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Clinical Cancer Research 13, 6182, October 15, 2007. doi: 10.1158/1078-0432.CCR-07-0534
© 2007 American Association for Cancer Research
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Cancer Therapy: Clinical

A Phase I and Pharmacologic Study of Belotecan in Combination with Cisplatin in Patients with Previously Untreated Extensive-Stage Disease Small Cell Lung Cancer

Dae Ho Lee1, Sang-We Kim1, Kyun-Seop Bae2, Jeong-Sook Hong1, Cheolwon Suh1, Yoon-Koo Kang1 and Jung-Shin Lee1

Authors' Affiliations: 1 Division of Oncology, Department of Internal Medicine and 2 Department of Clinical Pharmacology and Therapeutics, University of Ulsan, College of Medicine, Asan Medical Center, Seoul, Korea

Requests for reprints: Jung-Shin 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. Phone: 82-2-3010-3212; Fax: 82-2-3010-6961; E-mail: jayslee{at}amc.seoul.kr.


   Abstract
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 Abstract
Materials and Methods
 Results
 Discussion
 References
 
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 preliminary antitumor activity against SCLC were evaluated.

Experimental Design: Belotecan was administered i.v. as intermittent 30-min infusions on days 1 to 4, starting dose of 0.40 mg/m2/d with increment of 0.05 mg/m2/d. Intrapatient dose escalation 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 treated. The MTD of belotecan was 0.50 mg/m2/d with the dose-limiting toxicity of grade 4 neutropenia 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 analysis revealed that, at the dose of 0.50 mg/m2/d, plasma clearance of belotecan was 5.78 ± 1.32 L/h and terminal half-life was 8.55 ± 2.12 h. Fraction of excreted amount in urine was 37.36 ± 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 1 to 4 in combination with 60 mg/m2 cisplatin on day 1 every 3 weeks.

Combination chemotherapy remains the main treatment of patients with extensive-stage disease small cell lung cancer (SCLC). Etoposide and cisplatin combination has been used as a standard treatment. However, although initial response rates to etoposide-cisplatin combination were up to 80%, the median survival time of patients treated with etoposide-cisplatin regimen was reportedly only 8 to 9 months and 2-year survival of 4% (1–4). Several new drugs, such as paclitaxel, topotecan, and irinotecan, were shown to be active in chemotherapy-naive or chemosensitive patients with SCLC, in which the response rates had reached 40% (5–7). However, except the Japanese trial (8), new regimens containing these new drugs failed to show the survival benefit compared with the standard etoposide-cisplatin regimen (9–11). Irinotecan and cisplatin regimen showed survival advantage in Japan (8), but a subsequent trial in Western countries failed to confirm the survival benefit of this regimen over etoposide-cisplatin regimen (12).

Belotecan [Camtobell, CKD602, 7-[2-(N-isopropylamino)ethyl]-(20S)-camptothecin, Chong Keun Dang Corp.] is a novel camptothecin derivative, in which a water-solubilizing group is introduced at position of the B ring (13). The preclinical 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-diphenyltetrazolium bromide cell cytotoxicity assay and six human tumor xenografts (13, 14). Of interest, the mean ATI values of belotecan were over 2-fold higher than those of topotecan, suggesting that this drug would show encouraging antitumor activity in a clinical study. Although several in vitro and in vivo test systems developed to predicting the clinical activity have some limitations, the ATI values, defined as the area under the inhibition ratio (%) versus time curve plotted from 0 to 240 min as obtained by ex vivo pharmacodynamic assay and calculated by trapezoidal rule, showed a good clinical correlation with the clinical response (15). In a phase I study, the maximum tolerated dose (MTD) of single-agent belotecan was 0.7 mg/m2/d when given i.v. daily for 5 consecutive days every 3 weeks and the dose-limiting toxicity (DLT) was neutropenia (16). A subsequent phase II study of single-agent belotecan in extensive-stage disease SCLC showed a promising response rate of 46.6%, especially that of 63.6% in chemotherapy-naive patients (17). Based on those findings, we conducted the phase I study of belotecan in combination with cisplatin in patients with previously untreated extensive-stage disease SCLC. The main objectives were to determine the MTD and pharmacokinetics of belotecan and the toxicity profile of this combination. We also studied preliminary antitumor activity against SCLC.


   Materials and Methods
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 Materials and Methods
Results
 Discussion
 References
 
Eligibility criteria. Eligible patients had histologically or cytologically confirmed SCLC and evidence of extensive-stage disease defined as either disease not encompassed in a reasonable radiation port or extrathoracic disease. Patients had to meet the following criteria: age of 18 to 70 years; Eastern Cooperative Oncology Group performance status of 0 to 2; no prior chemotherapy; bidimensionally measurable disease(s); total WBC count ≥4,000/mm3; absolute neutrophil count ≥1,500/mm3; hemoglobin ≥9 g/dL; platelet count ≥100,000/mm3; total bilirubin ≤1.5 mg/dL; aspartate aminotransferase/alanine aminotransferase each ≤2 times the upper limits of normal; and serum creatinine ≤1.5 mg/dL or calculated (i.e., Cockcroft-Gault equation) creatinine clearance ≥60 mL/min. Exclusion criteria were as follows: previous or concurrent malignancy (except nonmelanoma skin cancer, in situ carcinoma of the cervix or breast, or other cancer if the patient has been disease-free for 5 years), a serious medical or psychiatric illness preventing informed consent, or survival limited to <2 months. Prior radiation was allowed at the discretion of treating physician. The study was approved by the Institutional Review Board at the Asan Medical Center before subject enrollment and was done in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. Written informed consent was obtained from all patients before study procedures.

Treatment plan. Before treatment, all patients had a complete history and physical examination, complete blood count with differential, electrolytes, glucose, liver, and renal function tests, staging chest and upper abdominal computed tomography scan, and bone scan.

Belotecan would be administered as a 30-min i.v. infusion on days 1 to 4, starting dose of 0.40 mg/m2/d with increment of 0.05 mg/m2/d. The dose escalation proceeded in cohorts of three patients if no DLT was observed. Intrapatient dose escalation was not allowed. Cisplatin was administered i.v. over 2 h on day 1 with a fixed dose of 60 mg/m2, which had been chosen in the trials of irinotecan or topotecan-cisplatin combination (8, 11, 12, 18, 19). DLT was determined during the first cycle only and defined as follows: grade 4 neutropenia (absolute neutrophil count <500/mm3) lasting 7 days; grade 4 neutropenia with fever (≤38.5°C) or sepsis; grade 4 thrombocytopenia (platelet <10,000/mm3); and grade 3 or 4 nonhematologic toxicity other than 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 dose level; if one of three patients had DLT, up to three additional patients were entered at that dose level, and if none of the second 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, dose escalation ceased and the next lower level was called the MTD.

The cycle length was planned to be 21 days. Absolute neutrophil count and platelet count were required to be at least 1,500/mm3 and 100,000/mm3, respectively, for subsequent cycles. If count recovery had not occurred by day 21, patients were required to delay the subsequent cycle by 1 week. If a patient required >35 days for hematologic recovery 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 discretion of treating physician.

Toxicity and efficacy assessment. Patients were evaluated weekly for toxicity during the first cycle and then every cycle thereafter using the National Cancer Institute Common Toxicity Criteria version 2.0 (20). Patients were evaluated for response every two cycles according to WHO response criteria (21). Complete response was defined as disappearance of all known disease for at least 4 weeks with no new lesion appearing. Partial response was defined as at least 50% decrease in the sum of the products of bidimensional diameters for at least 4 weeks without the appearance of new lesions. Stable disease was defined as failure to observe a partial response or complete response, with no progressive or new lesions observed for at least 4 weeks. Progressive disease was defined as a 25% or greater increase in the products of bidimensional diameters of any measurable lesion or the appearance of new lesions. Progression-free survival was defined as the interval between the date of the start of treatment and the date of documented disease progression or death from any cause. Overall survival was defined as the interval between the date of the start of treatment 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. All patients who were enrolled and received drug were included in the toxicity analysis. Data were updated as of January 31, 2007.

Belotecan pharmacokinetics. To estimate pharmacokinetics of belotecan, blood and urine were obtained from the patients at the first cycle only. On day 1, blood samples were taken immediately before, 15 min, 30 min, 45 min, 1 h, 2 h, 4 h, 8 h, and 12 h after administration of belotecan. On days 2 and 3, they were taken only before administration 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 administration of belotecan. Spot urine samples were taken before administration of belotecan. Additionally, on day 1, urine samples were collected during the first 4 h and then from 4 to 8 h, 8 to 12 h, and 12 to 24 h. On day 4, urine samples were collected with the same time interval to day 1. Within 10 min of being drawn, the blood was centrifuged at 1,500 x g for 10 min at 4°C. The plasma was then transferred to two clean opaque polyethylene tubes and stored at –70°C. The 20 mL of urine were taken and transferred to two opaque polyethylene tubes and stored at –70°C. The concentration of belotecan was measured with validated assay method independent to investigators (22).

Using noncompartmental analysis, individual pharmacokinetic variables estimated included the area under the time-concentration curve (AUC) from time 0 to the last point measured (AUClast) and extrapolated to infinity (AUCinf), maximum concentration, systemic clearance, ß or terminal half-life, volume of distribution at steady state, and fraction of excretion.


   Results
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 Materials and Methods
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Discussion
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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.


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  		Table 1. Patients' characteristics

 
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 trials was determined to be 0.50 mg/m2/d when combined with 60 mg/m2 cisplatin.


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  		Table 2. DLT and best overall response for all cohorts

 
Toxicity during all cycles of therapy. Table 3 shows the toxicity observed during the treatment for all cohorts with a total of 103 cycles (median, 6 cycles; range, 2-9). Of 17 patients, 16 (94%) had grade 3 or 4 hematologic toxicity, whereas only 4 patients had grade 3 or 4 nonhematologic toxicity. The most common nonhematologic toxicities were hyponatremia followed by febrile neutropenia, but which was manageable by supportive care. Of interest, all responders received six cycles or more and the reason for discontinuation was mostly due to progressive disease.


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  		Table 3. Toxicity profiles (n = 17)

 
Response and survival. There were 13 partial responses (76.5%; 95% confidence interval, 50.1-93.2%), whereas there were 1 stable disease and 3 progressive disease (Table 2). With a median follow-up of 22 months (range, 16-30), all patients progressed and 14 patients died of progressive disease. Therefore, the median progression-free and overall survival were 7.5 and 15.9 months, respectively (Fig. 1 ).


Figure 1
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  		Fig. 1. Kaplan-Meier estimates of progression-free and overall survival. Tick marks, censored data.

 
Pharmacokinetics of belotecan. The pharmacokinetic variables, obtained from all patients, are listed in Table 4 . At the dose of 0.50 mg/m2/d, the AUCinf and maximum concentration (Cmax) of belotecan were 155.64 ± 31.04 h·µg/L and 91.81 ± 12.97 µg/L, respectively (Fig. 2 ). Plasma clearance of belotecan was 5.78 ± 1.32 L/h, with terminal half-life of 8.55 ± 2.12 h. Fraction of excreted amount in urine was 37.36 ± 5.55%. Accumulation index showed that there was no accumulation of belotecan by repetitive administration for 4 days, which might be due to the short half-life of this agent. Pharmacokinetics of belotecan was not altered by administration of cisplatin compared with historical control (14).


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  		Table 4. Pharmacokinetic results (mean ± SD)

 

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

 

   Discussion
Top
 Abstract
 Materials and Methods
 Results
 Discussion
References
 
This phase I study was designed not only to determine the MTD of belotecan in combination with cisplatin but also to evaluate the preliminary antitumor activity against SCLC. The DLT of grade 4 neutropenia with fever occurred at the dose level of 0.55 mg/m2/d, and the MTD and recommended dose for subsequent phase II studies of belotecan was determined at the dose level of 0.50 mg/m2/d. We also observed that belotecan did not accumulate by repetitive administration and its pharmacokinetics did not alter by administration of cisplatin.

In the current study, we had selected the initial dose of belotecan (0.4 mg/m2/d) for 4 days with a total dose of 1.6 mg/m2, in spite that the MTD in the phase I study was 0.7 mg/m2/d for 5 days with a total dose of 3.5 mg/m2, and fixed dose of cisplatin (60 mg/m2), which was also rather lower than the usual dose of 80 to 100 mg/m2. In the preclinical study, intermittent dosing at the MTD level of belotecan showed more efficacious than single bolus injection (13), whereas in phase I and II clinical trials, grade 3 or 4 neutropenia requiring dose modification or treatment delay was observed in most courses of single-agent belotecan treatment, although that was brief and rarely associated with fever (16, 17). Therefore, we used a 4-day schedule of belotecan to preserve antitumor activity on dose-schedule difference with a higher single dose and more frequent administration. However, modified scheduling, such as administration for consecutive 3 days or on a weekly basis, can be more convenient. A weekly-based regimen of belotecan is currently being studied. On the other hand, given the high single-agent activity of belotecan against SCLC (17), a regimen with a higher dose of belotecan and a lower dose of cisplatin seemed likely to be more effective. In addition, recently conducted trials used 60 mg/m2 cisplatin for the combination of irinotecan or topotecan (8, 11, 12, 19).

We observed encouraging antitumor activity against SCLC with a response rate of 76.5% and a median survival of 15.9 months, although overinterpretation of efficacy should be cautioned in view of the small number of patients and inherent nature of phase I study. We also observed favorable toxicity profile, especially nonhematologic toxicity profile. During a total of 103 cycles, grade 3 or higher nonhematologic toxicities were observed in only four patients. This favorable toxicity profile seemed to enable this regimen be given six cycles or more in all responders. Of course, ideally, after having defined the recommended dose level, more patients should be included and treated accordingly in further studies to strengthen data on toxicity at the recommended dose.

In conclusion, in this phase I study, the DLT was grade 4 neutropenia with fever, and the MTD and recommended dose for subsequent phase II studies of belotecan was determined to be 0.50 mg/m2/d on days 1 to 4 in combination with cisplatin (60 mg/m2) on day 1 every 3 weeks in chemotherapy-naive patients. In addition, considering the preliminary data on antitumor activity and toxicity profile, a subsequent phase II trial was strongly warranted in patients with extensive-stage disease SCLC and is already in progress.


   Footnotes
 
Grant support: Korea Health 21 R&D Project, Ministry of Health and Welfare, Republic of Korea (A060775). Belotecan was provided by Chong Keun Dang Corp., Seoul, Korea.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 3/ 6/07; revised 7/ 3/07; accepted 8/ 8/07.


   References
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 Abstract
 Materials and Methods
 Results
 Discussion
 References
 

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