Multicenter phase 2 study of belotecan, a new camptothecin analog, and cisplatin for chemotherapy-naive patients with extensive-disease small cell lung cancer

Authors

Errata

This article is corrected by:

  1. Errata: Erratum Volume 116, Issue 2, 540, Article first published online: 15 December 2009

  • Belotecan (Camtobell; CKD602) was kindly provided by Chong Kun Dang Corp, Seoul, Korea.

Abstract

BACKGROUND:

The objective of this study was to investigate the efficacy of belotecan, a new camptothecin analog, combined with cisplatin for the treatment of chemotherapy-naive patients with extensive-disease small cell lung cancer (ED SCLC).

METHODS:

Treatment consisted of belotecan 0.5 mg/m2 daily on Days 1 through 4 and cisplatin 60 mg/m2 on Day 1 of a 3-week cycle for up to 6 cycles unless there was disease progression, unacceptable toxicity, or patient refusal. Response assessment was done every 2 cycles using the Response Evaluation Criteria in Solid Tumors, and toxicity assessment was done every cycle using the National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0.

RESULTS:

Between September 2006 and March 2008, 30 patients participated in the study. Among them, 21 patients achieved a partial response, and the response rate was 70% (95% confidence interval [CI], 50.6%-85.3%); and, after a median follow-up of 20.2 months, the median progression-free survival was 6.9 months (95% CI, 6.3-7.5 months), and the overall survival was 19.2 months (95% CI, 13.3-25.2 months). Grade 3 and 4 adverse events included neutropenia in 23 patients, thrombocytopenia in 8 patients, febrile neutropenia in 9 patients, nausea in 3 patients, and pneumonia in 3 patients. There was 1 treatment-related death from pneumonia. However, nonhematologic toxicity generally was mild and manageable.

CONCLUSIONS:

The belotecan and cisplatin combination that was studied demonstrated promising response rates and survival outcomes with a manageable toxicity profile for chemotherapy-naive patients who had ED SCLC. The authors concluded that the combination warrants further randomized trials. Cancer 2010. © 2010 American Cancer Society.

Belotecan (Camtobell; CKD602, 7-[2(N-isopropylamino) ethyl]-(20S)-camptothecin; Chong Kun Dang Corp, Seoul, Korea) is a new camptothecin analog in which a water-solubilizing group is introduced at position 7 of the B ring of camptothecin. In preclinical studies, belotecan was a more potent topoisomerase I inhibitor and had superior antitumor activity compared with camptothecin and topotecan in 6 human tumor xenografts.1, 2 In an early, multicenter, phase 2 study using single-agent belotecan in patients with small cell lung cancer (SCLC), good antitumor activity was observed in chemotherapy-naive patients with a response rate of 63.6% and a median survival of 11.9 months.3 A subsequent phase 1 study of belotecan in combination with a fixed dose of cisplatin for chemotherapy-naive patients with extensive-disease (ED) SCLC determined that the maximal tolerated dose for belotecan was 0.5 mg/m2 daily.2 Although the sample size was small, a high response rate of 76.5% was observed, and the median survival was 15.9 months.4 On the basis of those preliminary but promising results, we conducted a multicenter phase 2 study to investigate the efficacy and toxicity of belotecan and cisplatin in chemotherapy-naive patients with ED SCLC.

MATERIALS AND METHODS

Eligibility

The study included chemotherapy-naive patients with histologically or cytologically confirmed ED SCLC. Eligible patients met the following criteria: ages 18 years to 75 years; an Eastern Cooperative Oncology Group (ECOG) performance status (PS) from 0 to 2; unidimensionally measurable disease; and adequate organ function, which was defined as an absolute neutrophil count (ANC) ≥1500/mm3, hemoglobin ≥9 g/dL, platelet count ≥100,000/mm3, total bilirubin ≤1.5 mg/dL, aspartate and alanine aminotransferase levels both ≤2-fold the upper limit of normal, and serum creatinine ≤1.5 mg/dL or a calculated (ie, with the Cockcroft-Gault equation) creatinine clearance ≥60 mL per minute. Exclusion criteria were as follows: previous or concurrent malignancy (except for nonmelanoma skin cancer, in situ carcinoma of the cervix or breast, or other cancer if the patient had been disease free for 5 years); a serious medical or psychiatric illness that prevented informed consent; or life expectancy limited to <12 weeks. Prior radiation was allowed at the discretion of the treating physician. However, patients with brain metastasis or carcinomatosis meningitis were excluded. The study was approved by the ethics committees of all participating centers and was performed in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. Written informed consent was obtained from all patients before the study.

Treatment

Before treatment, all patients had complete history and physical examinations; a complete blood count (CBC) with differential cell analysis; electrolytes, glucose, and liver and renal function tests; a staging chest and upper abdominal computed tomography (CT) scan; and a bone scan. Treatment consisted of belotecan 0.5 mg/m2 daily intravenously over 30 minutes on Days 1 through 4 and cisplatin 60 mg/m2 intravenously over 2 hours on Day 1 of 3-week cycles. Each cycle was repeated if the ANC and platelet counts had recovered to at least 1500/mm3 and 100,000/mm3, respectively. If such recovery had not occurred, then the subsequent cycle was delayed by 1 week. If a treatment was delayed by 2 weeks and if the ANC and platelet counts had recovered to ≥1000/mm2 but <1500/mm3 or to ≥75,000/mm3 but <100,000/mm3, respectively, then the dose of belotecan was reduced by 20%. However, if any grade ≥3 nonhematologic toxicity occurred, then the doses of the 2 agents were reduced by 20%. Treatment interruptions or delays were not allowed for >2 weeks, and any such episode was regarded as unacceptable toxicity, leading to treatment discontinuation. Prophylactic use of granulocyte-colony–stimulating factor was not allowed, but therapeutic use of it was allowed at the discretion of the treating physician. The treatments were given for up to 6 cycles unless there was disease progression, unacceptable toxicity, or patient's withdrawal of consent.

Efficacy and Toxicity Assessment

Tumor responses were assessed every 2 cycles according to the Response Evaluation Criteria in Solid Tumors: A complete response (CR) is defined as the disappearance of all target lesions; a partial response (PR) is defined as a decrease ≥30% in the sum of the greatest dimensions of the target lesions taking as a reference the baseline sum of the greatest dimensions and/or the persistence of 1 or more nontarget lesion(s); progressive disease (PD) is defined as an increase ≥20% in the sum of the greatest dimensions taking as a reference the smallest sum of the greatest dimensions recorded since starting treatment, or the appearance of 1 or more new lesions, and/or unequivocal progression of existing nontarget lesions; and stable disease (SD) is defined as neither sufficient shrinkage to qualify as PR nor sufficient increase to qualify as PD taking as a reference the smallest sum of the greatest dimensions observed seen since starting treatment. For patients with a documented CR or PR, a confirmatory evaluation was performed after at least 4 weeks. Disease control was defined as the best tumor response, classified as CR, PR, or SD, that was confirmed and sustained for ≥6 weeks.

Progression-free survival (PFS) was defined as the interval between the date of starting treatment and the date of documented disease progression or death from any cause. Overall survival (OS) was defined as the interval between the date of starting treatment and the date of death from any cause. If a patient was lost to follow-up, then that patient was censored at the date of last contact. Toxicities were assessed every cycle using the National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0. All patients who had received drugs were included in the toxicity analysis. Data were updated on January 13, 2009.

Statistical Considerations

The group sequential design described by Chang et al. was used to determine the sample size and decision criteria for the current study.5 With a target activity level of 50% and the lowest response rate of interest set at 30%, the study was designed in 2 stages to have an 80% power to accept the hypothesis and a 5% significance level to reject the hypothesis. During the first stage, if ≥15 responses were observed in the first 30 patients, then the study would be terminated, and further investigation would be warranted; and, if ≤9 responses were observed, then the study also would be stopped early with no further investigation. Otherwise, 20 more patients would be enrolled. If ≥22 responses in 50 patients were observed, then we would conclude that the treatment offered clinical activity against SCLC. Confidence intervals (CIs) were calculated using the binomial test, and comparisons of results were performed using the chi-square test. Survival outcomes were calculated using the Kaplan-Meier method.

RESULTS

Patient Characteristics

Between September 2006 and March 2008, 30 patients participated in the study. Patients' characteristics are listed in Table 1. No patient received any previous radiotherapy. All patients received at least 1 cycle of therapy and were assessed for toxicity. However, 4 patients were regarded as “not assessable” for the overall response evaluation, because a sustained response of >4 weeks was not confirmed by a subsequent evaluation, there was a treatment delay of >2 weeks because of persistent neutropenia before the fourth cycle; there was a treatment delay because of a traumatic femur fracture after slipping that was not attributable to metastasis or treatment after the second cycle; a patient withdrew consent after the third cycle because of the long journey to the hospital; and exacerbation of underlying pulmonary disease after the third cycle in 1 patient each.

Table 1. Patient Characteristics
CharacteristicNo. of Patients (%)
  1. ECOG indicates Eastern Cooperative Oncology Group.

Total no. enrolled30
No. eligible for response26
Median age [range], y59.5 [42-73]
Sex
 Men25 (83.3)
 Women5 (16.7)
ECOG performance score
 02 (6.7)
 125 (83.3)
 23 (10)
Metastatic site
 Pleural seeding11 (36.7)
 Liver11 (36.7)
 Bone7 (23.3)
 Other lobe of the lung6 (20)
 Adrenal gland2 (6.7)
 Others4 (13.3)

Response and Survival Outcome

Of 30 enrolled patients, 21 patients achieved a PR, 2 patients had SD, and 3 patients had PD, for an overall response rate of 70% (95% CI, 50.6%-85.3%). It is noteworthy that the responses in 4 “not assessable” patients were regarded as PD, because we could not confirm their sustained responses for the reasons mentioned above, although all of them had a PR after 2 cycles (Table 2). With a median follow-up of 20.2 months, the median PFS was 6.89 months (95% CI, 6.3-7.5 months), and the median OS was 19.2 months (95% CI, 13.3-25.2 months) (Fig. 1).

Figure 1.

Kaplan-Meier estimates of survival outcomes are illustrated for the intention-to-treat cohort. Tick marks indicate censored data.

Table 2. Tumor Responses
ResponseNo. of Patients (%)
  • CR indicates complete response; PR, partial response; SD, stable disease; PD, progressive disease.

  • a

    There was 1 treatment delay for >2 weeks because of persistent neutropenia after the third cycle, 1 withdrawal of consent after the third cycle because of the long journey to the hospital, 1 treatment delay because of a traumatic femur fracture after the second cycle, and 1 exacerbation of underlying pulmonary disease after the third cycle.

CR0 (0)
PR21 (70)
SD2 (6.6)
PDa7 (23.4)a
Total30 (100)

Toxicity Profile

Toxicities were evaluated in all 30 patients over a total of 157 cycles. Toxicity profiles by patient and by cycle are shown in Table 3. The most common toxicity was neutropenia. Grade 3 or 4 toxicity occurred in 23 patients (76%) and 66 cycles (42%), whereas grade 3 or 4 febrile neutropenia occurred in 9 patients (30%) and 11 cycles (7%). Grade 3 or 4 nonhematologic toxicities were rather uncommon; nausea was reported in 3 patients and 4 cycles, and hyponatremia was reported in 6 patients and 7 cycles. During the treatment period, 1 patient died of pneumonia, which may have been related to disease progression rather than treatment, because his chest CT scan had evidence of tumor progression. However, a dose reduction of belotecan was required during 35 of 157 cycles (22.3%).

Table 3. Toxicity Profile by Patients and by Cycles
Adverse EventNo. of Patients (%), N = 30No. of Cycles (%), N = 157
Grade 1Grade 2Grade 3Grade 4Grade 1Grade 2Grade 3Grade 4
  • AST indicates aspartate aminotransferase; ALT, alanine aminotransferase; Cr, creatinine.

  • a

    Grade 5 toxicity occurred in 1 patient (3%).

Hematologic toxicity
 Leucopenia6 (20)9 (30)5 (17)3 (10)24 (15)21 (13)9 (6)3 (2)
 Neutropenia2 (7)5 (17)7 (23)16 (53)23 (15)24 (15)32 (20)34 (22)
 Anemia4 (13)17 (57)9 (30)0 (0)88 (56)56 (36)10 (6)0 (0)
 Thrombocytopenia7 (23)1 (3)6 (20)2 (7)13 (8)2 (1)8 (5)2 (1)
Nonhematologic toxicity
 Alopecia16 (53)4 (13)0 (0)0 (0)46 (29)16 (10)0 (0)0 (0)
 Anorexia16 (53)3 (10)1 (3)0 (0)38 (24)5 (3)1 (1)0 (0)
 Constipation7 (23)2 (6)0 (0)0 (0)10 (6)3 (2)0 (0)0 (0)
 Diarrhea8 (27)1 (3)0 (0)0 (0)9 (6)1 (1)0 (0)0 (0)
 Fatigue8 (27)0 (0)0 (0)0 (0)15 (10)0 (0)0 (0)0 (0)
 Febrile neutropenia0 (0)0 (0)8 (27)1 (3)0 (0)0 (0)9 (6)1 (1)
 Nausea12 (40)4 (13)2 (7)1 (3)36 (23)10 (6)3 (2)1 (1)
 Sensory neuropathy3 (10)3 (10)0 (0)0 (0)16 (10)7 (5)0 (0)0 (0)
 Pneumoniaa1 (3)3 (10)3 (10)0 (0)2 (1)5 (3)3 (2)0 (0)
 Vomiting5 (27)4 (13)0 (0)0 (0)15 (10)8 (5)0 (0)0 (0)
 Elevated AST/ALT6 (20)2 (7)0 (0)1 (3)15 (10)2 (1)0 (0)1 (1)
 Elevated bilirubin5 (17)0 (0)0 (0)0 (0)5 (3)0 (0)0 (0)0 (0)
 Elevated Cr2 (7)1 (3)0 (0)0 (0)2 (1)1 (1)0 (0)0 (0)
 Hyponatremia12 (40)0 (0)5 (17)1 (3)29 (19)0 (0)6 (4)1 (1)
 Hypoalbuminemia5 (17)6 (20)2 (7)0 (0)15 (10)12 (8)2 (1)0 (0)

Poststudy Treatment

Of 17 patients who received second-line chemotherapy after the documentation of PD, 4 patients (23.5%) achieved a PR, 5 patients had SD, and 8 patients had PD. Two additional PRs and 4 additional patients with SD were observed among 11 patients in settings of third-line or later therapy.

DISCUSSION

Belotecan is a new camptothecin analog and potently inhibits topoisomerase I. In the current multicenter phase 2 study, we observed a high objective response rate of 70% in the intention-to-treat (ITT) cohort. Because sustained tumor responses in 4 not assessable patients were not confirmed, the response rate in the per-protocol cohort was rather higher at 80.8% (21 of 26 patients). Although the response rate of 70% did not seem higher than expected; in the ITT cohort, the median PFS of 6.9 months and the median OS of 19.2 months was rather promising. In fact, the response rates and survival outcomes were comparable to those reported with other currently used combination regimens, although our small phase 2 study could not be compared directly with those in larger phase 3 studies (Table 4).6-10 It is noteworthy that the response rate and the disease control rate with subsequent second-line therapy (mainly etoposide and platinum) were 23.5% and 52.9%, respectively, which may translate into a better survival outcome. Therefore, the better survival outcome may have been caused by salvage treatment after progression; or by the inherent bias of the small, single-institution phase 2 study design; or by both, which should be addressed in a large, randomized phase 3 study.

Table 4. Efficacy and Toxicity Results From Other Phase 3 Studies
StudyTreatmentORR, %TTP, moOS, moToxicity Profile, %
  1. ORR indicates overall response rate; TTP, time to progression; OS, overall survival; EP, etoposide and cisplatin; IP, irinotecan and cisplatin; TP, topotecan and cisplatin; BeloP, belotecan and cisplatin.

Noda 20026EP vs IP66 vs 844.8 vs 6.99.4 vs 12.8Grade 3/4 neutropenia, 92.2 vs 65.3; febrile neutropenia, 2.6 vs 1.3; grade 3/4 diarrhea, 0 vs 16
Hanna 20067EP vs IP44 vs 484.6 vs 4.110.2 vs 9.3Grade 3/4 neutropenia, 86.5 vs 36.2; febrile neutropenia, 2.6 vs 3.7; grade 3/4 diarrhea, 0 vs 21.3
Eckardt 20068EP vs T(oral)P69 vs 635.8 vs 5.59.2 vs 9.0Grade 3/4 neutropenia, 84 vs 58; febrile neutropenia, 10 vs 4; grade 3/4 diarrhea, 2 vs 6
Natale 20089EP vs IP57 vs 605.2 vs 5.79.1 vs 9.9Grade 3/4 neutropenia, 68 vs 34; febrile neutropenia, 10 vs 4; grade 3/4 diarrhea, 3 vs 19
Heigener 200810EP vs TP46 vs 566 vs 79.4 vs 10.3Grade 3/4 neutropenia, 60.8 vs 61.3; febrile neutropenia, 3.9 vs 3.7; grade 3/4 diarrhea, 1.5 vs 2.9
Lee et al. (current study)BeloP706.919.2Grade 3/4 neutropenia, 76; febrile neutropenia, 3; grade 3/4 diarrhea, 0

In terms of the toxicity profile, hematologic toxicity, and especially neutropenia, was the most common toxicity, but the frequency was similar to that reported with other combination regimens,6-10 and dose reductions occurred in 22.3% of all cycles. Nonhematologic toxicity was mild and manageable. Disappointingly, this belotecan and cisplatin combination did not demonstrate any improvement in the toxicity profile compared with currently available regimens, some of which have better a toxicity profile.

In conclusion, the belotecan and cisplatin regimen that we studied demonstrated promising response rates and a manageable toxicity profile in chemotherapy-naive patients with ED SCLC. Further randomized trials comparing this regimen with standard treatment should be considered cautiously.

CONFLICT OF INTEREST DISCLOSURES

Supported in part by a grant from the Korea Health 21 R&D Project, Ministry of Health and Welfare, Republic of Korea (A060775).

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