Annals of Oncology Advance Access published online on September 6, 2007
Annals of Oncology, doi:10.1093/annonc/mdm437
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© 2007 European Society for Medical Oncology
Belotecan, new camptothecin analogue, is active in patients with small-cell lung cancer: results of a multicenter early phase II study
1 Division of Oncology, Department of Internal medicine, Asan Medical Center, Seoul
2 Department of Hematology & Oncology, Chung-Ang University Medical Center, Seoul
3 Department of Hemato-oncoloogy, Korea Cancer Center Hospital, Seoul
4 Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Seoul
5 Department of Oncology and Hematology, Korea University Medical Center, Seoul
6 Division of Hematology/Medical Oncology, Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea
* Correspondence to: Dr J.-S. Lee, Division of Oncology, Department of Internal Medicine, University of Ulsan, College of Medicine, Asan Medical Center, 388-1 Pungnap-2 dong, Songpa-gu, Seoul 138-736, Korea. Tel: +82-2-3010-3212; Fax: +82-2-3010-6961; E-mail: jayslee{at}amc.seoul.kr
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Abstract |
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Background: Belotecan (Camtobell®, Chong Keun Dang Corp, Seoul, Korea; CKD602) is a new camptothecin analogue. This study aimed to investigate the safety and efficacy of single-agent belotecan for small-cell lung cancer (SCLC).
Patients and methods: Twenty-seven patients with chemotherapy-naive or chemosensitive SCLC were treated with belotecan 0.5 mg/m2/day on days 1–5 of a 3-week cycle. All 27 patients were assessable for toxicity, and 21 patients assessable for response.
Results: Nine patients (42.9%) showed objective tumor responses including one complete response; seven (63.6%) in 11 chemotherapy-naive patients; and two (20.0%) in 10 chemosensitive patients. With a median follow-up of 5 years, median progression-free and survival time for chemotherapy-naive patients were 4.8 months and 11.9 months, respectively, while the corresponding values for chemosensitive patients were 3.3 months and 10.5 months, respectively. The most common toxicity was neutropenia.
Conclusion: Belotecan was active in SCLC patients as a single agent, warranting further investigations of belotecan in combination with platinum or other active agents.
belotecan, single agent, small-cell lung cancer
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introduction |
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TopAbstractintroductionpatients and methodsresultsdiscussionfundingAcknowledgementsReferences |
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Combination chemotherapy is the main treatment for small-cell lung cancer (SCLC). In limited-stage SCLC with good performance status, combination chemotherapy plus thoracic radiotherapy achieved median survival in excess of 17 months and 5-year survival rate of 12%–17% [1–3], while in extensive-stage disease, combination chemotherapy achieved median survival of 7–12 months and 5-year survival rate of only 1%–2% [4, 5]. Despite high responsiveness to initial chemotherapy, >95% of patients with SCLC will die of their disease [4].
Belotecan (Camtobell®; CKD602, 7-[-2(N-isopropylamino)ethyl]-(20S)-camptothecin, Chong Keun Dang Corp., Seoul, Korea) is a new camptothecin analogue, in which a water-solubilizing group is introduced at position of the B ring. In the preclinical studies, belotecan was a more potent topoisomerase I inhibitor and had superior antitumor activity to camptothecin and topotecan (Hycamtin®, GlaxoSmithKlein, Brentford, UK) in six human tumor xenografts [6]. In a phase I study of belotecan, the maximum-tolerated dose was 0.7 mg/m2/day when given intermittently for five consecutive days every 3 weeks and dose-limiting toxicity was neutropenia [7]. Based on those preclinical and phase I studies, we conducted a multicenter early phase II study to investigate the efficacy and toxicity profile of single-agent belotecan in patients with SCLC.
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patients and methods |
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eligibility
The main eligibility criteria included histologically confirmed SCLC, chemotherapy-naive patients with extensive disease (group 1) or those who responded to first-line chemotherapy and progressed after response duration of 3 months or more (group 2), and Karnofsky performance score of >60%. The other inclusion criteria were as follows: age 18–70; at least one bidimensional measurable lesions; adequate bone marrow, hepatic and renal functions defined as white blood cells
4000/mm3, absolute neutrophil count (ANC) 1500/mm3, platelet count 100 000/mm3, hemoglobin 9 g/dl, alanine aminotransferase/aspartate aminotransferase 
2.0 times the upper normal limit, serum bilirubin 1.5 mg/dl, and serum creatinine 1.5 mg/dl. Brain metastasis was not allowed. Prior chemotherapy with topoisomerase inhibitors such as topotecan and irinotecan (Campto®; Pfizer, NY) was also not allowed. All patients gave a written informed consent approved by the Institutional Review Board or Ethical Committee of all participating institutions. The study was carried out in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines.
study design
This was an open-label, multicenter, early phase II study of single belotecan for patients with extensive disease SCLC. Belotecan was to be diluted in a total volume of 100 ml of 5% dextrose water injection and administered i.v. >30 min once a day on days 1–5 of a 3-week course. In a phase I study, we observed the pharmacokinetic parameter variations of 30%–40% among the patients, which tended to be correlated with toxicity grade of neutropenia. Therefore, the dose of belotecan would be 0.5 mg/m2/day at the first cycle, but a dose adjustment for the subsequent cycles would be made according to the greatest degree of toxicity developed during the first cycle. However, after the dose adjustment would be made, further dose increment or reduction would not be allowed. The dose would be adjusted as follows: the dose would be decreased to 0.4 mg/m2/day when (i) ANC nadir of <500/mm3 for 4 days or more, (ii) febrile neutropenia, (iii) platelet nadir of <50 000/mm3 for 4 days or more, (iv) thrombocytopenia associated with bleeding episode or requiring transfusion, or (v) grade 3 or higher non-hematologic toxicity except alopecia nausea, and vomiting; the dose would be increased to 0.6 mg/m2/day when ANC nadir of 1000/mm3, platelet nadir of 75 000/mm3 and no grade 3 non-hematologic toxicity; otherwise, the same dose of 0.5 mg/m2/day was given. A new scheduled cycle could be administered if ANC was 1500 mm3, platelets was 100 000/mm3, and all non-hematologic toxic effects except alopecia, nausea, and vomiting recovered to grade 0 or 1. Otherwise, a new cycle should be delayed for up to 2 weeks. The treatment could be given until progressive disease (PD), unacceptable toxicity including treatment interruption for >2 weeks, or patient's withdrawal.
As a baseline, all patients underwent a complete history and physical examination, including documentation of concomitant medications, performance status and history of smoking, laboratory tests (complete blood count, biochemistry profile, and urinalysis), and electrocardiogram within 14 days before the study entry. Chest X-ray, computed tomography scans of chest (including upper abdomen), magnetic resonance imaging of brain, and radionuclide bone scan were carried out within 4 weeks before the study entry.
response and toxicity assessment
Tumor response was assessed every two cycles using World Health Organization criteria [8]. A complete response (CR) was defined as the disappearance of all known disease for 4 weeks with no new lesions appearing. A partial response (PR) was defined as a 50% reduction in the diameter product (product of two perpendicular diameters) of all measurable lesions with a response of 4 weeks in duration with no new lesions appearing. Stable disease (SD) was defined as a <50% reduction or <25% increase in the diameter product of all measurable lesions without the appearance of new lesions. PD was defined as an increase 25% in the diameter of all measurable disease or the appearance of new lesions. Toxicity was graded on days 5, 10, 14, and 18 in the first cycle, and then every cycle using National Cancer Institute—Common Toxicity Criteria v.2.0 [9]. Duration of response was defined as the interval between the date of documented response and the date of documented disease progression. Progression-free survival (PFS) was defined as the interval between the date treatment started and the date of documented disease progression or death from any cause. Overall survival (OS) was defined as the interval between the date treatment started and the date of death due to any cause. If a patient was lost to follow-up that patient was censored at the last date of contact.
statistical consideration
Group sequential design of Chang et al. was used to determine the sample size and decision criteria for this phase II study [10]. With the target activity level of 15% and the lowest response rate of interest set at 5%, the study was designed with three stages to have an 80% power to accept the hypothesis and a 5% significance level to reject the hypothesis. During the first stage, if four or more responses were observed in the first 20 patients, the study was stopped and further investigation was warranted and if there was no response, the study was also stopped early with no further investigation. Otherwise, we would enroll 15 more patients. If five or more responses were observed in a total of 35 patients, we stopped the study to conduct further investigation, while if there was no or one response, the study was stopped with no further investigation. Otherwise, we enroll 15 more patients again. If at least six responses were observed, we would conclude that belotecan has clinical activity against SCLC. Confidence intervals (CIs) were calculated using binomial CI and comparisons of results were carried out with 
2 test. OS and PFS and duration of response were calculated using the Kaplan–Meier method. Data were updated as of 10 April 2007.
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patients' characteristics
From October 2001 to December 2002, a total of 27 patients were entered into the study; 15 were in group 1 and 12 in group 2. The characteristics of the patients are listed in Table 1. Out of 27 patients, 21 were assessable for overall response rate. However, all patients received at least one cycle and were assessable for toxicity. The dose for the subsequent cycles was adjusted to 0.6 mg/m2/day in seven patients, 0.5 mg/m2/day in 10 patients, and 0.4 mg/m2/day in four patients.
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response and survival outcome
Six patients were not assessable; one died as a result of pneumothorax and pneumonia before the commencement of the second cycle; one who had a history of convulsion disorder had a confusion during the first cycle and did not receive further treatment although no metastasis to the central nervous system or cerebrospinal fluid was identified; two investigators inadvertently gave other therapy in one patient each; one withdrew consent after one cycle; and one did not receive treatment due to persistent neutropenia lasting >2 weeks. Of 21 patients assessable, nine had an objective tumor response, including one CR, for an overall response rate of 42.9% (Table 2). Although statistical significance was not reached, the patients in group 1 had a higher response rate of 63.6% compared with that of group 2 of 20.0% (P = 0.08). With a median follow-up of 5 years, median progression-free and survival time for group 1 were 4.8 months and 11.9 months, respectively, while the corresponding values for group 2 were 3.3 months and 10.5 months, respectively (Figure 1). The median progression-free and survival time for all patients were 4.6 months and 11.4 months, respectively. The median response duration of nine responders was 6.9 months.
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toxicity profile
The toxicity was evaluated in all 27 patients with a total of 103 cycles (median four cycles, range 1–11 cycles) given. According to the dose level, there was no difference in the toxicity profile (data not shown). The major observed toxicity was hematologic (Table 3). Grade 3 or 4 neutropenia developed in 20 patients (74%) and in 42 cycles (41%) while grade 3 or 4 thrombocytopenia developed in eight patients (30%) and nine cycles (9%). Grade 3 or 4 non-hematologic toxic effects were uncommon.
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salvage treatments after progression
Out of 11 chemotherapy-naive patients, eight patients received salvage chemotherapies, including etoposide and platinum combination as second-line treatment, and all reached a PR or SD, while out of 10 chemosensitive patients, seven patients received salvage chemotherapies, such as cyclophosphamide, doxorubicin and vincristine or taxane-based regimens, and six patients, interestingly, reached again a PR or SD.
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discussion |
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Belotecan is a new camptothecin analogue and inhibits topoisomerase I potently [6]. In this phase II study, we observed promising antitumor activity against SCLC with an overall response rate of 42.9% and the median survival of 11.4 months. Although we did not find the differences between chemotherapy-naive and chemosensitive patients groups in terms of survival outcomes, which might be mainly due to small sample size, a high response rate of up to 63.6% was observed in chemotherapy-naive patients. Camptothecin derivatives, such as topotecan and irinotecan, have been evaluated for SCLC. In phase II studies of single-agent topotecan, the response rate was reportedly 39% in chemotherapy-naive patients with extensive-stage disease (ED) SCLC [11], while the corresponding values were 24%–37% in chemotherapy-sensitive patients with ED SCLC [12, 13]. In phase II studies of irinotecan, the response rate was reportedly 50% in chemotherapy-naive patients [14] and 33%–47% in previously treated patients [14, 15]. Compared with other camptothecin analogs, belotecan showed promising antitumor activity. In terms of toxicity, although neutropenia was most common, it was reversible, not cumulative, and generally manageable, while other non-hematologic toxicity was very favorable. Of interest, the incidence of mild diarrhea was 7% but there was no grade 3 or 4 diarrhea, compared with that of grade 3 or 4 diarrhea for topotecan ranging from 1% to 7% and for irinotecan ranging from 11% to 22% [13, 16–19].
The platinum-based combination chemotherapy is widely accepted as first-line treatment of choice for ED SCLC. In addition, irinotecan and cisplatin combination showed survival advantage in Japan [20], although a subsequent trial failed to confirm the survival benefit of this regimen over etoposide and cisplatin combination regimen [21]. Given a high response rate in chemotherapy-naive patients, further investigations on how to integrate belotecan into first-line therapy in combination with platinum as well as other established agents, such as etoposide and paclitaxel, are warranted in first-line setting. For patients with poor performance status or comorbid disease who cannot tolerate current platinum-based chemotherapy, single-agent belotecan therapy could be a very attractive option considering our acceptable toxicity profile, and further studies for those subsets of patients are needed.
In conclusion, belotecan, a new camptothecin analogue, was active and promising in SCLC patients, especially chemotherapy-naive, which warrants further investigations of belotecan in combination with other active agents. Single-agent belotecan can also be considered for patients with poor performance status or comorbid diseases.
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This work was supported, in part, by a grant from Korea Health 21 R&D Project; Ministry of Health and Welfare; Republic of Korea (A060775).
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Belotecan (Camtobell®; CKD602) was kindly provided by Chong Keun Dang Corp., Seoul, Korea. This paper was presented in part at the 40th Annual Meeting of the American Society of Clinical Oncology, New Orleans, LA, 5–8 June 2004.
Received for publication June 12, 2007. Revision received July 28, 2007. Accepted for publication August 2, 2007.
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