Japanese Journal of Clinical Oncology Advance Access originally published online on January 17, 2006
Japanese Journal of Clinical Oncology 2006 36(1):12-16; doi:10.1093/jjco/hyi217
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© 2006 Foundation for Promotion of Cancer Research
Phase I Study of Amrubicin Hydrochloride and Cisplatin in Patients Previously Treated for Advanced Non-small Cell Lung Cancer
Department of Thoracic Oncology, National Kyushu Cancer Center, Fukuoka, Japan
For reprints and all correspondence: Yukito Ichinose, Department of Thoracic Oncology, National Kyushu Cancer Center, 3-1-1, Notame, Minami-ku, Fukuoka 811-1395, Japan. E-mail: yichinos{at}nk-cc.go.jp
Received July 21, 2005; accepted December 1, 2005
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Abstract |
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 TOP Abstract INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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Objective: A single-center phase I trial was designed to determine both the dose-limiting toxicities and the maximum tolerated dose (MTD) for amrubicin hydrochloride in combination therapy with cisplatin for advanced non-small cell lung cancer (NSCLC) patients with prior chemotherapy.
Methods: Eligible patients received amrubicin and cisplatin on days 1 through 3 every 3 or 4 weeks. Cisplatin was administered at a fixed dosage of 20 mg/m2 while the administered dose of amrubicin was started at 20 mg/m2. Each group comprised 3 or 6 patients. When dose limiting toxicities were noted in three or more of six patients at a particular level, that level was estimated to be the MTD.
Results: Fifteen patients were enrolled in this study, including 5 males and 10 females, with a median age of 57. The dose limiting toxicities included grade 4 neutropenia which lasted 4 or more days and febrile neutropenia. The non-hematologic toxicities were well managed and rarely severe. The MTD of amrubicin in this combination regimen was estimated to be 30 mg/m2.A partial response was observed in 4 of 15 patients (27%).
Conclusions: The recommended dose was thus determined to be 25 mg/m2 amrubicin with 20 mg/m2 cisplatin for 3 consecutive days. A phase II study is currently underway.
Key Words: amrubicin hydrochloride • cisplatin • non-small cell lung cancer • phase I study • prior chemotherapy
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INTRODUCTION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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Platinum-based combination chemotherapy has been the standard first line treatment for advanced non-small cell lung cancer (NSCLC) (1). The median survival time (MST), however, ranges from 7.4 to 8.1 months in patients treated with platinum-based combination chemotherapy and this treatment still remains unsatisfactory regarding its overall clinical effectiveness (2,3). On the other hand, docetaxel monotherapy has shown an approximately 7% response rate, thus leading to an average increased survival time of 3 months and a better quality of life when used as a second-line therapy in patients with advanced NSCLC, in comparison to the best supportive care (4,5). Based on these results, docetaxel monotherapy is widely regarded as a standard second-line treatment (6,7). Recently, pemetrexed has been shown to have the same effect as docetaxel in terms of the response rate and survival (8). In addition, epidermal growth factor receptor-tyrosine kinase inhibiting drugs such as gefitinib and erlotinib have also been approved for the treatment of NSCLC patients with prior chemotherapy (9,10). Although we now have several choices for the treatment of patients with a progressive disease either during or after undergoing other types of chemotherapy, the number of effective drugs for such patients still remains limited.
Amrubicin hydrochloride, which is a totally synthetic 9-aminoantracycline, is metabolically activated by a liver enzyme to amrubicinol. Amrubicin is reported to have either an equivalent or a stronger anti-tumor effects in comparison with doxorubicin in nude mice transplanted with human tumor cells (11–13). The anti-tumor mechanism of amrubicin itself and its active form, amrubicinol, is due to the break-down of DNA strands during the stabilization process of DNA-topoisomerase II cleavable complex (14). In a phase I trial of the intravenous administration of amrubicin for 3 consecutive days at 3-week intervals in patients without prior chemotherapy, the maximum tolerated dose (MTD) and the recommended dose were estimated to be 50 mg/m2 and 45/m2, respectively. The major dose limiting toxicity (DLT) was myelosuppression (15). A subsequent phase II trial in patients with advanced NSCLC without prior chemotherapy demonstrated a response rate of 23% with a MST of 9.4 months (16). These findings suggest that amrubicin may be a promising anti-tumor agent for treatment of NSCLC.
To our knowledge, no clinical trials using amrubicin in previously treated advanced NSCLC patients have yet been conducted. Since the main toxicity of amrubicin is myelotoxicity, it is expected that the administration of a full dose of amrubicin will not be tolerable for previously treated NSCLC patients. A synergistic or additive anti-tumor effect between cisplatin and amrubicin has been reported (17,18). Since the major toxicity of cisplatin is not only non-hematologic but it can also be reduced by dividing up the administered doses, the concurrent combination of amrubicin and cisplatin of a low dose may possibly augment the anti-tumor activity of amrubicin without any severe myelotoxicity, even in patients who have already received other types of platinum-based chemotherapy as prior treatment (19,20). Based on this hypothesis, we conducted a phase I trial to find the MTD of amrubicin which was concurrently administered with a low dose of cisplatin, 20 mg/m2, for 3 consecutive days, in advanced NSCLC patients with a history of prior chemotherapy.
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PATIENTS AND METHODS |
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ELIGIBILITY
Patients with either cytologically or histologically confirmed advanced NSCLC who demonstrated disease progression either during or after a prior chemotherapy were eligible. The eligibility criteria also included the following factors: an age ranging from 20 to 75 years; an Eastern Cooperative Oncology Group performance status
1; a life-expectancy of 
3 months; no chemotherapy or radiation therapy within 4 weeks of treatment; an adequate hematopoietic status [absolute neutrophil count (ANC) 2000/µl, hemoglobin level 10 g/dl, platelet count 100 000/µl], hepatic (transaminases 2 x institutional normal upper limit, total bilirubin 1.5 x institutional normal upper limit) and renal (creatinine institutional normal upper limit) functions; either measurable or evaluable but nonmeasurable disease such as numerous small sized pulmonary metastases, PaO2 60 torr; and left ventricle ejection fraction of 60% or more based on ultrasound cardiogram. Patients gave their written informed consent before treatment. The protocol was approved by the institutional review board of the National Kyushu Cancer Center.
DOSAGE AND DRUG ADMINISTRATION
Amrubicin and cisplatin were administered on days 1 through 3 of each 3 or 4-week cycle. Cisplatin was administered at a fixed dosage of 20 mg/m2/day for 3 consecutive days while amrubicin was started at 20 mg/m2/day for 3 consecutive days and then increased by 5 mg/m2/day until reaching the MTD. Amrubicin was dissolved in either 20 ml of a 5% glucose solution or saline for the intravenous injections. Following the administration of amrubicin, cisplatin was administered intravenously together with 1500 ml of hydration. At least, two cycles of this combination chemotherapy were administered every 3 or 4 weeks unless either a disease progression or unacceptable toxicity occurred. The MTD was defined as the lowest dose at which three or more of six patients experienced DLT during the first course of the treatment. At least three patients were treated at each dose level that did not result in DLT. If one or two of the initial three patients developed DLT, then three additional patients were entered at the same dose level. DLT was defined as follows; grade 4 leukopenia or neutropenia lasting for 4 days or more; an ANC of 1000/µl associated with fever (38.5°C), a platelet count of 20 000/µl; and a grade 3 or greater non-hematological toxicity (excluding anorexia, nausea and vomiting). The prophylactic use of growth factors was not permitted. However, at the discretion of the treating physician, granulocyte colony stimulating factor was used for the treatment of febrile neutropenia and grade 4 neutropenia. Toxicity was graded according to the National Cancer Institute Common Toxicity Criteria Version 2.0.
PRETREATMENT AND FOLLOW-UP STUDIES
The performance status, the interval toxicities, concurrent medications, physical examinations, complete blood counts, electrolytes and chemistries were evaluated before treatment and weekly thereafter. Pretreatment studies also included chest radiography, computed tomography scans to evaluate all sites of disease, an electrocardiogram and ultrasound cardiogram. Computed tomography scans were repeated every 4 weeks. A complete response was scored if there was a disappearance of all active disease on two measurements separated by a minimum period of 4 weeks, and a partial response required at least a 50% reduction in the sum of the product of the bi-dimensional measurements of all lesions documented separated by at least 4 weeks. Any concurrent increase in the size of any lesion by 25% or the appearance of any new lesion was considered to indicate progressive disease. No change was defined as the absence of a partial or complete response without progressive disease being observed for at least 4 weeks after the start of the treatment.
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RESULTS |
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GENERAL
Between July 2003 and March 2004, 15 patients were enrolled in this study. Table 1 shows the patient characteristics. The study included 5 males and 10 females with a median age of 57 years ranging from 51 to 72. Five and 10 patients had a performance status of 0 and 1, respectively, and most patients histologically had adenocarcinoma. Concerning previous treatments other than chemotherapy, four patients each underwent either surgery or thoracic radiotherapy. Regarding prior chemotherapy, platinum-based chemotherapy was performed in 14 patients while one patient received chemotherapy using gemcitabine plus vinorelbine. The chemotherapeutic regimens most frequently used as a prior treatment were cisplatin plus gemcitabine plus vinorelbine in nine patients, cisplatin plus docetaxel in six and carboplatin plus paclitaxel in five. The number of prior chemotherapy regimens ranged from 1 to 5, with a median number of 2.
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At an amrubicin dosage of 20 mg/m2, no DLT was observed. At an amrubicin dosage of 25 mg/m2, grade 4 neutropenia lasting 4 days or more was observed in one of the first three patients. Therefore, another three patients were treated at the same dose. Since these patients did not show any additional DLT, the dosage was then escalated to 30 mg/m2. Grade 4 neutropenia lasting 4 days or more was observed in two of the first three patients. Therefore, another three patients were assigned to receive the treatment at the same dose. Out of those three patients, one patient developed febrile neutropenia. Therefore, DLT was observed in three of six patients at an amrubicin dosage of 30 mg/m2. As a result, amrubicin 30 mg/m2 was determined to be the MTD. A total of 11 and 17 cycles of the treatment were performed at a dose of 20 and 25 mg/m2, respectively. DLT was observed in 0 of 11 cycles at 20 mg/m2 and in 1 of 17 cycles at 25 mg/m2.
TOXICITY
Myelosuppression, especially neutropenia, was the principal toxicity of this combination chemotherapy as shown in Table 2. At the MTD (amrubicin 30 mg/m2), all three DLTs were related to neutropenia. Two patients had grade 4 neutropenia which persisted for 4 days or more. The third patient with grade 4 neutropenia had a fever associated with neutropenia that lasted for 4 days. The other three patients at the MTD also had grade 4 neutropenia which persisted <4 days. All six patients were treated with G-CSF after grade 4 neutropenia had been found. Grade 3 neutropenia was observed in one patient at dose of 20 mg/m2 and grades 3/4 neutropenia in two at a dose of 25 mg/m2. The onset of neutropenia (ANC 1500/µl) occurred between days 9 and 21: the median time to nadir and the recovery of neutrophil count (ANC 1500/µl) from the nadir was 16 days (range 3–23) and 5 days (range 1–24), respectively. No grade 3 or greater thrombocytopenia was observed.
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The non-hematologic toxicity was mild. The toxicities mainly included nausea/vomiting, an elevation of AST/ALT and fatigue while all of them were rated as grade 2 or less and manageable.
ANTITUMOR ACTIVITY
A partial response was observed in four patients, no change in eight and progressive disease in three. Therefore, the overall response rate was 27% (95% confidence interval: 4–49%). Responding patients were observed at every dose level of amrubicin: 1/3 at 20 mg/m2, 2/6 at 25 mg/m2 and 1/6 at 30 mg/m2. Out of four patients with a partial response, two and two patients received three cycles and four cycles of amrubicin plus cisplatin chemotherapy, respectively. The responding duration of the four patients was 62, 65, 70 and 174 days.
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DISCUSSION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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The present study was designed to determine the recommended dose of amrubicin by estimating the MTD for combination chemotherapy using amrubicin and cisplatin in previously treated NSCLC patients. The MTD was estimated to be 30 mg/m2 when cisplatin at a dose of 20 mg/m2 was administered concurrently for 3 consecutive days. At the MTD (30 mg/m2), all six patients had grade 4 neutropenia which resulted in DLT in a half of these patients. Based on the MTD, the recommended dose was thus determined to be 25mg/m2. The observed hematological toxicities, except for neutropenia and non-hematological toxicities, were not severe and thus were manageable. Although this study included four patients who had previously undergone thoracic radiotherapy, neither an aggravation of radiation pneumonitis nor any acute pulmonary disorders occurred.
In lung cancer patients with no prior treatment, the recommended dose of amrubicin (days 1 to 3) has been reported to be 45 mg/m2 while it is 40 mg/m2 when cisplatin 60 mg/m2 is administered on day 1 (15,21). The main toxicity of amrubicin monotherapy and the combination chemotherapy tends to be myelosuppression, especially, neutropenia. Grade 3/4 neutropenia was observed in 75% of all patients with amrubicin monotherapy and in 95% of those with the combination chemotherapy (15,16,21). Therefore, the treatment regimens described above are considered to be intolerable in patients with prior chemotherapy whose bone marrow function has been, more or less, damaged.
In the present study, the concurrent administration of amrubicin and cisplatin of low dose for 3 consecutive days was performed based on the hypothesis that the addition of cisplatin to amrubicin may augment the anti-tumor activity of amrubicin. In an in vitro study using lung cancer cell lines, the addition of cisplatin to amrubicinol, which is an active metabolite of amrubicin , has been reported to not only enhance the inhibitory activity of topoisomerase II by amrubicinol but also to increase the formation of the DNA intestrand cross by cisplatin (18). In addition, the combination treatment with cisplatin has been shown not to alter the pharmacokinetics of either amrubicin or amrubicinol (21). These observations suggest that the concurrent administration of amrubicin and cisplatin may have an excellent anti-tumor activity without any unexpected severe toxicity, even in patients who had previously been administered platinum-based chemotherapy.
In conclusion, the MTD and recommended dose of amrubicin were determined to be 30 mg/m2 and 25 mg/m2, respectively, when cisplatin 20 mg/m2 was administered concurrently for 3 consecutive days, in NSCLC patients who had received prior chemotherapy. The DLTs included neutropenia lasting 4 days or more, and febrile neutropenia. The overall response rate was 27%. A Phase II study is currently underway in these patients.
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Acknowledgments |
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We would like to thank Mr Brian Quinn for his critical review and Ms Yumiko Oshima for her help in preparing the manuscript.
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References |
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