Belotecan for relapsing small-cell lung cancer patients initially treated with an irinotecan-containing chemotherapy: A phase II trial

Lung Cancer 70 (2010) 77–81

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Belotecan for relapsing small-cell lung cancer patients initially treated with an irinotecan-containing chemotherapy: A phase II trial Jaeheon Jeong a,b,c , Byoung Chul Cho a,b , Joo Hyuk Sohn a,b , Hye Jin Choi a,b , Se Hyun Kim a,b , Young Joo Lee c , Min Kyu Jung a,b , Sang Joon Shin a,b , Moo-Suk Park b , Se Kyu Kim b , Joon Chang b , Joo Hang Kim a,b,∗ a

Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Republic of Korea Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea c Center for Clinical Trials, National Cancer Center, Goyang-si, Gyeonggi-do, Republic of Korea b

a r t i c l e

i n f o

Article history: Received 25 August 2009 Received in revised form 5 January 2010 Accepted 7 January 2010 Keywords: Belotecan SCLC Topoisomerase I inhibitor

a b s t r a c t Background: Belotecan is a topoisomerase I inhibitor. This phase II trial was conducted to evaluate the efficacy and toxicity of belotecan in relapsing small-cell lung cancer (SCLC) patients after irinotecan failure. Patients and methods: SCLC patients, who had relapsed at least 3 months after achieving objective response to irinotecan plus platinum chemotherapy, were eligible. Belotecan was administered at a dose of 0.5 mg/m2 /day for 5 consecutive days every 3 weeks. Results: Twenty-seven patients were enrolled in this study. Twenty-five patients were evaluated for response, and 27 patients were evaluated for toxicity and survival. The overall response rate was 22%. The median time to progression was 4.7 months (95% CI, 3.6–5.8 months), and the median overall survival was 13.1 months (95% CI, 10.4–15.8 months). The most frequent grade 3/4 toxicities were neutropenia (93%) and thrombocytopenia (48%). There was one treatment-related death due to pneumonia. Conclusion: Belotecan showed modest activity and manageable toxicities in relapsing SCLC patients in this study which was conducted in Asia. But further study in Caucasian patients is needed. © 2010 Elsevier Ireland Ltd. All rights reserved.

1. Introduction In limited-stage (LD) SCLC, etoposide and cisplatin plus concurrent thoracic radiotherapy is the current standard of care [1], while in extensive-stage (ED) disease, platinum-based chemotherapy is the mainstay, based on two large meta-analyses [2]. Etoposide is the preferable platinum-based therapy in these cases, as a variety of platinum-based chemotherapies failed to show an efficacy superior to that of etoposide plus cisplatin in phase III trials [3–5]. In 2002, a Japanese phase III study (Japanese Clinical Oncology Group [JCOG] 9511) demonstrated that an irinotecan plus cisplatin combination as a first line chemotherapy had a superior efficacy to that of etoposide plus cisplatin [6]. However, two subsequent studies failed to confirm these results [7,8]. Despite this, JCOG 9511 made irinotecan plus platinum combination as a widely used first line chemotherapy regimens in Korea and Japan.

Belotecan (CKD602, 7-[-2(N-isopropylamino)ethyl]-(20S)camptothecin) is a potent inhibitor of topoisomerase I [9,10] and preclinical studies show that belotecan is three times more and slightly more potent than topotecan and camptothecin, respectively, as a topoisomerase inhibitor [10]. A phase I study of belotecan showed that the maximum tolerable dose is 0.7 mg/m2 /day and that the dose-limiting toxicity is neutropenia [9]. An early phase II study of belotecan reported that the overall response rate is 20% in chemosensitve patients who responded to etoposide–platinum chemotherapy [11]. Thus, we conducted this phase II study that was designed to determine the efficacy and toxicity of belotecan for SCLC patients who initially responded to irinotecan–platinum chemotherapy. 2. Patients and methods 2.1. Study design

∗ Corresponding author at: Yonsei Cancer Center, Department of Internal Medicine, Yonsei University College of Medicine, 250 Seongsanno, Seodaemun-Ku, CPO Box 8044, 120-752 Seoul, Republic of Korea. Tel.: +82 2 2228 8131; fax: +82 2 392 1508. E-mail address: [email protected] (J.H. Kim). 0169-5002/$ – see front matter © 2010 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.lungcan.2010.01.006

We conducted a single center, open-label, nonrandomized phase II trial for patients with relapsing after irinotecan failure. Between March 2006 and May 2008, 27 patients were enrolled into this trial. The primary objective was the response rate of belotecan in relapsing SCLC patients after irinotecan failure. The secondary

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objectives included time to progression, overall survival, response duration, and safety. 2.2. Patient eligibility Each patient was examined to ensure he or she met the following criteria: histologic or cytologic proof of SCLC; relapsed SCLC patients who relapsed at least 3 months after having achieved complete or partial response to 1st line irinotecan plus platinum chemotherapy; measurable disease; no chemotherapy, or chest radiotherapy within 4 weeks of study entry; life expectancy of at least 12 weeks; performance status of 2 or better according to the Eastern Cooperative Oncology Group scale: age ≥18, ≤70; and adequate bone marrow, hepatic, and renal functions. Patients with known brain metastases were eligible if they were asymptomatic and on a stable or a tapering steroid dose if they were on steroids. The treatment protocol was approved by the institutional review board (IRB), and all patients were required to provide signed informed consent. 2.3. Treatment Belotecan was administered intravenously as a 30-min infusion at a dose of 0.5 mg/m2 /day on days 1–5 every 3 weeks. The belotecan dose was 0.5 mg/m2 /day on the first cycle, but a dose adjustment was made for subsequent cycles based on the greatest degree of toxicity during the previous cycle. After dose adjustments, further increments or reductions were disallowed. Doses were adjusted as follows: the dose was decreased to 0.4 mg/m2 /day in cases of (i) ANC nadir of <500/mm3 for 4 days or more, (ii) febrile neutropenia, (iii) platelet nadir <50,000/mm3 for 4 days or more, (iv) thrombocytopenia associated with bleeding episode or required transfusions, or (v) grade 3 or higher non-hematologic toxicity except alopecia; the dose was increased to 0.6 mg/m2 /day in cases of 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 was administered if ANC was ≥1500 mm3 , platelet count 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 was delayed for up to 2 weeks. Chemotherapy was continued for up to 6 cycles, unless the disease progressed, there was unacceptable toxicity including treatment interruption for >2 weeks, or the patient refused further chemotherapy.

Fig. 1. Kaplan–Meier estimates for time-to-progression (n = 27).

2.5. Statistical analysis The group sequential design of Chang et al. was used to determine the sample size [13]. We chose a 15% response rate as a desirable target level and a 5% rate as the lowest response rate of interest. 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, we would conclude that belotecan was clinically active against SCLC. If there was no response, the study was also stopped with no further investigation. Otherwise, we enrolled 15 more patients. If 5 or more responses were observed in a total of 35 patients, we would conclude that belotecan was clinically active against SCLC. If there was no or 1 response, the study was stopped with no further investigation. Otherwise, we enrolled 15 more patients. If at least 6 responses were observed, we would conclude that belotecan was clinically active against SCLC. Time-dependent variables were analyzed using the Kaplan–Meier method (Figs. 1 and 2).

2.4. Patient evaluation Baseline evaluations included a complete medical history with a physical examination, performance status, complete blood count, serum chemistries, urine analysis, electrocardiography, and chest X-ray. A computed tomography scan of each lesion was acquired within 2 weeks of treatment. A physical examination, performance status, and laboratory evaluation (complete blood count, serum chemistries) were evaluated before each subsequent cycle. For tumor response evaluation, imaging studies were repeated every 2 cycles. Treatment response was evaluated using spiral computed tomography according to the guidelines of the Response Evaluation Criteria in Solid Tumors Committee [12]. All enrolled patients were included in the intent-to-treat analysis of efficacy. Toxicities were graded according to the National Cancer Institute Common Toxicity Criteria version 3.0. Time to progression was defined from the start of the treatment to disease progression or death from tumor, and overall survival was calculated from the treatment start to death of any cause.

Fig. 2. Kaplan–Meier estimates for overall survival (n = 27).

J. Jeong et al. / Lung Cancer 70 (2010) 77–81

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Table 2 Response evaluation by intention-to-treat analysis.

3. Results 3.1. Patient characteristics Between March 2006 and May 2008, 27 patients were enrolled into this trial. One patient was deemed ineligible for not having a measurable lesion and 1 patient died after 1 cycle of chemotherapy. Thus 25 patients were evaluated for response. The characteristics of the 27 patients are listed in Table 1. The median follow-up period was 11 months (range, 0.6–28.3) as of July 2008. After the first stage (n = 20), the efficacy criteria were met unexpectedly and we concluded that belotecan was clinically active against SCLC as described in statistical analysis. However, to improve the statistical power, we enrolled an additional 7 patients to investigate the efficacy and safety under IRB approval. One hundred and nineteen courses of chemotherapy were administered, with a median of 6 cycles (range, 1–6). The median dose intensity of belotecan was 0.78 mg/m2 /week (range, 0.58–0.96 mg/m2 /week). The relative dose intensity was 0.94 (range, 0.70–1.16). Dose reduction was required in 24 (20.2%) cycles of 12 patients. Twenty-two (18.5%) cycles were delayed in 13 patients. 3.2. Efficacy Response to therapy was assessable in all but 2 patients: 1 patient was ineligible for not having a measurable lesion and 1 patient died after 1 cycle of chemotherapy. At the first stage, which enrolled 20 patients, the response rate was 25% (95% CI, 8.7–49.1%). Table 1 Patient characteristics.

Response

No. of patients (n = 27)

%

CR PR SD PD NA

0 6 13 7 1

0 22 48 26 4

Total

27

100

CR, complete response; PR, partial response; SD, stable disease; PD, progression of disease.

Table 3 Toxicity profiles in patients (n = 27). Toxicity

Hematologic Leukopenia Neutropenia Anemia Thrombocytopenia Non-hematologic Anorexia Nausea Vomiting Diarrhea Peripheral neuropathy Fatigue Pneumonia Elevated creatinine Elevated AST Elevated ALT Hyperbilirubinemia Alopecia SIADH Dry mouth

≥Grade 3

Grade 1

2

3

4

No.

%

2 1 5 6

5 1 16 8

17 10 5 11

3 15 1 2

20 25 6 13

74 93 23 48

7 4 3 2 2 5 –

1 1 1 2 1 2 1

– – – – – –

– – – – – –

– – – – – – – 1 1 1 1 – – –

1 1 1 2 – 1

– 1 –

1 – – –

– – –

4 4 4 4

Characteristic

No. of patients

%

Total no. of patients Total evaluable patients

27 26

96

Sex Male/female

22/5

82/19

Age, years Median (range)

62 (36–70)

Performance status (ECOG) 0/1/2

8/18/1

30/67/4

Initial stage Limited/extensive

14/13

52/48

Sites of metastasis Lung/pleura Liver Lymph node Bone Adrenal gland Pancreas Brain

16 6 22 6 7 1 2

59 22 82 22 26 4 7

Prior therapy Chemotherapy alone Chemotherapy and chest irradiation Prophylactic cranial irradiation

13 14 5

48 52 19

Prior chemotherapy regimen Irinotecan/cisplatin Irinotecan/carboplatin

19 8

70 30

Out of 25 patients that progressed after belotecan chemotherapy, 20 (80%) were transferred to the third-line salvage chemotherapy. Nine patients who received third-line salvage chemotherapy were transferred to further salvage chemotherapy.

Response to prior chemotherapy CR/PR

5/22

19/82

4. Discussion

Chemotherapy-free-interval, days <90 ≥90

3 24

11 89

A British study published in the late 1980s demonstrated that second-line chemotherapy might produce a survival benefit [14]. In 2006, a randomized phase III trial of topotecan vs. best supportive care clearly demonstrated that chemotherapy with oral topotecan

ECOG, Eastern Cooperative Oncology Group; CR, complete response; PR, partial response.

The overall objective response rates are summarized in Table 2. The overall response rate (n = 27) by intent-to-treat analysis was 22%. Of the 6 patients who achieved partial response, 5 received irinotecan plus carboplatin, and 1 patient received irinotecan plus cisplatin as first line chemotherapy. Their median response duration was 3.1 months (95% CI, 0.7–5.5 months). 3.3. Toxicity The toxicity profile is summarized in Table 3. The one treatmentrelated death occurred after the first cycle of treatment and was attributed to pneumonia combined with hematologic toxic effects of the first cycle. Nineteen patients required G-CSF support, none of whom suffered febrile neutropenia. 3.4. Salvage treatment after progression

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is associated with prolongation of survival and quality of life benefit in patients with relapsed SCLC [15]. However, no agent with superior efficacy exists. The results of a JCOG 9511 made irinotecan as an important first line option in Korea and Japan [6], so we designed this phase II study in Korean patients. In the current study, we observed modest antitumor activity with a response rate of 22% (n = 27). This response rate is not promising compared to that of other toposiomerase I inhibitor topotecan, other single agents such as paclitaxel, docetaxel, gemcitabine, vinorelbine, pemetrexed and especially amrubicin that is under active clinical trial [16]. We also need more phase II studies to demonstrate the efficacy of beleotecan in Caucasians because the SWOG S0124 study showed that pharmacogenetic differences can exist between Asians and North Americans [8]. This study demonstrated that the median time to progression was 4.7 months (95% CI, 3.6–5.8) and the median overall survival was 13.1 months (95% CI, 10.4–15.8). In view of the mechanisms of resistance to camptothecins, several mechanisms are suggested [17]. However, there are currently few preclinical or clinical data regarding the cross-resistance of irinotecan and belotecan. Therefore, further preclinical and clinical studies are required to elucidate the different resistance mechanisms of irinotecan and belotecan. The most common toxic effects of grade 3/4 were neutropenia (93%) and thrombocytopenia (48%). The toxicity profile in this trial was predictable from the previous phases I and II studies [9,11]. Myelosuppression was the major toxic effect, and all adverse effects were manageable. In another study [18] which used topotecan or cyclophosphamide, doxorubicin, and vincristine (CAV) as a second line of treatment, the grade 3/4 neutropenia rate was 88.5% in the topotecan arm and 86.9% in the CAV arm. Also in another study [19] which used topotecan monotherapy, the grade 3/4 neutropenia rate was 92%. In this study, the neutropenia rate is comparable to these other studies and neutropenia is considered tolerable because all of the events were immediately improved by using G-CSF. Although neutropenia and thrombocytopenia were the main toxicities, there was no neutropenic fever or bleeding event. Non-hematologic toxicities were very mild. There was no grade 3/4 diarrhea, suggesting belotecan is more favorable than irinotecan and topotecan in terms of gastrointestinal toxicity. There was one treatment-related death attributed to pneumonia associated with neutropenia. In this study we did not use prophylactic antibiotics and G-CSF. Previous studies showed G-CSF use reduced febrile neutropenia in the first cycle of chemotherapy in small-cell lung cancer [20], and some studies showed that prophylactic antibiotics use can reduce febrile neutropenia and febrile episodes but they did not show a difference in severe infections [21,22]. Therefore, in further trials using belotecan, prophylactic antibiotics, and prophylactic, G-CSF use should be cautiously considered. There is no data with regards to western populations so it will be difficult to extrapolate the Asian data on western populations because Asian patients seem to be a separate patient population [8]. Phase II studies would be needed in Caucasians and the phase I dose-finding may have to be repeated in western patients, too. In further investigations, patients with progressive diseases on cisplatinum/etoposide should be included. Therefore, a test of belotecan vs. topotecan in randomized phase II in Caucasian patients following first line cisplatin/etoposide is one option and belotecan vs. best supportive care in third-line treatment is another option. This could show the overall value of belotecan in western patients. Finally, belotecan did not show promising efficacy in this study. However, similar drugs in the same market (e.g. Erlotinib vs. gefitinib, sunitinib vs. sorafenib, capecitabine vs. S-1, doxorubicin vs. epirubicin, cispaltin vs. carboplatin) will give patients more opportunities and economical benefits.

In conclusion, the topoisomerase I inhibitor belotecan had a 22% response rate and favorable toxicity in this study which was conducted in Asia. But we need further study to confirm the value of belotecan, especially in western patients. Conflicts of interest statement All authors have no financial or personal relationships with other people or organizations that could inappropriately influence our work. References [1] Turrisi AT, Kim K, Blum R, Sause WT, Livingston RB, Komaki R, et al. Twicedaily compared with once-daily thoracic radiotherapy in limited small-cell lung cancer treated concurrently with cisplatin and etoposide. N Engl J Med 1999;340(4):265–71. [2] Rosti G, Bevilacqua G, Bidoli P, Portalone L, Santo A, Genestreti G. Small cell lung cancer. Ann Oncol 2006;17(Suppl. 2):ii5–10. [3] Eckardt JR, von Pawel J, Manikhas G, Papai Z, Tomova A, Tzekova V, et al. 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