation of liposome-encapsulated doxorubicin. J Clin Oncol 8: 1093-1100, 1990[Abstract]
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Gelmon KA, Tolcher A, Diab AR, et al: Phase I study of liposomal vincristine. J Clin Oncol 17: 697-705, 1999 27. Loos WJ, Verweij J, Kehrer DFS, et al: Identification and biological activity of 7-ethyl-10,11-ethylenedioxy-20(S)-camptothecin, a photodegradant of lurtotecan. Clin Cancer Res (in press) Submitted June 4, 2001; accepted November 13, 2001. This article has been cited by other articles:
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ABSTRACT
INTRODUCTION
is the Hill constant, which describes the sigmoidicity of the curve. Models were evaluated for goodness of fit by minimization of sums of the squared residuals and by reduction of the estimated coefficient of variation (CV) for fitted parameters. Significance of the relationships was assessed by construction of contingency tables with subsequent 
2 analysis. 
) in a single patient after administration of NX 211 at a dose level of 3.8 mg/m2.
) and feces (
) in a single patient after administration of NX 211 at a dose level of 3.8 mg/m2.
), and platelet count (
) at nadir relative to pretreatment values. Data were obtained from 29 patients.
