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Phase I Pharmacologic Study of Oral Topotecan and Intravenous Cisplatin: Sequence-Dependent Hematologic Side Effects

From the Department of Medical Oncology, Rotterdam Cancer Institute (Daniel den Hoed Kliniek) and University Hospital Rotterdam, Rotterdam, the Netherlands; and SmithKline Beecham Pharmaceuticals, Harlow, Essex, United Kingdom.

Address reprint requests to Maja J.A. de Jonge, MD, PhD, Department of Medical Oncology, Rotterdam Cancer Institute (Daniel den Hoed Kliniek) and University Hospital Rotterdam, Groene Hilledijk 301, 3075 EA Rotterdam, the Netherlands; email jonge{at}onch.azr.nl

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: In in vitro studies, synergism and sequence-dependent effects were reported for the combination of topotecan and cisplatin. Recently, an oral formulation of topotecan became available. This phase I study was performed to assess the feasibility of the combination of oral topotecan and cisplatin, the pharmacokinetic interaction, and sequence-dependent effects.

PATIENTS AND METHODS: Topotecan was administered orally (PO) daily for 5 days in escalating doses and cisplatin was given intravenously (IV) at a fixed dose of 75 mg/m² either before topotecan administration on day 1 (sequence CT) or after topotecan administration on day 5 (sequence TC) once every 3 weeks. Patients were treated in a randomized cross-over design.

RESULTS: Forty-nine patients were entered onto the study; one patient was not eligible. Sequence CT induced significantly more severe myelosuppression than did sequence TC, and the maximum-tolerated dosage of topotecan in sequence CT was 1.25 mg/m²/d x 5. In sequence TC, the maximum-tolerated dosage of topotecan was 2.0 mg/m²/d x 5. Dose-limiting toxicity consisted of myelosuppression and diarrhea. Pharmacokinetics of topotecan and cisplatin were linear over the dose range studied; no sequence-dependent effects were observed. In addition, topotecan did not influence the protein binding of cisplatin or the platinum-DNA adduct formation in peripheral leukocytes in either sequence.

CONCLUSION: The recommended dosages for phase II studies involving patients like the patients in our study are topotecan 1.25 mg/m²/d PO x 5 preceded by cisplatin 75 mg/m² IV day 1 once every 3 weeks, and topotecan 2.0 mg/m²/d PO followed by cisplatin 75 mg/m² IV day 5. No pharmacokinetic interaction could be discerned in our study. The antitumor efficacy of both schedules should be evaluated in a randomized phase II study.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
TOPOTECAN (9-dimethylaminomethyl-10-hydroxycamptothecin; Hycamtin [SmithKline Beecham Pharmaceuticals, Harlow, United Kingdom]) is a water-soluble topoisomerase I inhibitor (camptothecin). DNA topoisomerase I is a nuclear enzyme involved in cellular replication and transcription. It exists in two forms in a pH-dependent dynamic balance, a balance between the closed lactone ring (active) form and the carboxy acid (inactive) form. By forming a covalent adduct between topoisomerase I and DNA, named the cleavable complex, topoisomerase I inhibitors interfere with the process of DNA breakage and resealing during DNA synthesis. The stabilized cleavable complex blocks the progress of the replication fork, resulting in irreversible DNA double-strand breaks leading to cell death.^1-3 On the basis of their mechanisms of action, synergism was suspected for the combination of topoisomerase I inhibitors and DNA-damaging agents such as cisplatin. Preclinical studies confirmed this hypothesis. However, the observed interaction seemed to depend on the cell line studied and the schedule of administration of topotecan and cisplatin used.^4-17 When topotecan administration was preceded by cisplatin administration, synergism was increased compared with concomitant incubation with both drugs in the IGROV-1 ovarian cancer cell line and the MCF7 cell line.^5,6 Also, in the clinical setting drug sequencing seems to be important.¹⁷

To date, topotecan has demonstrated prominent activity in several malignancies, most notably in ovarian cancer,^18-23 small-cell lung carcinomas,^24-26 and hematologic malignancies.^27-30 Cisplatin is also highly active in these malignancies. Recently, an oral formulation of topotecan became available, making administration of the drug more convenient. The oral formulation has a bioavailability of 32% to 44%,^31-33 with moderate intrapatient variability. The maximum-tolerated dosage for oral topotecan, administered as a gelatin capsule for 5 days every 21 days, is 2.3 mg/m²/d, with myelosuppression (in particular, neutropenia) as the dose-limiting toxicity (DLT).³⁴ Nonhematologic toxicities are generally mild and not dose limiting; they include fatigue, anorexia, nausea, vomiting, and diarrhea. Randomized studies in ovarian cancer³⁵ and small-cell lung cancer³⁶ suggest that the oral (PO) formulation is equivalent to the intravenous (IV) formulation.

We conducted a phase I study, in which patients were treated in a randomized cross-over design, to determine the maximum-tolerated dose (MTD) of oral topotecan given daily for 5 days and combined with cisplatin 75 mg/m² IV day 1 or day 5 every 21 days; to describe and quantitate the toxicities of the combination; and to determine whether the sequence of topotecan and cisplatin administration has an influence on the observed toxicity or the pharmacokinetic interaction between the drugs.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patient Selection
Eligible patients had a histologically or cytologically confirmed diagnosis of a malignant solid tumor that was resistant to standard forms of therapy. Other eligibility criteria included the following: age between 18 and 75 years; Eastern Cooperative Oncology Group performance status 2; no previous anticancer therapy for at least 4 weeks (6 weeks in the case of treatment with a nitrosourea or mitomycin); no previous therapy with a topoisomerase I inhibitor; and adequate hematopoietic function (absolute neutrophil count 1.5 x 10⁹/L and platelet count 100 x 10⁹/L), renal function (creatinine clearance 60 mL/min), and hepatic function (total serum bilirubin level 1.25 times the upper limit of normal and AST and ALT levels 2.0 times the upper limit of normal; in the case of liver metastasis, serum AST and ALT levels 3.0 times the upper limit of normal). Specific exclusion criteria included the existence of gross ascites and any gastrointestinal condition that would alter absorption or motility. All patients gave written informed consent before study entry.

Dosage and Dose Escalation
Escalating doses of oral topotecan were combined with a fixed dose of cisplatin, 75 mg/m², administered IV over 3 hours once every 3 weeks. The starting dosage of topotecan was 0.75 mg/m²/d for 5 consecutive days, which is 33% of the recommended dose of oral topotecan when the drug is administered as a single agent. Dose escalation depended on prior-dose-level toxicities. At least three patients were treated at each dose level. If one of three patients experienced DLT, three additional patients were entered at that dose level. MTD was defined as the dose level below the dose that induced DLT in three of six patients during the first course in any sequence. DLT was defined as grade 4 neutropenia (National Cancer Institute common toxicity criteria) lasting 5 days or more or complicated by fever requiring hospitalization, grade 4 thrombocytopenia, and/or grade 3 nonhematologic toxicity (grade 2 renal toxicity), excluding nausea. Intrapatient dose escalation was not permitted. If a patient experienced DLT, the dose of topotecan was decreased one dose level at the time of retreatment. The treatment was resumed when the neutrophil count had recovered to 1.0 x 10⁹/L and the platelet count to 100 x 10⁹/L. A maximum of six cycles were administered to each patient.

Drug Administration and Sequencing
In the first part of the study, patients were randomly assigned at study entry to one of two treatment groups. Six patients were treated at each dose level.

In the first treatment group, in the first treatment course, patients received cisplatin as a 3-hour infusion diluted in 250 mL of hypertonic saline (3% [wt/vol] sodium chloride) on day 1, immediately followed by oral topotecan (sequence CT), which was given for 5 consecutive days on an empty stomach, at least 10 minutes before meals. In the second course, the sequence of administration of topotecan and cisplatin was reversed: oral topotecan was administered for 5 days and cisplatin was given on day 5, 3 hours after the last administration of topotecan (sequence TC).

In the second treatment group, patients received the two treatment courses in reverse order. The third and following courses were administered using the least toxic sequence, with a 24-hour interval, in the third course, between administration of cisplatin and topotecan to allow study of the pharmacokinetics of both drugs to rule out the possibility of any pharmacokinetic interaction.

In the second part of our study, after determination of the MTD in the most toxic sequence, further escalation of topotecan dose was pursued in the reversed sequence. Patients who were then enrolled onto the study were assigned to that single sequence, with a 24-hour interval between administration of topotecan and cisplatin in the second course only.

In all patients, premedication consisted of ondansetron 8 mg IV combined with dexamethasone 10 mg IV, administered 30 minutes before the start of the cisplatin infusion. For prevention of cisplatin-induced renal damage, administration of cisplatin was preceded by infusion of 1,000 mL of a mixture of 5% (wt/vol) dextrose and 0.9% (wt/vol) sodium chloride over 4 hours and followed by another 3,000 mL with the addition of 20 mmol/L potassium chloride and 2 g/L magnesium sulfate over 16 hours. Topotecan capsules containing either 0.25 or 1.00 mg of the active compound were supplied by SmithKline Beecham Pharmaceuticals. Cisplatin (Platosin) was purchased as a powder from Pharmachemie (Haarlem, the Netherlands).

Treatment Assessment
Before therapy, a complete medical history was obtained and a physical examination was performed. A complete blood cell count (including WBC and differential counts) and serum biochemistry studies (including determination of sodium, potassium, calcium, phosphorus, urea, creatinine, total protein, albumin, total bilirubin, alkaline phosphatase, AST, ALT, gamma-glutamyltransferase, glucose, and uric acid levels) were performed, as was measurement of creatinine clearance. Weekly evaluations included history, physical examination, toxicity assessment using National Cancer Institute common toxicity criteria, and serum chemistry studies. Complete blood cell counts were performed twice weekly. Tumor evaluation was performed after three courses in the first part of the study and after every two courses in the second part, using World Health Organization criteria for response. Duration of response was calculated from the start of treatment. Patients received at least three cycles of therapy in the first part of the study and two cycles in the second part, unless disease progression or unacceptable toxicity occurred.

Sample Collection for Pharmacokinetic Analysis
Blood samples for pharmacokinetic analysis were obtained during the first three treatment courses until the MTD was reached in the most toxic sequence. Thereafter, samples were taken only during the first two courses. Blood sampling for topotecan pharmacokinetics was performed on the first and fifth days of drug dosing, whereas for cisplatin pharmacokinetics, sampling was performed on the day of administration (day 1, 5, or 6, depending on the schedule). At the doses recommended for further study, additional topotecan pharmacokinetic analysis was performed on day 2 of the first treatment course. Blood was drawn from a vein in the arm opposite that used for drug infusion and was collected in 4.5-mL glass tubes containing lithium heparin as anticoagulant. For analysis of topotecan kinetics, samples were obtained before dosing and 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours after administration of topotecan. Immediately after sampling, tubes were briefly immersed in an ice bath kept at the bedside, and plasma was separated within 10 minutes by centrifugation at 3,000 x g for 5 minutes at 4°C. Next, 250-µL aliquots of the plasma supernatant were added to 2.0-mL polypropylene vials (Eppendorf, Hamburg, Germany) containing 750 µL of ice-cold (-20°C) methanol. After vortex mixing for 10 seconds, samples were stored at -80°C until the day of analysis.

Blood samples for measurement of cisplatin concentrations were obtained immediately before infusion; 1, 2, and 3 hours after the start of the infusion; and 0.5, 1, 2, 3, and 18 hours after the end of the infusion. Sample volumes were 4.5 mL each except before infusion and 1 and 18 hours after infusion, at which times they were 21 (3 x 7) mL each. Immediately after sampling, plasma was separated by centrifugation at 3,000 x g for 10 minutes. Next, 500-µL aliquots of the plasma supernatant were added to 1.0 mL of ice-cold (-20°C) ethanol. After vortex mixing for 10 seconds, samples were stored at -80°C until the day of analysis. Blood samples for determination of cisplatin-DNA adduct levels were obtained immediately before infusion and 1 and 18 hours after the end of the infusion.

Pharmacokinetic Assays
Samples for topotecan kinetic analysis were analyzed using a reversed-phase high-performance liquid chromatographic method³⁷ that allowed simultaneous determination of the lactone and hydrolyzed ring-opened carboxylate forms. Before drug analysis, samples were removed from the freezer and centrifuged for 5 minutes at 23,000 x g at 4°C. A volume of 100 µL was transferred to a clean microtube containing 400 µL of phosphate buffer. Of this mixture, 200 µL was used for analysis. The high-performance liquid chromatographic system consisted of a constaMetric 4,100 solvent delivery system (LDC Analytic, Riviera Beach, FL), a Waters 717Plus autosampler (Waters Instruments, Bedford, MA), and a Jasco FP 920 fluorescence detector (Jasco Inc, Hachioji, Japan). Chromatographic separations were achieved at 35°C on a Shandon Hypersil BDS column (internal diameter, 100 x 3 mm; 3-µm particles) from Applied Science (Breda, the Netherlands), with a mobile phase composed of 10 mmol/L aqueous potassium dihydrogen phosphate containing 22% (vol/vol) methanol and 0.2% triethylamine, with the pH adjusted to 6.0 (orthophosphoric acid). The mobile phase was filtered using 0.45-µm Millipore HA filters (Millipore, Milford, MA) and degassed by ultrasonication. The flow rate was set at 0.7 mL/min, and the column effluent was monitored at excitation and emission wavelengths of 381 and 525 nm, respectively, with the emission bandwidth set at 40 nm. Peak detection was performed using the Fisons ChromCard data analysis system (Fisons, Milan, Italy). Drug concentrations in unknown samples were determined by interpolation on linear calibration curves, constructed in blank human plasma, by least squares linear regression of peak heights versus 1/x. The mean percentage deviations from nominal values (accuracy) and precision (within-run and between-run variability) were always less than 15%. The lower limit of quantitation for both the lactone and carboxylate forms was 100 pg/mL.

Non–protein-bound and total cisplatin concentrations in plasma were determined using a validated analytic procedure based on measurement of platinum atoms by flameless atomic-absorption spectrometry as described.^38,39 For measurement of unbound cisplatin, 500-µL aliquots of plasma were extracted with 1,000 µL of neat, ice-cold ethanol in a 2-mL polypropylene vial. After a 2-hour incubation at -20°C, the supernatant was collected by centrifugation at 23,000 x g for 5 minutes at 4°C and transferred to a clean vial. A volume of 600 µL was evaporated to dryness under nitrogen at 60°C, and the residue was reconstituted in 200 or 600 µL of water containing 0.2% (vol/vol) Triton X-100 and 0.06% (wt/vol) cesium chloride by vigorous mixing. A volume of 20 µL was eventually injected into the spectrometer. For determination of total cisplatin concentration, 100 µL of plasma was added to 900 µL of water containing 0.2% (vol/vol) Triton X-100 and 0.06% (wt/vol) cesium chloride, and vortex mixing for 10 seconds followed. Of this solution, a volume of 20 µL was injected into the spectrometer. Samples were analyzed with a Perkin Elmer 4110 ZL spectrometer (Perkin Elmer) with Zeeman-background correction using peak area signal measurements at a wavelength of 265.9 nm and a slid width of 0.7 nm.^38,39 The injection temperature was set at 20°C. Platinum-DNA adduct levels in peripheral leukocytes were determined as described,⁴⁰ with modification.⁴¹ After DNA isolation from buffy coat preparations, samples were digested with DNAse I and zinc chloride and injected into the furnace using a four-times multiple-sampling feature of the Perkin Elmer spectrometer. The cisplatin-DNA adduct levels were expressed as picogram of platinum per microgram of DNA.

Pharmacokinetic Data Analysis
Individual plasma concentrations of topotecan were fit to a two-compartment model using the software package Siphar v4.0 (SIMED, Créteil, France). The concentration-time profiles were obtained after zero-order input, with weighted least squares analysis in which a weighting factor of 1/y was applied. The topotecan area under the plasma concentration–time curve (AUC) was determined for both the lactone (AUC_(L)) and carboxylate (AUC_(c)) forms on the basis of the best-fitted curves. The apparent plasma clearance of topotecan lactone was calculated by dividing the dose administered (expressed in free base equivalents) by the observed AUC. The terminal disposition half-life of topotecan was calculated as ln2/k, where k is the terminal elimination rate constant (expressed in h^-1). The peak plasma concentrations and the time to peak plasma concentration were determined graphically from the (observed) experimental values. The ratio of the systemic exposure of topotecan lactone to total drug was defined as AUC_(L)/(AUC_(L) + AUC_(c)).

Kinetic profiles of cisplatin were obtained similarly using a two-compartment linear model with extended least squares regression analysis as reported earlier.⁴² The AUC of cisplatin was calculated to the last sampling time point with detectable drug levels (C_last) using the linear trapezoid method and extended to infinity by addition of C_last/k_term, where k_term is the slope obtained by log-linear regression of the final plasma concentration values.

Statistical Considerations
Pharmacokinetic data for all compounds are reported as mean ± SD. The difference in pharmacokinetic data between sequences was evaluated statistically using a paired Student’s t test. Probability values (two-sided) of < .05 were regarded as statistically significant. All calculations were performed using the statistical packages NCSS Version 5.X (J.L. Hintze, Kaysville, UT) and STATGRAPHICS Plus Version 2.0 (Manugistics Inc, Rockville, MA).

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Forty-nine patients were entered onto this study between January 1997 and February 1999. Patient characteristics are listed in Table 1. One patient was ineligible because of reduced renal function at the time of study entry, and one patient was not assessable for toxicity because of the occurrence of a cerebrovascular accident after 2 days of treatment with topotecan (the patient was taken off the study). Forty-seven patients were assessable for toxicity and 45 patients for response.

Myelosuppression and diarrhea were the principal DLTs of this regimen. Seven patients required dose reductions after experiencing DLT. Once dose reduction had taken place, the courses administered to these patients were evaluated for toxicity at the lower dose level.

Hematologic Toxicity and Drug Sequencing
The severity of the observed hematologic toxicity was clearly dependent on the sequence of drug administration. At each dose level studied, both neutropenia and thrombocytopenia were more severe when cisplatin administration preceded administration of topotecan (sequence CT) (Table 2 and Fig 1); there were significantly lower absolute neutrophil count nadirs and percentage decrements in neutrophil and platelet counts (neutropenia: P < .00001; thrombocytopenia: P < .00001) with this sequence. At the topotecan dose level of 1.0 mg/m² in sequence CT, two of six patients experienced grade 4 neutropenia lasting for 5 days or more (one of the study’s definitions of DLT). At the next dose level (topotecan 1.25 mg/m²), with cisplatin 75 mg/m² in sequence CT, one of the six patients treated experienced neutropenic fever, and another patient had grade 4 neutropenia lasting for more than 5 days in combination with grade 3 diarrhea and grade 4 vomiting. Four additional patients were treated at this dose level, and one experienced DLT (grade 4 neutropenia lasting longer than 5 days). Another patient, who was ineligible because of reduced renal function at study entry, experienced grade 4 neutropenia and thrombocytopenia in the second course and died as a result of the complications of this toxicity. Because three of nine patients (or four of 10, if the ineligible patient is taken into account) experienced DLT, no further dose escalation was attempted. MTD was defined as the dose level below that level at which three of six patients experienced DLT. Topotecan 1.25 mg/m²/d days 1 through 5 combined with cisplatin 75 mg/m² day 1 is considered the recommended dosage for this sequence, but only for non-pretreated or marginally pretreated patients in good physical condition and under strict conditions of control, like the patients under study.

View larger version (18K): [in this window] [in a new window]   Fig 1. (A) Absolute neutrophil count (ANC) nadirs and (B) topotecan clearance (CL/f(L))during the first and second courses in sequences CT () and TC (). Data are expressed as mean (bars) ± SD (error bars).

Overall, hematologic toxicity was relatively mild (Table 2). Grade 3 to 4 neutropenia was observed in 55 (31%) of 175 courses. It was complicated by neutropenic fever in only four patients. The onsets of neutropenia and thrombocytopenia were relatively late. Nadir neutrophil counts usually occurred around day 19 (range, days 4 to 30) after the start of the treatment and lasted for a median of 5 days (range, 1 to 15 days). Thrombocytopenia was mild, being grade 3 or 4 in only 8% of cycles, and always occurred in conjunction with neutropenia. Despite the limited severity of myelosuppression, treatment had to be delayed in 34% of the courses because of prolonged myelosuppression. A marked inhibition of erythropoiesis was observed. The percentage of patients requiring erythrocyte transfusions was 72%; transfusions were required in 74 of 175 courses.

Nonhematologic Toxicity
Gastrointestinal toxicity was mild to moderate (Table 2) and was generally comparable to the toxicities that result from similar single-agent doses of topotecan and cisplatin. No sequence-dependent effects were noted. Grade 2 or 3 nausea was observed in 60 (34%) of 175 courses and grade 3 or 4 vomiting in 15 (9%) of 175 courses. Both were in time related to the administration of cisplatin. Grade 3 or 4 diarrhea occurred in seven cycles (4%); the median day of onset was day 8 (range, days 7 to 14) and the median duration was 4 days (range, 2 to 10 days). The diarrhea was self-limiting or resolved after low-dose loperamide therapy in all but two patients, who were hospitalized for IV rehydration.

Consistent with the profile of cisplatin 75 mg/m², 17 patients developed grade 1 nephrotoxicity and four patients developed grade 2 nephrotoxicity, after a median of two cycles (range, one to six cycles). Grade 1 peripheral neurotoxicity occurred in 18 patients. Twenty patients experienced mostly reversible grade 2 ototoxicity (tinnitus) and two patients developed grade 3 ototoxicity, after a median of two cycles (range, one to six cycles). One patient at dose level 2.3 mg/m² developed grade 4 bilirubinemia due to obstruction of a biliary stent. One patient with nasopharyngeal cancer, treated at a dose level of 2.0 mg/m², developed progressive dyspnea accompanied by fever during the second course. A chest x-ray showed interstitial enhancement with a reticulonodular pattern, more prominent at the bases. Pulmonary function tests demonstrated reduced lung volumes compatible with restrictive lung disease. Bronchoscopy revealed no abnormalities. Despite therapy with antibiotics and low-dose corticosteroids, the patient’s condition worsened and an open lung biopsy was performed. Pathologic examination revealed interstitial fibrosis with a marked infiltration with eosinophils, which was considered related to topotecan treatment. The patient was treated with high-dose corticosteroids, and the symptoms improved (de Jonge et al, manuscript submitted for publication).

Other side effects were mucositis (8% of cycles), alopecia (grade 1: 19 patients; grade 2: seven patients), and fatigue.

Antitumor Activity
Six patients achieved a partial response. The tumor types included non–small-cell and small-cell lung cancer, adenocarcinoma unknown primary (ACUP), and renal and pancreatic cancer. The patient with small-cell lung cancer was pretreated twice with combination chemotherapy (doxorubicin, etoposide, and cyclophosphamide), achieving major responses of 30 and 25 weeks’ duration. Her response to cisplatin-topotecan chemotherapy lasted 22 weeks. The patient with pancreatic cancer was pretreated with fluorouracil in combination with a dehydropyrimidine dehydrogenase inhibitor and achieved a partial response for 19 weeks. When treated with cisplatin-topotecan chemotherapy, he achieved a partial response for 26 weeks. The patient with renal cancer did not respond to prior therapy with a farnesyltransferase inhibitor. His response to cisplatin-topotecan therapy lasted 20 weeks. The other three patients were not pretreated. The durations of their responses were 21 (non–small-cell lung cancer), 30 (ACUP), and 30⁺ (ACUP) weeks. Twenty-nine patients showed disease stabilization, with a median duration of 20 weeks (range, 8 to 68 weeks).

Topotecan and Cisplatin Pharmacokinetics
The possible effect of drug sequence on the pharmacokinetics of topotecan and cisplatin was investigated in the first 18 patients, who were randomized to administration sequences in a cross-over design. All of these patients were administered the fixed cisplatin dose of 75 mg/m² and a topotecan dosage of 0.75, 1.00, or 1.25 mg/m²/d x 5. Listed in Table 3 are the main pharmacokinetic data from a compartmental analysis of the two drugs, with topotecan given at a dosage of 0.75 mg/m²/d x 5. The sequence of drug administration did not significantly influence the disposition of topotecan lactone; mean (± SD) AUC values for sequences CT and TC were 7.52 ± 2.51 and 6.18 ± 1.56 ng·h/mL, respectively (P = .31) (Fig 2). The apparent plasma clearance of topotecan lactone was clearly dose independent in the range of 0.75 to 1.25 mg/m² (similar to single-agent treatment findings) and not significantly different between study courses (107 ± 33.0 L/h/m² [sequence CT] v 109 ± 53.5 L/h/m² [sequence TC]; P = .38, paired Student’s t test) (Fig 1). Similarly, the ratio of lactone AUC to total drug AUC was independent of the sequence, and average ratios were 0.36 ± 0.04 (sequence CT) and 0.33 ± 0.08 (sequence TC). Topotecan pharmacokinetic data obtained on the fifth administration day were essentially similar to the data from day 1 (data not shown). To rule out a potential effect of the interval between drug administration, we obtained kinetic data from the first 18 patients (three assigned to sequence CT and another three assigned to the reversed order at each dose level) treated at topotecan dosages of 0.75, 1.0, or 1.25 mg/m²/d x 5. Unpaired analysis indicated that changing the interval to 24 hours had no significant influence on any of the studied parameters (P > .05, Mann-Whitney U test; Table 3). The peak plasma levels and the plasma clearance of unbound cisplatin were also independent of the drug sequence plus interval (3-hour or 24-hour) between administration (Table 3). Over the three dose levels studied, cisplatin clearance was not dependent on the topotecan dose, and average clearances were 817 ± 463 mL/min (sequence CT) and 747 ± 177 mL/min (sequence TC) (P = .19) with the 3-hour interval (Fig 2). Similarly, sequence and topotecan dose had no influence on the protein binding of cisplatin (overall mean, 93.1% ± 2.8%) and on the peak platinum-DNA adduct levels in peripheral-blood leukocytes (4.58 ± 4.12 pg platinum/µg DNA [sequence CT] v 5.72 ± 4.66 pg platinum/µg DNA [sequence TC] across all three dose levels; P = .55).

View larger version (14K): [in this window] [in a new window]   Fig 2. Plasma concentration–time curves of (A) topotecan lactone and (B) unbound cisplatin in six patients treated with topotecan 0.75 mg/m2/d and cisplatin 75 mg/m2 in sequences CT (•) and TC (). Data are expressed as mean values (• and ) ± SD (error bars).

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

Neutropenia and diarrhea were the DLTs of oral topotecan combined with cisplatin in this schedule. Other toxicity was usually mild to moderate and consisted of nausea and vomiting, mucositis, fatigue, neurotoxicity, nephrotoxicity, and alopecia.

Myelosuppression was significantly more severe when cisplatin administration preceded topotecan administration. This observation is in accordance with the data reported for the combination of the IV formulation of topotecan and cisplatin.¹⁷ The onset of neutropenia was relatively late; the median day of onset of the neutrophil count nadir was day 19 (range, days 4 to 30). These data are in line with the data reported by Miller et al.⁴⁴ The combination of topotecan, administered IV on days 1 through 5, with cisplatin, administered on day 1, resulted in a neutrophil count nadir around day 12 (range, days 8 to 25). Compared with the median time to neutrophil count nadir of 12 days (range, 9 to 15 days) for single-agent oral topotecan³⁴ and day 9 (range, 6 to 10 days)¹⁹ for single-agent IV topotecan, the nadir in our study was delayed. This resulted in treatment delay due to prolonged myelosuppression in 34% of the courses. Although grade 3 or 4 neutropenia was observed in 31% of the courses, the incidence of neutropenic fever was only 2%.

The dosages in this sequence (cisplatin administration followed by topotecan administration) that we can recommend for phase II studies are topotecan 1.25 mg/m²/d PO days 1 through 5 and cisplatin 75 mg/m² day 1, but we recommend these dosages only for non-pretreated or minimally pretreated patients in good clinical condition and under strict medical surveillance, like the patients treated in this study. In other circumstances, dosage adjustment of topotecan should be considered. In other phase I studies, in which cisplatin 50 mg/m² day 1 was combined with IV topotecan as a 30-minute infusion given daily for 5 consecutive days, neutropenia and thrombocytopenia were the principal toxicities. The recommended dosage of topotecan for further trials was 0.75 to 1.0 mg/m²/d, combined with cisplatin 50 mg/m², accounting for 50% to 66% of the single-agent IV dose of topotecan.^17,44 This percentage is similar to the percentage we noted at the recommended dose of oral topotecan in the CT sequence, ie, 54% of single-agent oral topotecan in a daily-times-five schedule.³⁴ We recognize that oral availability of topotecan is not taken into account. However, the relevance of bioavailability becomes questionable in view of the results of recent studies indicating that oral administration of topotecan at a dosage of 2.3 mg/m²/d is as effective as IV administration of topotecan 1.5 mg/m²/d^35,36 in both ovarian cancer and small-cell lung cancer.

For the reversed sequence, the recommended dosages are topotecan 2.0 mg/m²/d PO days 1 through 5 followed by cisplatin 75 mg/m² day 5. This constitutes a topotecan dose of 87% of the single-agent dose. However, as indicated, use of topotecan and cisplatin at these dosages should be limited to patients like those studied in this trial—ie, non-pretreated or minimally pretreated patients with a good performance status and under strict medical surveillance. In all other circumstances, topotecan dose reduction is recommended. This sequence of drug administration was also studied for the combination of the IV formulation of topotecan given for 5 consecutive days in escalating doses and cisplatin 50 mg/m² in an alternating schedule with carboplatin, cisplatin, teniposide, and vincristine in patients with small-cell lung cancer.⁴⁵ Preliminary data indicate that it is feasible to combine topotecan 1.5 mg/m²/d IV, the recommended dosage of single-agent topotecan, with cisplatin 50 mg/m². Thus, the observed hematologic toxicity is sequence dependent both for the IV and oral formulations of topotecan in combination with cisplatin, with topotecan having a higher dose-intensity when it is administered before cisplatin.

The observed pharmacokinetic parameters of the lactone and carboxylate forms of topotecan demonstrated linear and dose-independent behavior over the total dose range studied, and the data were similar to single-agent data⁴⁶ and comparable to the data obtained in the schedule with a 24-hour interval between administration of topotecan and that of cisplatin in our study, indicating no apparent pharmacokinetic interaction between topotecan and cisplatin. The sequence of drug administration also had no influence on the pharmacokinetics of topotecan at the dose levels used, on days 1, 2, and 5. This is in contrast with the reported reduced clearance of topotecan given IV after cisplatin administration.¹⁷ Sequence-dependent differences in toxicity and pharmacokinetics can be obscured by a large intrapatient variability in AUC. However, the intrapatient variability in AUC of topotecan lactone for oral topotecan expressed as a coefficient of variation is 18.5%³⁴ and is comparable to the intrapatient variability in AUC observed after IV administration of topotecan (coefficient of variation, 12.6%).⁴⁷ Because patients were treated in a cross-over design, sequence-dependent toxicologic and pharmacologic differences could be assessed as accurately as in an IV study.

Also, the ratio of topotecan AUC of lactone to total drug corresponds well with data from a previous study in which oral topotecan was administered as a single agent³⁴ and did not vary with the sequence of drug administration.

The plasma clearance and volume of distribution of unbound cisplatin as well as the AUC up to the last measured time point of total cisplatin in plasma indicated no significant influence of topotecan on the protein binding and plasma disposition of cisplatin. Preclinical studies indicated that reversal of cisplatin-induced DNA interstrand cross-links was delayed by concomitant incubation with a topoisomerase I inhibitor,^48-50 without modification of their formation. In our study, however, the values of the maximal platinum-DNA adduct formation in peripheral leukocytes and the area under the DNA adduct–versus-time curve were consistent with single-agent data⁴² and were independent of the drug sequence. Although the preclinical observations might not be extrapolated to the clinical setting, it is possible that given the extreme variability in platinum-DNA adduct values, small alterations in adduct formation, if any were present, might not be noted. It is also possible that other mechanisms may contribute to the enhanced toxicity associated with sequence CT. In in vitro studies, induction of topoisomerase I⁵¹ and enhanced topoisomerase I ⁵² inhibitory activity were observed after incubation with cisplatin followed by administration of a topoisomerase I inhibitor. Simultaneous incubation of platinum derivatives and topoisomerase I inhibitors resulted in enhanced S-phase arrest in human colon and ovarian cancer cell lines, indicative of increased topoisomerase I inhibitor–induced cytotoxicity.^48,49 This observation might indicate that the synergistic toxicity observed with the combination of topoisomerase I inhibitors and platinum derivatives can partly be explained by a modification in cellular response to DNA damage.

Given the available data, the importance of the sequence of drug administration and the enhanced toxicity observed when cisplatin administration is followed by topotecan administration cannot be applied to the antitumor activity of the combination. However, a sequence-dependent effect on antitumor activity cannot be ruled out. Further randomized phase II studies involving patients with topotecan-sensitive tumor types are needed to elucidate the importance of drug sequencing and possible cytotoxic interaction, and the potential relevance of the higher dose-intensity of both drugs, that can be achieved when the less toxic sequence of drug administration is used.

In conclusion, the recommended dosages for phase II studies involving selected patients are topotecan 1.25 mg/m²/d PO for 5 consecutive days preceded by cisplatin 75 mg/m² IV day 1 once every 3 weeks, and topotecan 2.0 mg/m²/d PO days 1 through 5 followed by cisplatin 75 mg/m² IV day 5. No pharmacokinetic interaction could explain the enhanced myelosuppression observed in sequence CT.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
1. Hsiang Y-H, Liu LF: Identification of mammalian DNA topoisomerase I as an intracellular target of the anticancer drug camptothecin. Cancer Res 48:1722-1726, 1988[Abstract/Free Full Text]

2. Eng W-K, Faucette L, Johnson RK, et al: Evidence that DNA topoisomerase I is necessary for the cytotoxic effects of camptothecin. Mol Pharmacol 34:755-760, 1988[Abstract]

3. Hsiang Y-H, Lihou MG, Liu LF: Arrest of replication forks by drug-stabilized topoisomerase I-DNA cleavable complexes as a mechanism of cell killing by camptothecin. Cancer Res 49:5077-5082, 1989[Abstract/Free Full Text]

4. De Jonge MJA, Sparreboom A, Verweij J: The development of combination therapy involving camptothecins: A review of preclinical and early clinical studies. Cancer Treat Rev 24:205-220, 1998[Medline]

5. Ma J, Maliepaard M, Nooter K, et al: Synergistic cytotoxicity of cisplatin and topotecan or SN-38 in a panel of eight solid-tumor cell lines in vitro. Cancer Chemother Pharmacol 41:307-316, 1998[Medline]

6. Maliepaard M, van Klink Y, Floot BJG, et al: Schedule-dependent cytotoxicity of topotecan or SN-38 and platinum (II) and (IV) compounds in vitro. Presented at the 8th Conf DNA Topoisomerase, Amsterdam, the Netherlands, October 15-17, 1997 (abstr 92)

7. Masumoto N, Nakano S, Esaki T, et al: Inhibition of cisdiaminodichloroplatinum (II)-induced DNA interstrand cross-link removal by 7-ethyl-10-hydroxy-camptothecin in HST-1 human squamous carcinoma cells. Int J Cancer 62:70-75, 1995[Medline]

8. Kano Y, Suzuki K, Akutsu M, et al: Effects of CPT-11 in combination with other anti-cancer agents in culture. Int J Cancer 50:604-610, 1992[Medline]

9. Romanelli S, Perego P, Pratesi G, et al: In vitro and in vivo interaction between cisplatin and topotecan in ovarian carcinoma systems. Cancer Chemother Pharmacol 41:385-390, 1998[Medline]

10. Chou T-C, Motzer RJ, Tong Y, et al: Computerized quantitation of synergism and antagonism of Taxol, topotecan, and cisplatin against human teratocarcinoma cell growth: A rational approach to clinical protocol design. J Natl Cancer Inst 86:1517-1524, 1994[Abstract/Free Full Text]

11. Blay J, Poon A, Skillings JR, et al: Cytotoxicity of topotecan with cisplatin or etoposide (VP-16) on lung, breast and colon carcinoma cells in vitro. Can J Physiol Pharmacol 72:198, 1994 (abstr P2.2.15)

12. Jensen PB, Holm B, Sorensen M, et al: In vitro cross-resistance and collateral sensitivity in seven resistant small-cell lung cancer cell lines: Preclinical identification of suitable drug partners to Taxotere, Taxol, topotecan and gemcitabine. Br J Cancer 75:869-877, 1997[Medline]

13. Waud WR, Rubinstein LV, Kalyandrug S, et al: In vivo combination chemotherapy evaluations of topotecan with cisplatin and temozolomide. Proc Am Assoc Cancer Res 37:292, 1996 (abstr 1988)

14. Kaufmann SC, Peereboom D, Buckwalter CA, et al: Cytotoxic effects of topotecan combined with various anticancer agents in human cancer cell lines. J Natl Cancer Inst 88:734-741, 1996[Abstract/Free Full Text]

15. Keane TE, El-Galley RE, Sun C, et al: Camptothecin analogues/cisplatin: An effective treatment of advanced bladder cancer in a preclinical in vivo model system. J Urol 160:252-256, 1998[Medline]

16. Takiyama I, Terashima M, Ikeda K, et al: Remarkable synergistic interaction between camptothecin analogs and cisplatin against human esophageal cancer cell lines. Proc Am Assoc Cancer Res 38:15, 1997 (abstr 101)

17. Rowinsky EK, Kaufmann SH, Baker SD, et al: Sequences of topotecan and cisplatin: Phase I, pharmacologic, and in vitro studies to examine sequence dependence. J Clin Oncol 14:3074-3084, 1996[Abstract]

18. Kudelka AP, Tresukosol D, Edwards CL, et al: Phase II study of intravenous topotecan as a 5-day infusion for refractory epithelial ovarian carcinoma. J Clin Oncol 14:1552-1557, 1996[Abstract/Free Full Text]

19. Creemers GJ, Bolis G, Gore M, et al: Topotecan, an active drug in the second-line treatment of epithelial ovarian cancer: Results of a large European phase II study. J Clin Oncol 14:3056-3061, 1996[Abstract]

20. Hoskins P, Eisenhauer E, Beare S, et al: Randomized phase II study of two schedules of topotecan in previously treated patients with ovarian cancer: A National Cancer Institute of Canada Clinical Trials Group study. J Clin Oncol 16:2233-2237, 1998[Abstract]

21. ten Bokkel Huinink W, Gore M, Carmichael J, et al: Topotecan versus paclitaxel for the treatment of recurrent epithelial ovarian cancer. J Clin Oncol 15:2183-2193, 1997[Abstract/Free Full Text]

22. Bookman MA, Malmström H, Bolis G, et al: Topotecan for the treatment of advanced ovarian cancer: An open label phase II study in patients treated after prior chemotherapy that contained cisplatin or carboplatin and paclitaxel. J Clin Oncol 16:3345-3352, 1998[Abstract]

23. Swisher EM, Mutch DG, Rader JS, et al: Topotecan in platinum- and paclitaxel-resistant ovarian cancer. Gynecol Oncol 66:480-486, 1997[Medline]

24. Schiller JH, Kim K-M, Hutson P, et al: Phase II study of topotecan in patients with extensive-stage small-cell carcinoma of the lung: An Eastern Cooperative Oncology Group trial. J Clin Oncol 14:2345-2352, 1996[Abstract]

25. Perez-Soler R, Glisson BS, Lee JS, et al: Treatment of patients with small-cell lung cancer refractory to etoposide and cisplatin with the topoisomerase I poison topotecan. J Clin Oncol 14:2785-2790, 1996[Abstract/Free Full Text]

26. Ardizzoni A, Hansen H, Dombernowsky P, et al: Topotecan, a new active drug in the second-line treatment of small-cell lung cancer: A phase II study in patients with refractory and sensitive disease. J Clin Oncol 15:2090-2096, 1997[Abstract/Free Full Text]

27. Rowinsky EK, Adjie AA, Donehower RC, et al: A phase I and pharmacodynamic study of topoisomerase I inhibitor topotecan in patients with refractory acute leukemia. J Clin Oncol 12:2193-2203, 1994[Abstract/Free Full Text]

28. Kantarjian HM, Beran M, Ellis A, et al: Phase I study of topotecan, a new topoisomerase I inhibitor in patients with refractory or relapsed leukemia. Blood 81:1146-1151, 1993[Abstract/Free Full Text]

29. Beran M, Kantarjian H: Topotecan in the treatment of hematologic malignancies. Semin Hematol 35:26-31, 1998[Medline]

30. Beran M, Kantarjian HM, Keating M, et al: Results of combination chemotherapy with topotecan and high-dose cytosine arabinoside (ara-C) in previously untreated patients with high-risk myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML). Blood 90, 1997 (suppl 1, abstr 2593)

31. Kuhn J, Rizzo J, Eckardt J, et al: Phase I bioavailability study of oral topotecan. Proc Am Soc Clin Oncol 14:474a, 1995 (abstr 1538)

32. Schellens JHM, Creemers GJ, Beijnen JH, et al: Bioavailability and pharmacokinetics of oral topotecan, a new topoisomerase I inhibitor. Br J Cancer 73:1268-1271, 1996[Medline]

33. Herben VMM, Rosing H, ten Bokkel Huinink WW, et al: Oral topotecan: Bioavailability and effect of food co-administration. Br J Cancer 80:1380-1386, 1999[Medline]

34. Gerrits CJH, Burris H, Schellens JHM, et al: Five days of oral topotecan (Hycamtin), a phase I and pharmacological study in adult patients with solid tumours. Eur J Cancer 34:1030-1035, 1998

35. Gore M, Rustin G, Calvert H, et al: A multicenter, randomized, phase III study of topotecan (T) administered intravenously or orally for advanced epithelial ovarian carcinoma. Proc Am Soc Clin Oncol 17:349a, 1998 (abstr 1346)

36. Von Pawel J, Gatzemeier U, Harstrick A, et al: A multicenter randomized phase II study of oral topotecan versus iv topotecan for second line therapy in sensitive patients with small cell lung cancer. Proc Am Soc Clin Oncol 18:471a, 1999 (abstr 1816)

37. Loos WJ, Stoter G, Verweij J, et al: Sensitive high-performance liquid chromatographic fluorescence assay for the quantitation of topotecan (SKF 104864-A) and its lactone ring-opened product (hydroxy acid) in human plasma and urine. J Chromatogr B Biomed Appl 678:309-315, 1996[Medline]

38. Ma J, Verweij J, Planting AST, et al: Current sample handling methods for measurement of platinum-DNA adducts in leukocytes in man lead to discrepant results in DNA adduct levels and DNA repair. Br J Cancer 71:512-517, 1995[Medline]

39. Ma J, Stoter G, Verweij J, et al: Comparison of ethanol plasma-protein precipitation with plasma ultrafiltration and trichloroacetic acid protein precipitation for the measurement of unbound platinum concentrations. Cancer Chemother Pharmacol 38:391-394, 1996[Medline]

40. Reed E, Sauerhoff S, Poirier MC: Quantitation of platinum-DNA binding after therapeutic levels of drug exposure: A novel use of graphite furnace spectrometry. Atomic Spectrom 9:93-95, 1988

41. Ma J, Verweij J, Kolker HJ, et al: Pharmacokinetic-dynamic relationship of cisplatin in vitro: Simulation of an i.v. bolus and 3 h and 20 h infusion. Br J Cancer 69:858-862, 1994[Medline]

42. Schellens JHM, Ma J, Planting AST, et al: Relationship between the exposure to cisplatin, DNA-adduct formation in leukocytes and tumour response in patients with solid tumours. Br J Cancer 73:1569-1575, 1996[Medline]

43. Cheng M-F, Chatterjee S, Berger NA: Schedule-dependent cytotoxicity of topotecan alone and in combination chemotherapy regimens. Oncol Res 6:269-279, 1994[Medline]

44. Miller AA, Hargis JB, Lilenbaum RC, et al: Phase I study of topotecan and cisplatin in patients with advanced solid tumors: A Cancer and Leukemia Group B study. J Clin Oncol 12:2743-2750, 1994[Abstract/Free Full Text]

45. Sorensen M, Jensen PB, Sehested M, et al: Phase I/II study of topotecan and cisplatin alternating with carboplatin, cisplatin, teniposide and vincristine in previously untreated patients with small-cell lung cancer. Proc Am Soc Clin Oncol 17:501a, 1998 (abstr 1931)

46. van Warmerdam LJC, Verweij J, Schellens JHM, et al: Pharmacokinetics and pharmacodynamics of topotecan administered daily for 5 days every 3 weeks. Cancer Chemother Pharmacol 35:237-245, 1995[Medline]

47. van Warmerdam LJC, Creemers GJ, Rodenhuis S, et al: Pharmacokinetics and pharmacodynamics of topotecan given on a daily-times-five schedule in phase II clinical trials using a limited-sampling procedure. Cancer Chemother Pharmacol 38:254-260, 1996[Medline]

48. Goldwasser F, Bozec L, Zeghari-Squalli N, et al: Cellular pharmacology of the combination of oxaliplatin with topotecan in the IGROV-1 human ovarian cancer cell line. Anticancer Drugs 10:195-201, 1999[Medline]

49. Goldwasser F, Valenti M, Torres R, et al: Potentiation of cisplatin cytotoxicity by 9-aminocamptothecin. Clin Cancer Res 2:687-693, 1996[Abstract]

50. Zeghari-Squalli N, Raymond E, Cvitkovic E, et al: Cellular pharmacology of the combination of the DNA topoisomerase I inhibitor SN-38 and the diaminocyclohexane platinum derivative oxaliplatin. Clin Cancer Res 5:1189-1196, 1999[Abstract/Free Full Text]

51. Maliepaard M, van Klink YCF, Ruiz van Haperen VWT, et al: Topoisomerase I protein level involved in schedule-dependent cytotoxicity of topotecan (TPT) or SN-38 and platinum (II) and (IV) drugs in vitro. Proc Am Assoc Cancer Res 40:108, 1999 (abstr 721)

52. Fukuda M, Nishio K, Kanzawa F, et al: Synergism between cisplatin and topoisomerase I inhibitors, NB-506 and SN-38, in human small cell lung cancer cells. Cancer Res 56:789-793, 1996[Abstract/Free Full Text]

Submitted June 7, 1999; accepted February 4, 2000.

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