1 Cancer Research UK Medical Oncology Unit, Churchill Hospital, Oxford, UK; 2 Vrije Universiteit Medical Center, Amsterdam, De Boelelaan, Amsterdam, The Netherlands; 3 Daiichi Pharmaceuticals UK Ltd, London, UK
Received 15 November 2002; accepted 3 December 2002
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Abstract |
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The topoisomerase I inhibitor exatecan mesylate (DX-8951f ) is a water-soluble hexacyclic analogue of camptothecin that does not require enzymatic activation. This study determined the toxicity, maximum tolerated dose (MTD), pharmacokinetics and pharmacodynamics of a weekly intravenous (i.v.) schedule of DX-8951f.
Patients and methods:
Thirty-five patients with advanced solid malignancies, stratified as minimally (MP) or heavily (HP) pre-treated, received escalating doses of DX-8951f as 30-min i.v. infusions for three out of every 4 weeks. Pharmacokinetics were described after the first infusion of DX-8951f.
Results:
Infusions (244) of DX-8951f were administered with a median of two cycles (range 110). The main toxicity observed was haematological. There was no significant gastrointestinal toxicity. Two patients (6%) had confirmed partial responses. Twelve patients (39%) had stable disease. DX-8951f had a terminal elimination half-life of 8 h and a clearance of 2 l/h/m2. The area under the plasma concentration versus time curve (AUC
) and the maximum plasma concentration (Cmax) increased linearly with the dose. A linear relationship was present for the percentage decrease in neutrophil counts or platelet counts and AUC
as well as Cmax.
Conclusions:
The dose-limiting toxicity of DX-8951f is neutropenia for MP patients and neutropenia and thrombocytopenia for HP patients. Evidence for clinical activity was seen, suggesting phase II study of the drug is indicated. Using this schedule the recommended dose is 2.75 mg/m2/week for MP patients and 2.10 mg/m2/week for HP patients.
Key words: exatecan mesylate, phase I, topoisomerase inhibitor
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Introduction |
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Exatecan mesylate [DX-8951f: (1S,9S)-1-amino-9-ethyl-5-fluoro-1,2,3,9,12,15-hexahydro-9-hydroxy-4-methyl-10H,13H-benzo (de)-pyrano(3,4: 6,7)-indolizino (1,2-b) quinoline-10,13-dione monomethane sulfonate (salt), dihydrate] (Daiichi Pharmaceutical Co., Ltd, Tokyo, Japan) is a water-soluble hexacyclic analogue of camptothecin that does not require enzymatic activation [18]. In vitro, DX-8951f was shown to be a more potent topoisomerase I inhibitor than camptothecin, topotecan and 10-hydroxy-7-ethylcamptothecin (SN-38), the active metabolite of irinotecan, against various human cancer cell lines [18, 19]. Multi-drug resistance mediated by P-glycoprotein did not affect the cytotoxicity of DX-8951f [18, 20], and the compound was a poor substrate for the breast cancer resistance protein (BCRP) [2022]. Antitumour activity was seen in human tumour xenografts, with enhanced efficacy noted using multiple dosing schedules [18, 19, 23, 24]. The toxicological profile of DX-8951f has been evaluated in pre-clinical studies in mice, rats and dogs. The toxic dose low (TDL) values in the most sensitive species, the Beagle dog, were 10 mg/m2 in single doses or 0.3 mg/m2/day in five daily dose schedules. The dose-limiting toxicity (DLT) was non-cumulative myelosuppression. Gastrointestinal toxicity was also seen [25].
The principal objectives of this study were to determine the toxicity characteristics and maximum tolerated dose (MTD) of DX-8951f when administered as a 30-min intravenous (i.v.) infusion weekly for 3 weeks every 4 weeks in both minimally and heavily pre-treated patients. Secondary objectives were to determine the pharmacokinetic profile of DX-8951f, its pharmacokineticpharmacodynamic relationship and identify potential antitumour activity of the drug.
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Patients and methods |
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Ethical considerations
This study was conducted according to the European Good Clinical Practice Guidelines [26] and the Declaration of Helsinki [27]. Written informed consent was obtained from all patients and the study was approved by the Central Oxford Research Ethics Committee and the Ethics Committee, Vrije Universiteit Medical Centre, Amsterdam.
Study design and treatment plan
The study was conducted as an open label phase I dose-escalation study in two clinical centres, the Cancer Research UK Medical Oncology Unit, Oxford and the Vrije Universiteit Medical Centre, Amsterdam. DX-8951f was provided by Daiichi Pharmaceutical Co. Ltd. Glass vials containing 2 or 5 mg of DX-8951f, calculated as anhydrous free base equivalent, as lyophilised powder, were reconstituted in 2 or 5 ml of 0.9% saline to make a stock solution of 1 mg/ml. The appropriate dose was diluted in 100 ml of 0.9% saline, and administered as a 30-min i.v. infusion via a peripheral vein or central venous catheter. The first dose of DX-8951f was administered on an in-patient basis, with patients monitored for at least 24 h. Prophylactic treatments for drug-related symptoms, for example anti-emetics, were not permitted for the first administration in each patient. Subsequent treatments were administered on an out-patient basis and prophylactic anti-emetics were administered where indicated. Each patient received treatment weekly for 3 weeks followed by an interval of 1 week (one cycle), to a maximum of two cycles. Further cycles of DX-8951f were administered at the discretion of the investigators.
The starting dose selected for DX-8951f was 1 mg/m2/week based on one-third of the TDL in dogs [25]. Dose escalation was based on the National Cancer Institute common toxicity criteria (NCI-CTC, version 1) [28]. If the NCI toxicity grade for all patients in a cohort was <2 then the dose increment was 100%. Once the toxicity was grade 2 or higher then the dose increment to the next cohort was 33%. A minimum of 7 days was allowed between the entry of new patients in the same cohort. Dose escalation was permitted after a minimum of 28 days from the first infusion of the last patient entered. DLT was based on the first cycle. This was defined as grade 3 haematological toxicity or grade 2 non-haematological toxicity (excluding alopecia) between the first and second infusion. Between infusion 2, infusion 3 and infusion 1 of the second cycle, DLT was determined as a grade 4 haematological toxicity, grade 3 non-haematological toxicity (excluding nausea, vomiting and alopecia) or grade 4 vomiting in patients with maximum anti-emetic supportive care. The MTD was defined as the highest dose at which no more than one of six patients experienced DLT.
If a patient experienced a grade 3 haematological toxicity or a grade 2 non-haematological toxicity (excluding alopecia) following the second infusion of a cycle of treatment then the third infusion was omitted and up to 3 weeks was permitted for the toxicity to resolve prior to further treatment. If an individual patient experienced a DLT the dose of DX-8951f could be decreased by one dose level for that patient. If further DLT was observed then the patient was withdrawn from the study. No intra-patient dose escalation was allowed and no concurrent antitumour treatment was permitted with the exception of local palliative radiotherapy to painful bone metastases.
Patients were stratified as heavily pre-treated (HP) or minimally pre-treated (MP). HP patients were defined as those who had received six or more prior cycles with an alkylating agent, four or more cycles of carboplatin, two or more cycles of mitomycin C or a nitrosourea, or radiation therapy to >25% of haemopoietic reserves. This definition was used in all phase I studies of DX-8951f. Retrospective stratification was applied to the first 18 patients studied and MTD was determined separately in MP and HP patients.
Toxicity and response monitoring
Patients enrolled in the study had screening investigations performed within 28 days of starting treatment. These included clinical history and examination by a physician, evaluation of measurable lesions by appropriate radiological investigation, electrocardiogram, chest X-ray, urinalysis for protein and laboratory parameters including complete blood count with differential, coagulation profile, serum chemistry, protein, albumin and electrolyte level. Following the first infusion, patients were monitored for 24 h and then assessed weekly. At each assessment monitoring of toxicity by clinical and laboratory methods was performed and toxicity graded according to NCI-CTC [28]. End of study assessment was performed 7 days after the last infusion and tumour response determined after two cycles of treatment using the South West Oncology Group (SWOG) standard response criteria [29]. Patients regarded as having progressive disease or unacceptable toxicity during the first two cycles were withdrawn from the study.
Pharmacokinetic samples
Samples for pharmacokinetic analysis were collected during and after the first infusion of DX-8951f. Venous blood samples were taken before the start of the infusion (T = 0 h), 0.25 h after the start of the infusion, at the end of the infusion (T = 0.5 h) and then at 0.25, 0.5, 1, 2, 4, 6, 8 and 24 h after the end of the infusion. Samples were taken from the arm contralateral to the infusion line and were collected into heparin-containing glass vacutainer tubes. The blood was centrifuged at 3000 r.p.m. for 15 min to separate the plasma. Plasma was transferred to a labelled sample tube and frozen at 20°C within 1 h of collection. Urine samples were collected in sterile containers pre-infusion (T = 0 h), at 06 h, and 624 h after the infusion. The total volume of urine was measured for each collection period and, after shaking, 2 ml were drawn off and frozen at 20°C in labelled containers.
All collected urine and plasma samples were despatched on dry ice to Phoenix International Life Sciences Ltd, Montreal, Canada, for pharmacokinetic analysis using validated high-performance liquid chromatography techniques (HPLC) [30]. The lower limit of quantitation was 0.22 ng/ml for plasma DX-8951 and 2.51 ng/ml for urine DX-8951.
Pharmacokinetic analysis
Non-compartmental pharmacokinetic parameters for plasma DX-8951 (the anhydrous form of DX-8951f) were calculated and values were normalised for body surface area. These parameters included: the area under the plasma concentration versus time curve from time 0 to the last measurable concentration (AUC0t), calculated by the linear trapezoidal method; the AUC from time 0 to infinity (AUC), calculated as the sum of the AUC0t plus the ratio of the last measurable plasma concentration to the terminal elimination constant; the maximum measured plasma concentration over the time of sample collection (Cmax); the total body clearance rate (CL), calculated as the dose divided by the AUC
; the volume of distribution at steady state (Vdss), calculated according to the formula: (k0 x ti x AUMC
)/(AUC
2)(k0 x ti2)/(2 x AUC
), in which AUMC
represents the area under the moment curve from time 0 to the last measurable concentration, ti is the duration of the infusion and k0 is the drug administration rate; the mean residence time (MRT) calculated as (AUMC
/AUC
)(t1/2); and the terminal half-life (t1/2), calculated by dividing CL by
z, in which
z is the rate constant associated with the elimination phase. Individual plasma concentration versus time data were modelled separately using non-linear least-squares regression analysis [WinNonlin, version 1.0; Scientific Consulting Inc., Apex, NC (now Pharsight Inc.)]. The blood sampling schedule was adjusted according to the infusion start time (T = 0 h). Total DX-8951 plasma concentration data were also analysed using model-dependent methods as described previously [31].
Pharmacokinetic parameters for DX-8951 in urine were calculated by non-compartmental analysis as follows: the amount of drug excreted unchanged in urine from 0 to 24 h after beginning or end of administration; the percentage of the drug DX-8951f administered which was excreted unchanged in urine from 0 to 24 h after beginning or end of drug administration.
Statistical analysis
Linear regression lines were drawn to evaluate relationships between AUC or Cmax and the dose administered. The pharmacodynamic parameters of the absolute numbers and percentages of decrease in neutrophil counts and platelet counts in the first DX-8951f treatment cycle were used to determine the relationship between haematological toxicity and the pharmacokinetic parameters, such as AUC
and Cmax, by linear regression.
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Results |
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Ten patients were withdrawn during the first two cycles (six with progressive disease, three with adverse events and one with a combination of progressive disease and adverse events). Fourteen patients discontinued treatment after two cycles and 11 patients entered a continuation phase with one patient receiving six cycles and another receiving 10 cycles of DX-8951f. Five patients missed the third infusion of cycle 1 due to adverse events, including neutropenia (two HP patients at 2.35 mg/m2 and one MP patient at 3.13 mg/m2), infection but no neutropenia (one MP patient at 2.75 mg/m2) and dysphagia attributed to disease progression (one MP patient at 2.75 mg/m2). Five patients required a reduction in dose during the first two cycles of the study because of neutropenia (two HP patients initially started at 2.35 mg/m2, one MP patient at 2.75 mg/m2 and two MP patients at 3.13 mg/m2).
Fourteen patients were regarded as HP and 21 as MP. The MTD for HP patients was determined as 2.10 mg/m2. Of 21 patients who were regarded as MP, two out of three experienced DLT of grade 4 neutropenia at 3.13 mg/m2. The highest dose of DX-8951f resulting in no more than one out of six patients experiencing DLT was 2.75 mg/m2 and this was determined as the MTD for MP patients.
The principal toxicity observed was haematological with DLT being neutropenia and thrombocytopenia for HP patients and neutropenia for MP patients. The typical nadir for neutropenia was 1421 days after the first infusion of each cycle. There was a clear increase in frequency and severity of haematological toxicity with increasing dose of DX-8951f (Table 2 and Figure 1). In all patients the myelosuppression was reversible. Other adverse events considered related to DX-8951f included fatigue, nausea and vomiting, diarrhoea, anorexia, headache and alopecia (Table 3). Non-haematological toxicity did not appear to be dose-related and there was no grade 3 diarrhoea seen.
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Pharmacokinetics
The pharmacokinetics of DX-8951 was described after the first infusion in all patients. The DX-8951 peak plasma concentration was reached at the end of the 30-min i.v. infusion. Data for the non-compartmental pharmacokinetic parameters AUC0t, AUC, Cmax, CL, Vdss and MRT normalised for body surface area are summarised in Table 4. In this study, DX-8951 had a t1/2 of
8 h and a CL of
2 l/h/m2. This is, however, based on the current sampling schedule which was 24 h after the end of dose infusion. Based on individual subject pharmacokinetic modelling, observed concentrations of the drug could be described with a two- or three-compartmental pharmacokinetic model. Estimation of pharmacokinetic parameters was similar between non-compartmental and compartmental analyses. The mean percentage of DX-8951 excreted unchanged in urine in 24 h was 6% (range 0.9415.68%).
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Discussion |
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In contrast to irinotecan, only moderate non-haematological toxicity was observed after DX-8951f treatment, with the principal toxicity being nausea and vomiting, diarrhoea, headache and fatigue. In particular, no clinically significant diarrhoea was observed in this study (Table 3). The non-haematological toxicity was considered mild or moderate and did not appear to differ between dose levels of DX-8951f. The toxicity profile in this study was similar to that observed in other phase I studies with DX-8951f administered in different schedules including a daily x5 infusion every 3 weeks, a 30-min infusion every 3 weeks, and a 24-h infusion every 3 weeks. In each of these studies the dose-limiting toxicity was dose-related, reversible neutropenia with some patients also developing dose-limiting thrombocytopenia. As in this study, the main reported non-haematological adverse events were nausea, vomiting, diarrhoea, fatigue and alopecia. In all trials these toxicities were considered mild to moderate [3134]. These phase I data imply that the overall toxicity profile of DX-8951f is similar to that seen with topotecan rather than irinotecan. In the continuation phase of this study two patients died, one of haemorrhagic pancreatitis and one from a cerebrovascular event. Whilst not proven, in both patients the investigators considered the causality to be possibly related to treatment, although at the time of the events neither patient was thrombocytopenic. Pancreatitis was not predicted from pre-clinical studies, but has been observed in one other patient treated with DX-8951f in a phase I study using a 24-h continuous infusion every 3 weeks [34].
Whilst the principal aim of this study was to determine an MTD of DX-8951f using a weekly schedule, a secondary objective was to assess tumour response. Confirmed partial responses were seen in two (6%) patients (mixed large and small cell lung cancer and sarcoma). Stable disease was observed in 12 (39%) patients (lung, colorectal, ovary and melanoma). This early assessment of response suggests that DX-8951f may have clinical activity and warrants further phase II evaluation in a range of tumour types.
Pharmacokinetic analysis of DX-8951f during, and for 24 h after, the first infusion of this study found that the Cmax of DX-8951f was reached at the end of the 30-min infusion. The pharmacokinetic profile appeared linear within the dose range assessed (1.03.13 mg/m2) and is consistent with the pharmacokinetics reported from other phase I studies (Figure 2). The t1/2 was 8 h according to the sampling schedule used, with
6% DX-8951f excreted unchanged in the urine. This suggests that, in contrast to topotecan, DX8951f undergoes extensive hepatic metabolism [35]. With the principal DLT in this study being haematological toxicity, pharmacokineticpharmacodynamic relationships between AUC
or Cmax and percentage decrease in neutrophil or platelet counts were recognised (Figure 3). The extent of previous cytotoxic treatment was an important factor in predicting toxicity of DX-8951f. This has implications for the choice of dose in phase II studies. We propose that, in future, studies of DX-8951f patients are stratified by the extent of previous treatment, as defined in Patients and methods.
DX-8951f, in MP and HP populations with good performance status and without significant biochemical changes, appears to be well tolerated with neutropenia as the dose-limiting toxicity in both patient categories. Thrombocytopenia and anaemia were also clinically significant toxicities in HP patients. This study has demonstrated that it is feasible to administer DX-8951f weekly and that the relative dose intensity achieved in this study was at least as high, or greater, than that seen in other phase I schedules of DX-8951f. In some patients in this trial antitumour activity was observed, and this should therefore encourage further broad assessment of DX-8951f in phase II studies. In particular, further clinical trials in patients with lung cancer are indicated. From this phase I study, the recommended dose for phase II trials using a weekly schedule for three out of every 4 weeks is 2.10 mg/m2/week for HP patients or those with poor marrow reserve, and 2.75 mg/m2/week for non-treated or MP patients.
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Acknowledgements |
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Footnotes |
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References |
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2. Li LH, Fraser TJ, Olin EJ et al. Action of camptothecin on mammalian cells in culture. Cancer Res 1972; 32: 26432650.[ISI][Medline]
3. Drewinko B, Freireich EJ, Gottlieb JA. Lethal activity of camptothecin sodium on human lymphoma cells. Cancer Res 1974; 34: 747750.[ISI][Medline]
4. Gallo RC, Whang-Peng J, Adamson RH. Studies on the antitumor activity, mechanism of action, and cell cycle effects of camptothecin. J Natl Cancer Inst 1971; 46: 789795.[ISI][Medline]
5. Eng WK, Faucette L, Johnson RK et al. Evidence that DNA topoisomerase I is necessary for the cytotoxic effects of camptothecin. Mol Pharmacol 1988; 34: 755760.[Abstract]
6. Jaxel C, Kohn KW, Wani MC et al. Structureactivity study of the actions of camptothecin derivatives on mammalian topoisomerase I: evidence for a specific receptor site and a relation to antitumor activity. Cancer Res 1989; 49: 14651469.[Abstract]
7. Hsiang YH, Liu LF. Identification of mammalian DNA topoisomerase I as an intracellular target of the anticancer drug camptothecin. Cancer Res 1988; 48: 17221726.[Abstract]
8. Rothenberg ML. Topoisomerase I inhibitors: review and update. Ann Oncol 1997; 8: 837855.[Abstract]
9. Muggia FM, Creaven PJ, Hansen HH et al. Phase I clinical trial of weekly and daily treatment with camptothecin (NSC-100880): correlation with preclinical studies. Cancer Chemother Rep 1972; 56: 515521.[ISI][Medline]
10. Slichenmyer WJ, Rowinsky EK, Donehower RC et al. The current status of camptothecin analogues as antitumor agents. J Natl Cancer Inst 1993; 85: 271291.[Abstract]
11. Cunningham D, Pyrhonen S, James RD et al. Randomised trial of irinotecan plus supportive care versus supportive care alone after fluorouracil failure for patients with metastatic colorectal cancer. Lancet 1998; 352: 14131418.[CrossRef][ISI][Medline]
12. Rougier P, Van Cutsem E, Bajetta E et al. Randomised trial of irinotecan versus fluorouracil by continuous infusion after fluorouracil failure in patients with metastatic colorectal cancer. Lancet 1998; 352: 14071412.[CrossRef][ISI][Medline]
13. Saltz LB, Cox JV, Blanke C et al. Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. Irinotecan Study Group. N Engl J Med 2000; 343: 905914.
14. Douillard JY, Cunningham D, Roth AD et al. Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial. Lancet 2000; 355: 10411047.[CrossRef][ISI][Medline]
15. 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 1996; 14: 5661.
16. Ten Bokkel Huinink W, Gore M, Carmichael J et al. Topotecan versus paclitaxel for the treatment of recurrent epithelial ovarian cancer. J Clin Oncol 1997; 15: 21832189.[Abstract]
17. Bookman MA, Malmstrom H, Bolis G et al. Topotecan for the treatment of advanced epithelial ovarian cancer: an open-label phase II study in patients treated after prior chemotherapy that contained cisplatin or carboplatin and paclitaxel. J Clin Oncol 1998; 16: 33453352.[Abstract]
18. Mitsui I, Kumazawa E, Hirota Y et al. A new water-soluble camptothecin derivative, DX-8951f, exhibits potent antitumor activity against human tumors in vitro and in vivo. Jpn J Cancer Res 1995; 86: 776782.[ISI][Medline]
19. Takiguchi S, Kumazawa E, Shimazoe T et al. Antitumor effect of DX-8951, a novel camptothecin analog, on human pancreatic tumor cells and their CPT-11-resistant variants cultured in vitro and xenografted into nude mice. Jpn J Cancer Res 1997; 88: 760769.[ISI][Medline]
20. Ishii M, Iwahana M, Mitsui I et al. Growth inhibitory effect of a new camptothecin analog, DX-8951f, on various drug-resistant sublines including BCRP-mediated camptothecin derivative-resistant variants derived from the human lung cancer cell line PC-6. Anticancer Drugs 2000; 11: 353356.[CrossRef][ISI][Medline]
21. Joto N, Ishii M, Minami M et al. DX-8951f, a water-soluble camptothecin analog, exhibits potent antitumor activity against a human lung cancer cell line and its SN-38-resistant variant. Int J Cancer 1997; 72: 8086.
22. Maliepaard M, van Gastelen MA, Tohgo A et al. Circumvention of breast cancer resistance protein (BCRP)-mediated resistance to camptothecins in vitro using non-substrate drugs or the BCRP inhibitor GF120918. Clin Cancer Res 2001; 7: 935941.
23. Kumazawa E, Jimbo T, Ochi Y et al. Potent and broad antitumor effects of DX-8951f, a water-soluble camptothecin derivative, against various human tumors xenografted in nude mice. Cancer Chemother Pharmacol 1998; 42: 210220.[CrossRef][ISI][Medline]
24. Vey N, Giles FJ, Kantarjian H et al. The topoisomerase I inhibitor DX-8951f is active in a severe combined immunodeficient mouse model of human acute myelogenous leukemia. Clin Cancer Res 2000; 6: 731736.
25. Kajimura T. DX-8951f: Single intravenous dose toxicity study in dogs. Daiichi Pharmaceutical Co. Ltd. In house study report (8951J-TOXO19), 1996.
26. ICH Harmonised Tripartite Guidelines for Good Clinical Practice: CPMP/ICH/135/95 which applies to all studies commencing after 17 January, 1997.
27. Declaration of Helsinki: Recommendations guiding physicians in biomedical research involving human subjects, 1989.
28. National Cancer Institute: Guidelines for the Reporting of Adverse Drug Reactions. Bethesda, MD, Division of Cancer Treatment, National Cancer Institute 1988.
29. Green S, Weiss G. Southwest Oncology Group standard response criteria, endpoint definitions and toxicity criteria. Invest New Drugs 1992; 10: 239253.[ISI][Medline]
30. Oguma T, Ohshima Y, Nakaoka M. Sensitive high-performance liquid chromatographic method for the determination of the lactone form and the lactone plus hydroxy-acid forms of the new camptothecin derivative DX-8951 in human plasma using fluorescence detection. J Chromatogr B Biomed Sci Appl 2000; 740: 237245.[CrossRef][Medline]
31. Rowinsky EK, Johnson TR, Geyer CE Jr et al. DX-8951f, a hexacyclic camptothecin analog, on a daily-times-five schedule: a phase I and pharmacokinetic study in patients with advanced solid malignancies. J Clin Oncol 2000; 18: 31513163.
32. Boige V, Raymond E, Faivre S et al. Phase I and pharmacokinetic study of the camptothecin analog DX-8951f administered as a 30-minute infusion every 3 weeks in patients with advanced cancer. J Clin Oncol 2000; 18: 39863992.
33. De Jager R, Cheverton P, Tamanoi K et al. DX-8951f: summary of phase I clinical trials. Ann NY Acad Sci 2000; 922: 260273.
34. Royce ME, Hoff PM, Dumas P et al. Phase I and pharmacokinetic study of exatecan mesylate (DX-8951f): a novel camptothecin analog. J Clin Oncol 2001; 19: 14931500.
35. OReilly S, Rowinsky EK, Slichenmyer W et al. Phase I and pharmacologic study of topotecan in patients with impaired renal function. J Clin Oncol 1996; 14: 30623073.[Abstract]