Cancer Therapy: Clinical

A Phase I and Pharmacologic Study of Belotecan in Combination with Cisplatin in Patients with Previously Untreated Extensive-StageDiseaseSmallCellLungCancer Dae Ho Lee,1Sang-We Kim,1Kyun-Seop Bae,2 Jeong-Sook Hong,1Cheolwon Suh,1 Yoon-Koo Kang,1and Jung-Shin Lee1

Abstract Purpose: Belotecan (Camtobell, CKD602) is a novel camptothecin derivative. This study was designed to determine the maximum tolerated dose (MTD), toxicity profile, and dose- limiting toxicity of belotecan in combination with cisplatin in patients with previously untreated extensive-stage disease small cell lung cancer (SCLC). Furthermore, pharmacokinetics and pre- liminary antitumor activity against SCLC were evaluated. Experimental Design: Belotecan was administered i.v. as intermittent 30-min infusions on days 1to 4, starting dose of 0.40 mg/m2/d with increment of 0.05 mg/m2/d. Intrapatient dose escala- tion was not allowed. Cisplatin (60 mg/m2) was given on day 1.The treatments were repeated every 3 weeks. Pharmacokinetics was determined during the first cycle using noncompartmental pharmacokinetic analysis. Results: Seventeen chemotherapy-naive patients with extensive-stage disease SCLC were trea- ted. The MTD of belotecan was 0.50 mg/m2/d with the dose-limiting toxicity of grade 4 neutro- penia with fever. A partial response was seen in 13 of 17 patients (76.5%). The most common toxicity was neutropenia but nonhematologic toxicity was very favorable. Pharmacokinetic anal- ysis revealed that, at the dose of 0.50 mg/m2/d, plasma clearance of belotecan was 5.78 F 1. 3 2 L/h and terminal half-life was 8.55 F 2.12 h. Fraction of excreted amount in urine was 37.36 F 5.55%. Pharmacokinetics of belotecan was not altered by administration of cisplatin compared with historical control. Conclusions: The MTD and recommended dose of belotecan for phase II studies was 0.50 mg/m2/d on days 1to 4 in combination with 60 mg/m2 cisplatin on day 1every 3 weeks.

Combination chemotherapy remains the main treatment of trial (8),new regimens containing these new drugs failed to patients with extensive-stage disease small cell lung cancer show the survival benefit compared with the standard etopo- (SCLC). Etoposide and cisplatin combination has been used as side-cisplatin regimen (9–11). Irinotecan and cisplatin regimen a standard treatment. However,although initial response rates showed survival advantage in Japan (8),but a subsequent trial to etoposide-cisplatin combination were up to 80%,the me- in Western countries failed to confirm the survival benefit of dian survival time of patients treated with etoposide-cisplatin this regimen over etoposide-cisplatin regimen (12). regimen was reportedly only 8 to 9 months and 2-year survival Belotecan [Camtobell,CKD602,7-[2-( N-isopropylami- of 4% (1–4). Several new drugs,such as paclitaxel,topotecan, no)ethyl]-(20S)-camptothecin,Chong Keun Dang Corp.] is a and irinotecan,were shown to be active in chemotherapy-naive novel camptothecin derivative,in which a water-solubilizing or chemosensitive patients with SCLC,in which the response group is introduced at position of the B ring (13). The preclinical rates had reached 40% (5–7). However,except the Japanese studies showed that belotecan was a more potent topoisomerase I inhibitor in the cleavable complex assay and had superior in vitro and in vivo antitumor activity to camptothecin and topotecan in the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetra- Authors’ Affiliations: 1Division of Oncology, Department of Internal Medicine and 2Department of Clinical Pharmacology and Therapeutics, University of Ulsan, zolium bromide cell cytotoxicity assay and six human tumor College of Medicine, Asan Medical Center, Seoul, Korea xenografts (13,14). Of interest,the mean ATI values of belotecan Received 3/6/07; revised 7/3/07; accepted 8/8/07. were over 2-fold higher than those of topotecan,suggesting that Grant support: Korea Health 21 R&D Project, Ministry of Health and Welfare, this drug would show encouraging antitumor activity in a clinical Republic of Korea (A060775). Belotecan was provided by Chong Keun Dang study. Although several in vitro and in vivo test systems developed Corp., Seoul, Korea. The costs of publication of this article were defrayed in part by the payment of page to predicting the clinical activity have some limitations,the ATI charges. This article must therefore be hereby marked advertisement in accordance values,defined as the area under the inhibition ratio (%) versus with 18 U.S.C. Section 1734 solely to indicate this fact. time curve plotted from 0 to 240 min as obtained by ex vivo Requests for reprints: Jung-Shin Lee, Division of Oncology, Department of pharmacodynamic assay and calculated by trapezoidal rule, Internal Medicine, University of Ulsan, College of Medicine, Asan Medical Center, showed a good clinical correlation with the clinical response 388-1 Pungnap-2 dong, Songpa-gu, Seoul 138-736, Korea. Phone: 82-2-3010- 3212; Fax: 82-2-3010-6961;E-mail: [email protected]. (15). In a phase I study,the maximum tolerated dose (MTD) of 2 F 2007 American Association for Cancer Research. single-agent belotecan was 0.7 mg/m /d when given i.v. daily for doi:10.1158/1078-0432.CCR-07-0534 5 consecutive days every 3 weeks and the dose-limiting toxicity

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Declaration of Helsinki and Good Clinical Practice guidelines. Written Table 1. Patients’ characteristics informed consent was obtained from all patients before study procedures. Treatment plan. Before treatment,all patients had a complete Characteristic No. patients (%) history and physical examination,complete blood count with differen- Total patients 17 tial,electrolytes,glucose,liver,and renal function tests,staging chest and Age (y) upper abdominal computed tomography scan,and bone scan. Median 60 Belotecan would be administered as a 30-min i.v. infusion on days 1 Range 52-69 to 4,starting dose of 0.40 mg/m 2/d with increment of 0.05 mg/m2/d. Sex The dose escalation proceeded in cohorts of three patients if no DLT Male 17 (100.0) was observed. Intrapatient dose escalation was not allowed. Cisplatin Female 0 (0.0) 2 Eastern Cooperative Oncology Group status was administered i.v. over 2 h on day 1 with a fixed dose of 60 mg/m , Grade 0-1 16 (94.1) which had been chosen in the trials of irinotecan or topotecan-cisplatin Grade 2 1 (5.9) combination (8,11,12,18,19). DLT was determined during the Metastatic site first cycle only and defined as follows: grade 4 neutropenia (absolute Liver 4 (23.5) neutrophil count <500/mm3) lasting 7 days; grade 4 neutropenia Bone 7 (41.2) with fever (V38.5jC) or sepsis; grade 4 thrombocytopenia (platelet Adrenal gland 2 (11.8) 3 Neck lymph node 1 (5.9) <10,000/mm ); and grade 3 or 4 nonhematologic toxicity other than Contralateral lung parenchyma 7 (41.2) nausea,vomiting,and alopecia. DLT occurring in the first treatment course was used to make the following decisions: if zero of three patients at a given dose level had DLT,escalation proceeded to the next (DLT) was neutropenia (16). A subsequent phase II study of dose level; if one of three patients had DLT,up to three additional single-agent belotecan in extensive-stage disease SCLC showed a patients were entered at that dose level,and if none of the second promising response rate of 46.6%,especially that of 63.6% in cohort of three patients experienced DLT,then the dose was to be escalated; and if two or more patients at a given dose level had DLT, chemotherapy-naive patients (17). Based on those findings,we dose escalation ceased and the next lower level was called the MTD. conducted the phase I study of belotecan in combination with The cycle length was planned to be 21 days. Absolute neutrophil cisplatin in patients with previously untreated extensive-stage count and platelet count were required to be at least 1,500/mm3 and disease SCLC. The main objectives were to determine the MTD 100,000/mm3,respectively,for subsequent cycles. If count recovery had and pharmacokinetics of belotecan and the toxicity profile of this not occurred by day 21,patients were required to delay the subsequent combination. We also studied preliminary antitumor activity cycle by 1 week. If a patient required >35 days for hematologic recovery against SCLC. to the specified values,the study was to be terminated and the event was regarded as a DLT. Responders were scheduled to be treated for six cycles but could be treated for a maximum of nine cycles at the Materials and Methods discretion of treating physician. Toxicity and efficacy assessment. Patients were evaluated weekly for Eligibility criteria. Eligible patients had histologically or cytologi- toxicity during the first cycle and then every cycle thereafter using the cally confirmed SCLC and evidence of extensive-stage disease defined as National Cancer Institute Common Toxicity Criteria version 2.0 (20). either disease not encompassed in a reasonable radiation port or Patients were evaluated for response every two cycles according to WHO extrathoracic disease. Patients had to meet the following criteria: age of response criteria (21). Complete response was defined as disappearance 18 to 70 years; Eastern Cooperative Oncology Group performance of all known disease for at least 4 weeks with no new lesion appearing. status of 0 to 2; no prior chemotherapy; bidimensionally measurable Partial response was defined as at least 50% decrease in the sum of the disease(s); total WBC count z4,000/mm3; absolute neutrophil count products of bidimensional diameters for at least 4 weeks without the z1,500/mm3; hemoglobin z9 g/dL; platelet count z100,000/mm3; appearance of new lesions. Stable disease was defined as failure to total bilirubin V1.5 mg/dL; aspartate aminotransferase/alanine amino- observe a partial response or complete response,with no progressive or transferase each V2 times the upper limits of normal; and serum new lesions observed for at least 4 weeks. Progressive disease was defined creatinine V1.5 mg/dL or calculated (i.e.,Cockcroft-Gault equation) as a 25% or greater increase in the products of bidimensional diameters creatinine clearance z60 mL/min. Exclusion criteria were as follows: of any measurable lesion or the appearance of new lesions. Progression- previous or concurrent malignancy (except nonmelanoma skin cancer, free survival was defined as the interval between the date of the start of in situ carcinoma of the cervix or breast,or other cancer if the patient treatment and the date of documented disease progression or death from has been disease-free for 5 years),a serious medical or psychiatric illness any cause. Overall survival was defined as the interval between the date of preventing informed consent,or survival limited to <2 months. Prior the start of treatment and the date of death due to any cause. If a patient radiation was allowed at the discretion of treating physician. The study was lost to follow-up,that patient was censored at the last date of contact. was approved by the Institutional Review Board at the Asan Medical All patients who were enrolled and received drug were included in the Center before subject enrollment and was done in accordance with the toxicity analysis. Data were updated as of January 31,2007.

Table 2. DLT and best overall response for all cohorts

Dose level (mg/m2/d) No. patients enrolled DLT (no. patients) Best overall response 0.40 3 — 2 PRs, 1 PD 0.45 3 — 3 PRs 0.50 6 Thrombocytopenia (1) 5 PRs, 1 SD 0.55 5 Febrile neutropenia (2) 3 PRs, 2 PD

Abbreviations: PRs, partial responses; SD, stable disease; PD, progressive disease.

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Table 3. Toxicity profiles (n = 17)

Adverse effect Grade 0 Grade 1 Grade 2 Grade 3 Grade 4 Hematologic toxicity, no. patients (%) Neutropenia 0 (0) 0 (0) 1 (6) 6 (35) 10 (59) Anemia 0 (0) 3 (18) 10 (59) 4 (24) 0 (0) Thrombocytopenia 2 (12) 4 (24) 6 (35) 3 (18) 2 (12) Nonhematologic toxicity, no. patients (%) Alopecia 2 (12) 7 (41) 9 (22) — — Anorexia 3 (18) 10 (59) 4 (24) 0 (0) 0 (0) Nausea 5 (29) 7 (41) 4 (24) 1 (6) 0 (0) Vomiting 10 (59) 2 (12) 5 (29) 0 (0) 0 (0) Constipation 12 (71) 3 (18) 2 (12) 0 (0) 0 (0) Diarrhea 13 (76) 4 (24) 0 (0) 0 (0) 0 (0) Fatigue 9 (53) 5 (29) 3 (18) 0 (0) 0 (0) Dizziness 12 (71) 4 (24) 1 (6) 0 (0) 0 (0) Neuropathy 15 (88) 1 (6) 1 (6) 0 (0) 0 (0) Febrile neutropenia 13 (76) 1 (6) 0 (0) 3 (18) 0 (0) Elevated AST/ALT 14 (82) 1 (6) 1 (6) 1 (6) 0 (0) Hypoalbuminemia 10 (59) 4 (24) 3 (18) 0 (0) 0 (0) Hypomagnesemia 12 (71) 2 (12) 3 (18) 0 (0) 0 (0) Hyponatremia 10 (59) 3 (18) 0 (0) 1 (6) 3 (18)

Abbreviations: AST, aspartate aminotransferase; ALT, alanine aminotransferase.

Belotecan pharmacokinetics. To estimate pharmacokinetics of belote- Toxicity during all cycles of therapy. Table 3 shows the toxicity can,blood and urine were obtained from the patients at the first cycle observed during the treatment for all cohorts with a total of 103 only. On day 1,blood samples were taken immediately before,15 min, cycles (median,6 cycles; range,2-9). Of 17 patients,16 (94%) had 30 min,45 min,1 h,2 h,4 h,8 h,and 12 h after administration of grade 3 or 4 hematologic toxicity,whereas only 4 patients had belotecan. On days 2 and 3,they were taken only before administration grade 3 or 4 nonhematologic toxicity. The most common of belotecan. On day 4,they were taken with the same time interval to day 1 and additional samples were done 24 and 48 h after the last nonhematologic toxicities were hyponatremia followed by febrile administration of belotecan. Spot urine samples were taken before neutropenia,but which was manageable by supportive care. Of administration of belotecan. Additionally,on day 1,urine samples were interest,all responders received six cycles or more and the reason collected during the first 4 h and then from 4 to 8 h,8 to 12 h,and 12 to for discontinuation was mostly due to progressive disease. 24 h. On day 4,urine samples were collected with the same time interval Response and survival. There were 13 partial responses to day 1. Within 10 min of being drawn,the blood was centrifuged at (76.5%; 95% confidence interval,50.1-93.2%),whereas there 1,500 Â g for 10 min at 4jC. The plasma was then transferred to two were 1 stable disease and 3 progressive disease (Table 2). With a j clean opaque polyethylene tubes and stored at -70 C. The 20 mL of urine median follow-up of 22 months (range,16-30),all patients were taken and transferred to two opaque polyethylene tubes and stored progressed and 14 patients died of progressive disease. at -70jC. The concentration of belotecan was measured with validated Therefore,the median progression-free and overall survival assay method independent to investigators (22). Using noncompartmental analysis,individual pharmacokinetic were 7.5 and 15.9 months,respectively (Fig. 1). variables estimated included the area under the time-concentration Pharmacokinetics of belotecan. The pharmacokinetic varia- curve (AUC) from time 0 to the last point measured (AUClast) and bles,obtained from all patients,are listed in Table 4. At the 2 extrapolated to infinity (AUCinf),maximum concentration,systemic dose of 0.50 mg/m /d,the AUC inf and maximum concentra- clearance, h or terminal half-life,volume of distribution at steady state, tion (Cmax) of belotecan were 155.64 F 31.04 hÁAg/L and and fraction of excretion.

Results

Patients’ characteristics. Between July 2004 and September 2005,a total of 17 patients participated in this trial. All of them were actually treated and evaluable for response and toxicity assessment. Patients’ characteristics are shown in Table 1. None of the patients had any prior radiotherapy,although that was not an eligibility criterion. All of them except one had a good performance status with an Eastern Cooperative Oncology Group performance status of 0 or 1. First-cycle DLT. A summary of first-cycle DLTs for all cohorts is shown in Table 2. At the dose level of 0.55 mg/m2/d,two of five patients experienced DLTs of grade 4 neutropenia with fever. The MTD and recommended dose for subsequent phase II 2 trials was determined to be 0.50 mg/m /d when combined with Fig. 1. Kaplan-Meier estimates of progression-free and overall survival. Tick marks, 60 mg/m2 cisplatin. censored data.

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Table 4. Pharmacokinetic results (mean F SD)

Pharmacokinetic variables Dose (mg/m2/d) 0.40 (n = 3) 0.45 (n = 3) 0.50 (n = 6) 0.55 (n =5)

C max (Ag/L) Day 1 58.23 F 12.40 66.47 F 28.73 91.81 F 12.97 91.78 F 69.87 Day 4 47.37 F 1.07 70.78 F 7.23 75.69 F 5.82 86.50 F 49.55

AUCinf (hÁAg/L) Day 1 117.32 F 19.98 111.72 F 21.65 155.64 F 31.04 179.25 F 177.30 Day 4 102.74 F 10.44 115.85 F 13.58 148.06 F 24.94 182.16 F 108.80

Cls (L/h) Day 1 6.00 F 1.50 7.56 F 1.51 5.78 F 1.32 9.16 F 5.51 Day 4 7.36 F 0.83 7.57 F 0.59 6.60 F 1.21 8.50 F 5.40

T 1/2,h (h) Day 1 8.63 F 1.26 5.16 F 3.30 8.55 F 2.12 8.75 F 0.60 Day 4 9.03 F 0.71 6.35 F 4.38 8.74 F 1.11 11.57 F 4.46

V ss (L) Day 1 38.38 F 12.87 31.42 F 16.88 35.02 F 12.35 64.25 F 51.61 Day 4 52.86 F 10.45 35.75 F 19.78 46.68 F 8.68 86.90 F 95.67 Fe (%) Day 1 50.35 F 2.49 38.30 F 7.83 37.36 F 5.55 37.63 F 5.42 Day 4 48.97 F 4.87 40.95 F 7.73 38.36 F 11.22 45.99 F 7.72

Abbreviations: Cmax, maximum concentration; AUCinf, AUC from time 0 to time extrapolated to infinity using the elimination constant; Cls, clearance; T1/2,h, terminal half-life; Vss, volume of distribution at steady state; Fe, fraction of urine excretion.

Fig. 2. The AUC and maximum concentration (Cmax) of belotecan according to the dose level.

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91.81 F 12.97 Ag/L,respectively (Fig. 2). Plasma clearance of schedule of belotecan to preserve antitumor activity on dose- belotecan was 5.78 F 1.32 L/h,with terminal half-life of schedule difference with a higher single dose and more frequent 8.55 F 2.12 h. Fraction of excreted amount in urine was administration. However,modified scheduling,such as admin- 37.36 F 5.55%. Accumulation index showed that there was istration for consecutive 3 days or on a weekly basis,can be more no accumulation of belotecan by repetitive administration for convenient. A weekly-based regimen of belotecan is currently 4 days,which might be due to the short half-life of this agent. being studied. On the other hand,given the high single-agent Pharmacokinetics of belotecan was not altered by adminis- activity of belotecan against SCLC (17),a regimen with a tration of cisplatin compared with historical control (14). higher dose of belotecan and a lower dose of cisplatin seemed likely to be more effective. In addition,recently conducted trials 2 Discussion used 60 mg/m cisplatin for the combination of irinotecan or topotecan (8,11,12,19). This phase I study was designed not only to determine the We observed encouraging antitumor activity against SCLC with MTD of belotecan in combination with cisplatin but also to a response rate of 76.5% and a median survival of 15.9 months, evaluate the preliminary antitumor activity against SCLC. The although overinterpretation of efficacy should be cautioned in DLT of grade 4 neutropenia with fever occurred at the dose view of the small number of patients and inherent nature of phase level of 0.55 mg/m2/d,and the MTD and recommended dose for I study. We also observed favorable toxicity profile,especially subsequent phase II studies of belotecan was determined at the nonhematologic toxicity profile. During a total of 103 cycles, dose level of 0.50 mg/m2/d. We also observed that belotecan did grade 3 or higher nonhematologic toxicities were observed in only not accumulate by repetitive administration and its pharmaco- four patients. This favorable toxicity profile seemed to enable this kinetics did not alter by administration of cisplatin. regimen be given six cycles or more in all responders. Of course, In the current study,we had selected the initial dose of belo- ideally,after having defined the recommended dose level,more tecan (0.4 mg/m2/d) for 4 days with a total dose of 1.6 mg/m2, patients should be included and treated accordingly in further in spite that the MTD in the phase I study was 0.7 mg/m2/d studies to strengthen data on toxicity at the recommended dose. for 5 days with a total dose of 3.5 mg/m2,and fixed dose of In conclusion,in this phase I study,the DLT was grade 4 cisplatin (60 mg/m2),which was also rather lower than the usual neutropenia with fever,and the MTD and recommended dose dose of 80 to 100 mg/m2. In the preclinical study,intermittent for subsequent phase II studies of belotecan was determined to dosing at the MTD level of belotecan showed more efficacious be 0.50 mg/m2/d on days 1 to 4 in combination with cisplatin than single bolus injection (13),whereas in phase I and II clinical (60 mg/m2) on day 1 every 3 weeks in chemotherapy-naive trials,grade 3 or 4 neutropenia requiring dose modification or patients. In addition,considering the preliminary data on anti- treatment delay was observed in most courses of single-agent tumor activity and toxicity profile,a subsequent phase II trial belotecan treatment,although that was brief and rarely was strongly warranted in patients with extensive-stage disease associated with fever (16,17). Therefore,we used a 4-day SCLC and is already in progress.

References 1. Fukuoka M, Furuse K, Saijo N, et al. Randomized trial tive Study Group. Gan To Kagaku Ryoho 1991;18: camptothecin derivative. Ann N Y Acad Sci 2000; of cyclophosphamide, doxorubicin and vincristine ver- 1013 ^ 9. 922:324 ^ 5. sus cisplatin and etoposide versus alteration of these 8. Noda K, Nishiwaki Y, Kawahara M, et al. Irinotecan 15. Sasaki Y, Shinkai T, Eguchi K, et al. Prediction of the regimens in small cell lung cancer. J Natl Cancer Inst plus cisplatin compared with etoposide plus cisplatin antitumor activity of new platinum analogs based on 1991;83:855 ^ 61. for extensive small-cell lung cancer. N Engl J Med their ex vivo pharmacodynamics as determined by bio- 2. Roth BJ, Johnson D, Einhorn L, et al. Randomized 2002;346:85 ^ 91. assay. Cancer Chemother Phamacol 1991;27:263 ^ 70. study of cyclophosphamide, doxorubicin and vincris- 9. Mavroudis D, Papadakis E, Veslemes M, et al. A 16. Kim HK, BangYJ, Heo DS, et al. Phase I trial of CKD- tine versus etoposide and cisplatin versus alternation multicenter randomized clinical trial comparing pac- 602, a novel camptothecin derivative, in patients with of these two regimens in extensive small cell lung can- litaxel-cisplatin-etoposide versus cisplatin-etoposide advanced solid tumors [abstract 393]. Proc Am Soc cer. A phase III trial of the Southeastern Cancer Study as first-line treatment in patients with small-cell lung Clin Oncol 2002;21. Group. J Clin Oncol 1992;10:281 ^ 92. cancer. Ann Oncol 2001;12:463 ^ 70. 17. Lee JH, Lee SJ, Kim JS, et al. Phase II trial of CKD- 3. Chute JP, Chen T, Feigal E, et al. Twenty years of 10. Niell HB, Herndon JE, Miller AA, et al. Randomized 602, a new camptothecin analogue, in patients with phase III trials for patients with extensive-stage small- phase III intergroup trial (CALGB 9732) of etoposide small cell lung cancer (SCLC) [abstract 7210]. Proc cell lung cancer: perceptible progress. J Clin Oncol (VP-16) and cisplatin (DDP) with or without paclitaxel Am Soc Clin Oncol 2004;22. 1999;17:1794^801. (TAX) and G-CSF in patients with extensive-stage 18. Masuda N, Fukuoka M, Kudoh S, et al. Phase I and 4. Sundstrom S, Bremnes RM, Kaasa S, et al. Cisplat- small cell lung cancer (ED-SCLC) [abstract 1169]. pharmacologic study of irinotecan in combination in and etoposide regimen is superior to cyclophos- Proc Am Soc Clin Oncol 2002;21. with cisplatin for advanced lung cancer. Br J Cancer phamide, epirubicin, and vincristine regimen in 11. Eckardt JR, von Pawel J, Papai Z, et al. Open-label, 1993;68:777 ^ 82. small-cell lung cancer: results from a randomized multicenter, randomized, phase III study comparing 19. Kudoh S, FujiwaraY,TakadaY,et al. Phase II study of phase III trial with 5 years’ follow-up. J Clin Oncol oral topotecan/cisplatin versus etoposide/cisplatin as irinotecan combined with cisplatin in patients with 2002;20:4665^72. treatment for chemotherapy-naI« ve patients with previously untreated small cell lung cancer. J Clin 5. Ettinger DS, Finkelstein DM, Sarma RP, et al. Phase extensive-disease small-cell lung cancer. J Clin Oncol Oncol 1998;16:1068^ 74. II study of paclitaxel in patients with extensive- 2006;24:2044^51. 20. National Cancer Institute. Cancer Therapy Evalu- disease small cell carcinoma of the lung: an Eastern 12. Hanna NH, Bunn PA, Langer C, et al. Randomized ation Program, Common Toxicity Criteria, version Cooperative Oncology Group Study. J Clin Oncol phase III trial comparing irinotecan/cisplatin with eto- 2.0. Bethesda (MD): National Cancer Institute; 1995;13:1430^5. poside/cisplatin in patients with previously untreated 1999. 6. Schiller JH, Kim KM, Hutson P, et al. Phase II extensive-stage disease small-cell lung cancer. J Clin 21. World Health Organization. Handbook for reporting study of topotecan in patients with extensive-stage Oncol 2006;24:2038^43. results of cancer treatment. WHO Offset Publication small-cell carcinoma of the lung: an Eastern Coop- 13. Lee JH, Lee JM, Kim JK, et al. Antitumor activity of No. 48. Geneva (Switzerland): World Health Organi- erative Oncology Group Trial. J Clin Oncol 1996;14: 7-[2(N-isopropylamino)ethyl]-(20S)-camptothecin, zation; 1979. 2345 ^ 52. CKD602, as a potent DNA topoisomerase I inhibitor. 22. ChoJY,SeoHB,YuKS,etal.Simpleandsensitive 7. Negoro S, Fukuoka M, Niitani H, et al. A phase II Arch Pharm Res 1998;21:581 ^ 90. determination of the new antitumor drug CKD-602 in study of CPT-11, a camptothecin derivative in 14. Lee JH, Lee JM, Lim KH, et al. Preclinical and human plasma by liquid chromatography. J Chroma- patients with primary lung cancer. CPT-11 Coopera- phase I clinical studies with CKD-602, a novel togr B 2003;784:25 ^ 31.

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Dae Ho Lee, Sang-We Kim, Kyun-Seop Bae, et al.

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