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A Phase I Study of Amrubicin and Carboplatin for Previously Untreated Patients with Extensive-Disease Small Cell Lung Cancer
ORIGINAL ARTICLE
A Phase I Study of Amrubicin and Carboplatin for Previously Untreated Patients with Extensive-Disease Small Cell Lung Cancer Minoru Fukuda, MD, PhD,* Yoichi Nakamura, MD, PhD,† Takashi Kasai, MD, PhD,‡ Seiji Nagashima, MD, PhD,§ Katsumi Nakatomi, MD, PhD,† Seiji Doi, MD, PhD,† Hirofumi Nakano, MD, PhD,† Hiroshi Takatani, MD, PhD,‡ Masaaki Fukuda, MD, PhD,‡ Akitoshi Kinoshita, MD, PhD,储 Hiroshi Soda, MD, PhD,§ Kazuhiro Tsukamoto, MD, PhD,¶ Mikio Oka, MD, PhD,# and Shigeru Kohno, MD, PhD†; Nagasaki Thoracic Oncology Group
Background: Amrubicin and cisplatin are active in the treatment of small cell lung cancer (SCLC), and carboplatin is an analogue of cisplatin with less nonhematological toxicity. The appropriate dose of amrubicin and carboplatin combination chemotherapy for previously untreated patients with extensive-disease (ED) SCLC has not been established. Purpose: To determine the maximum-tolerated dose and doselimiting toxicity (DLT) of amrubicin and carboplatin in ED-SCLC. Patients and methods: Eligibility criteria were chemotherapy-naive ED-SCLC patients, performance status 0 –1, age ⱕ75, and adequate hematological, hepatic, and renal function. Patients received escalating amrubicin doses under a fixed target area under the curve (AUC) 5 of carboplatin (Chatelut formula). Amrubicin and carboplatin were administered by intravenous (IV) infusion on days 1, 2, and 3, and day 1, respectively. The initial dose of amrubicin was 30 mg/m2, and the dose was escalated to 35 and 40 mg/m2. Results: Sixteen patients were enrolled and 15 eligible patients were evaluated. One of six patients in level 1, one of six in level 2, and three of three in level 3 experienced DLTs. The presentation of DLTs included neutropenia, leukopenia, thrombocytopenia, febrile neutropenia, and liver dysfunction. Evaluation of responses were two complete response, nine partial response, three stable disease, and one progressive disease (response rate 73%), and the median survival time was 13.6 months. The maximum-tolerated doses of amrubicin and carboplatin were determined as 40 mg/m2 and AUC 5.
*Department of Medicine, Nagasaki Municipal Hospital; †Second Department of Internal Medicine, Nagasaki University School of Medicine; ‡Japanese Red Cross Nagasaki Atomic Bomb Hospital; §Sasebo General Hospital; 储National Hospital Organization Nagasaki Medical Center; ¶Nagasaki University School of Pharmaceutical Science, Nagasaki; and #Division of Respiratory Diseases, Department of Medicine, Kawasaki Medical School, Kurashiki, Japan. Disclosure: The authors declare no potential conflicts of interest. Address for correspondence: Minoru Fukuda, MD, PhD, Department of Medicine, Nagasaki Municipal Hospital, 6-39 Shinchi, Nagasaki 8508555, Japan. E-mail: [email protected] Copyright © 2009 by the International Association for the Study of Lung Cancer ISSN: 1556-0864/09/0406-0741
Journal of Thoracic Oncology • Volume 4, Number 6, June 2009
A dose of 35 mg/m2 amrubicin and carboplatin AUC 5 was recommended in this regimen. Conclusions: This regimen is associated with an acceptable tolerability profile, and warrants evaluation in the phase II setting. Key Words: Amrubicin, Carboplatin, Small cell lung cancer, Phase I study. (J Thorac Oncol. 2009;4: 741–745)
L
ung cancer is the leading cause of cancer death worldwide. It is also the leading cause of death in Japan with 63,255 deaths (19.2% of all cancer deaths) in 2006.1 Of all lung cancer cases, approximately 20% is small cell lung cancer (SCLC).2 Despite this cancer being highly responsive to chemotherapy initially, most of patients will ultimately relapse and die of recurrent disease within 2 years.3 Recently, combination chemotherapy with irinotecan and cisplatin for extensive-disease (ED) SCLC produced equal or better survival with increased toxicities compared with etoposide and cisplatin, the worldwide standard regimen since 1981.4 – 6 As the therapy provided 2-year survival rates of only 8.0 to 19.5%, with a median survival time (MST) of 9.3 to 12.8 months, new and more effective agents are clearly needed against SCLC. Amrubicin is a completely synthetic anthracycline derivative characterized by a 9-amino group and a simple sugar moiety. The chemical structure and acute toxicity of amrubicin are similar to that of doxorubicin7,8; however, amrubicin shows almost no cardiotoxicity.9,10 Amrubicin alone and combination chemotherapy with cisplatin exhibited high response rates of 75.8% and 87.8% and MSTs of 11.7 and 13.6 months in previously untreated ED-SCLC, respectively.11,12 Carboplatin is a platinum derivative with less renal toxicity and less nausea and vomiting than cisplatin,13 and which has been combined with other newer agents in chemotherapy for SCLC.14 Pharmacodynamic studies have been performed to predict clearance (CL) and administer the appropriate dose of carboplatin in individual patients.15–17 The preceding study evaluated the Chatelut formula, and reported that
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predicted carboplatin CL was closely correlated with the actual CL, and the actual area under the curves (AUCs) of carboplatin nearly reached the target AUC of 5.18 Based on these results, a phase I study of amrubicin and carboplatin was conducted for SCLC. The main objective of this study was to determine the maximum-tolerated dose (MTD) of this combination chemotherapy.
PATIENTS AND METHODS The study protocol was reviewed and approved by the Ethics Committee of each institution, and written informed consent was obtained from all study participants. This study is an independent collaborative (not sponsored) group study.
Patients and Evaluation Eligibility criteria for patients in this study included the following: a histologically and/or cytologically confirmed diagnosis of SCLC; extensive stage disease19; no prior chemotherapy or radiotherapy; age ⱕ75 years; Eastern Cooperative Oncology Group performance status ⱕ1; life expectancy greater than 12 weeks; adequate bone marrow function (leukocyte count ⱖ4000/l, platelet count ⱖ10.0 ⫻ 104/l, and hemoglobin level ⱖ10.0 g/dl); serum bilirubin level ⱕ1.5 mg/dl; alanine aminotransferase (ALT) and aspartate transaminase (AST) levels ⱕ2 times the normal upper limit; serum creatinine level less than the normal upper limit; and no medical problems severe enough to prevent compliance with the protocol.
Treatment and Dose Escalation Under a fixed-target AUC of 5 mg/min/ml for carboplatin on day 1, the starting dose of amrubicin was 30 mg/m2 administered on days 1 to 3. The dose of carboplatin was determined by multiplying the target AUC of 5 by the carboplatin CL, which was predicted with the Chatelut formula17 using the Jaffe´ method to measure serum creatinine.20 The values of serum creatinine obtained using the enzymatic method (X) were converted by the Jaffe´ method (Y) using the formula Y ⫽ 0.97X ⫹ 0.27. Then, the estimated CL (ml/min) was calculated as follows: CL ⫽ 0.134 ⫻ weight ⫹ (218 ⫻ weight ⫻ (1 ⫺ 0.00457 ⫻ age) ⫻ (1 ⫺ 0.314 ⫻ sex)) ⫻ 116.4 ⫻ 10⫺4/(sCr ⫹ 0.28) (with weight in kg, age in years, and sex ⫽ 0 if male and sex ⫽ 1 if female). In Japanese institutions, the measurement method of serum creatinine was changed to the enzymatic method. The dose of amrubicin was increased by 5 mg/m2 as shown in Table 1. Carboplatin was administered during a 60-minute intravenous (IV) infusion of 250 ml of 5% dextrose. Amrubicin was diluted in 20 ml of normal saline and administered as an IV injection during a drip infusion of normal saline. Intrapatient dose escalation was not allowed.
TABLE 1. Dose Escalation Schedule Dose Level 1 2 3
No. of Patients
Amrubicin (mg/m2)
Carboplatin Target AUC (mg/min/ml)
6 6 3
30 35 40
5 5 5
AUC, area under the concentration-time curve.
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Granulocyte colony-stimulating factor was administrated when the neutrophil count reached ⬍1000/l and discontinued when the count recovered to ⬎5000/l. The next cycle at each level commenced after leukocyte and platelet counts reached at least 3000/l and 100,000/l, respectively. In patients showing a response, this chemotherapy was repeated every 3 weeks for four cycles. The dose-limiting toxicity (DLT) was evaluated at the first cycle and defined as follows: grade 4 leukopenia or neutropenia lasting 4 days or more; grade 3 febrile neutropenia; platelets ⬍20,000/l; grade 3 or worse nonhematological toxicity except for nausea, vomiting, anorexia, fatigue, hyponatremia, and infection. For dose escalation, three patients were enrolled at each dose level, and the dose was escalated to the next level when none of patients experienced DLT. When two or more patients experienced DLT, the dose level was defined as the MTD. When one of three patients experienced DLT, an additional three patients were treated at the same level. When none of the additional patients experienced DLT, the dose was escalated to the next level. When one or more of the additional patients experienced DLT, the dose level was also defined as the MTD. The recommended dose (RD) of this regimen for a phase II study was defined as the previous level below the MTD. Dose escalation was determined based only on the data from the first course of chemotherapy. Leukocytes ⱖ3000/l and platelets ⱖ10 ⫻ 104/l were mandatory to commence the second cycle of treatment, and if levels fell below these limits, the second cycle was postponed until the counts recovered. Doses of amrubicin and carboplatin were reduced to 80% when DLT occurred during the first treatment cycle.
Toxicity and Response Evaluation Eligibility, assessability, and tumor responses were determined by external reviewers. Drug toxicity was graded according to the National Cancer Institute Common Toxicity Criteria, Version 2.0.21 Before the first cycle, a blood cell count, urinalysis, and biochemistry tests were performed to assess renal and hepatic function, and electrolytes. This monitoring was repeated during treatment, whereas other investigations were repeated as necessary, to evaluate marker lesions. After the completion of treatment, each disease was assessed and tumors restaged. Tumor response was classified according to Response Evaluation Criteria in Solid Tumors (RECIST) and tumor markers were excluded from the criteria.22 Complete response was defined as the complete disappearance of all clinically detectable tumors for at least 4 weeks and no new lesions. Partial response was defined as at least a 30% decrease in the sum of the longest diameters of target lesion, taking as reference the baseline sum of the longest diameters, the required nonprogression in nontarget lesions, and no new lesions for at least 4 weeks. Stable disease included regression of target lesions insufficient to meet the criteria for partial response, a ⬍20% increase in the sum of the longest diameters of target lesion, taking as reference the smallest sum of the longest diameters recorded since the start of treatment, the required nonprogression in nontarget lesions, and no new lesions for at least 6 weeks. Progressive disease indicated a ⬎20% increase in the sum of the longest diame-
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ters of the target lesion, taking as reference the smallest sum of the longest diameter recorded since the start treatment and/or unequivocal progression of existing nontarget lesions and/or appearance of new lesions. The evaluation of objective tumor response for all patients was performed by external reviewers.
Sixteen patients were enrolled and 15 patients treated in this trial, between July 2003 and August 2007. One patient did not receive the protocol therapy because radiotherapy was needed after enrollment. All patients who received the planned therapy were evaluated for toxicity, response, and survival. The baseline patient characteristics are shown in Table 2.
Treatment Administration A total of 49 cycles of this therapy were administered with a median of 4 cycles per patient: 1 cycle in 2 patients (13%), 2 cycles in 2 (13%), 3 cycles in 3 (20%), 4 cycles in 6 (40%), and 5 cycles in 2 (13%). Six patients were treated at dose levels 1 and 2, and 3 patients were treated at dose level 3.
Dose Escalation At level 1, one of the three original patients experienced DLTs (grade 4 neutropenia lasting 10 days, grade 4 leukopenia lasting 7 days, and grade 4 AST/ALT elevation), but none of the three additional patients experienced DLT. At level 2, one of the three original patients experienced DLT (thrombocytopenia ⬍20,000/ml), but none of three additional patients experienced DLT. At level 3, all three patients experienced DLTs as follows: three patients experienced TABLE 2. Patient Characteristics Gender Male Female Age (yr) Median Range Performance status (ECOG) 0 1 Stage IIIB IV No. of metastasis sites ⱕ1 ⬎1 LDH Normal Increased Weight loss ⱖ5% ⬍5%
grade 4 neutropenia lasting ⱖ4 days, one patient experienced grade 4 leukopenia ⱖ4 days, thrombocytopenia ⬍20,000/ml, febrile neutropenia, and grade 3 mucositis. Level 3 was considered to be too toxic and determined to be the MTD. Therefore, level 2 (amrubicin 35 mg/m2 and carboplatin AUC 5) was regarded as the RD of this regimen for the phase II study.
Hematological Toxicity
RESULTS
Characteristics
Phase I of Amrubicin and Carboplatin in SCLC
No. of Patients 15 0 67 49–75 2 13 6 9 10 5 8 7 2 13
ECOG, Eastern Cooperative Oncology Group; LDH, lactate dehydrogenase.
The worst grades of hematological toxicities experienced by each patient are listed Table 3. Leukopenia, neutropenia, thrombocytopenia, and febrile neutropenia were the principal toxicities. Of the 15 patients, 6 (40%) experienced grade 4 hematological toxicities and 5 (33%) experienced hematological DLTs. At dose level 1, 1 patient (17%) experienced grade 4 hematological toxicity as a DLT. At dose level 2, 2 patients (33%) experienced grade 4 hematological toxicity including 1 (17%) hematological DLT. At dose level 3, all 3 patients experienced grade 4 hematological toxicities as DLTs, and one patient required platelet transfusion. Anemia requiring blood transfusion was observed one patient each at levels 1 and 2. There was one treatment-related death due to severe hematological toxicity. In the third cycle of dose level 3, a patient treated with 32 mg/m2 amrubicin and carboplatin with a target AUC of 4 mg/min/ml because of 20% dose reduction experienced grade 4 leukopenia, neutropenia, and thrombocytopenia and grade 3 febrile neutropenia on day 16. Despite intensive care, the patient developed sepsis due to methicillin-resistant Staphylococcus aureus, and died on day 23.
Nonhematological Toxicity The worst grades of nonhematological toxicity experienced by each patient are listed Table 4. Frequent nonhematological adverse events included nausea, liver dysfunction (AST and ALT elevation), and mucositis of the oral cavity. In total, 2 patients (13%) experienced nonhematological DLTs. At dose level 1, 1 patient experienced grade 4 liver dysfunction. At dose level 3, 1 patient experienced grade 3 mucositis of the oral cavity.
Efficacy All 15 patients were assessable for response. Objective tumor response was observed in 11 patients, with an overall response rate of 73% (95% confidence interval, 45–92%) (Table 5). Two patients (13%) had complete response. At the survival assessment in July 2008, 3 patients were still alive and the other 12 patients had died. The overall survival of 15 patients is shown in Figure 1. MST was 13.6 months and the 1-year survival rate was 50.3%.
DISCUSSION Amrubicin has shown excellent activity for the treatment of previously untreated patients with ED-SCLC. In a single agent phase II study with 45 mg/m2 amrubicin on days 1–3, the overall response rate, MST, and 1-year and 2-year survival rates were 75.8%, 11.7 months, 48.5%, and 20.2%, respectively.11 Because recent randomized trials of cisplatin/ etoposide have demonstrated MSTs of 9.1 to 10.2 months,4 – 6 this single agent might be comparable with standard combi-
Copyright © 2009 by the International Association for the Study of Lung Cancer
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TABLE 3. Hematological Toxicities Anemia Dose Level
Leukopenia
Neutropenia
Plt
No. of Patients
Gr 2
3
2
3
4
2
3
4
3
4
FN 3
6 (1) 6 (1) 3 (3)a
1 2 3
0 0 0
2 3 0
1 2 1
1 (1) 0 2 (1)
1 0 0
4 4 0
1 (1) 2 3 (3)
1 2 1
0 1 (1) 1 (1)
1 (1) 0 1 (1)
1 2 3
The numbers in parentheses are the number of patients who experienced dose-limiting toxicities. a One patient experienced grade 4 leukopenia, neutropenia, thrombocytopenia, and febrile neutropenia. Plt, thrombocytopenia; FN, febrile neutropenia.
TABLE 4. Nonhematological Toxicities Nausea Dose Level
No. of Patients
1 2 3
>2
Gr 1
6 (1) 6 (1) 3 (3)
s-AST
2 2 1
>2
1
2 0 0
s-ALT
1 0 1
1 (1) 0 0
1 a
0 0 2
s-Cr
>2 1 (1) 0 0
a
Mucositis
1
>2
1
>2
1 0 0
0 0 1
0 0 0
0 0 1 (1)b
The numbers in parentheses are the number of patients who experienced dose-limiting toxicities. a Grade 4 toxicity. b Grade 3 toxicity.
TABLE 5. Tumor Response Dose Level
CR
PR
SD
PD
1 2 3 Rate (%)
0 1 1 13
4 5 0 60
2 0 1 27
0 0 1 7
Overall response 73% (95% confidence interval, 45–92%). CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease.
100
MST: 13.6 months 1-year survival rate: 50.3%
Overall survival rate (%)
90 80 70 60 50 40 30 20 10 0
0
3
6
9 12 15 18 Survival time (months)
21
24
27
FIGURE 1. Overall survival curves of the 15 patients enrolled in the present study.
nation chemotherapy. In combination with cisplatin, amrubicin demonstrated promising overall response, MST, and 1-year survival rate of 87.8%, 13.6 months, and 56.1%, respectively.12 Carboplatin is a platinum derivative with similar activity and less nonhematologic toxicity than cisplatin. Thus, taken together with carboplatin and the most active single agent amrubicin, the present combination chemotherapy for SCLC was considered to be worthwhile.
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In vivo comparison between single day therapy and repeated 5-consective-day therapy on several cell lines revealed superior antitumor effects for the 5-day administration of amrubicin.23 As for clinical, phase I trials, both day 1 therapy and 5-consecutive-day therapy every 3 weeks were performed in patients with various types of malignant tumors that had been treated previously.24,25 However, a clear tumor shrinking effect was not seen. Finally, because another anthracycline reported higher response26 and in consideration of its convenience for practical use, 3-consecutive-day administration every 3 weeks came to be recommended for amrubicin. In a phase I/II trial of previously untreated patients with non-small cell lung cancer, the RD of single agent amrubicin was determined as 45 mg/m2.27 This dose was also used in SCLC.11 In combination with cisplatin, the RD of amrubicin was decreased to 40 mg/m2.12 In present study of amrubicin 40 mg/m2 and carboplatin AUC 5 level, all three patients experienced severe hematological toxicities, and it was considered that this dose level was too toxic. The RD of amrubicin in combination with carboplatin was determined as 35 mg/m2. In combination chemotherapy with irinotecan, which is also a topoisomerase inhibitor, the RD of carboplatin (50 mg/m2) is lower than cisplatin (60 mg/m2).28,18 Considering the hematological toxicity of carboplatin, it is reasonable to lower RD level compared with cisplatin. The principal toxicity in the present study was myelotoxicity. In the toxicity profile of amrubicin, neutropenia was most severe toxicity for determining of the RD for amrubicin. Grade 4 leukopenia, neutropenia, and thrombocytopenia occurred in 12, 42, and 18% of patients treated with amrubicin alone,11 17, 78, and 0% at the RD of amrubicin/cisplatin,12 and 0, 33, and 17% at the RD in the present study, respectively. Although the numbers were small for the comparisons, the rate of grade 4 neutropenia in amrubicin/cisplatin seems too high. Recently, a phase I trial of amrubicin/carboplatin for elderly
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patients was reported.29 The RD of amrubicin was 35 mg/m2 (but with carboplatin AUC 4), which is same as the present study. Grade 4 neutropenia in this study at the RD29 also occurred at high rate of 78%. Unfortunately, one patient died due to severe hematological toxicities during the third cycle of dose level 3. This was discussed at an investigator’s meeting, and it was determined to decrease the dose modification of 80 to 75% for next cycle in the phase II trial. Based on these data, careful hematological toxicity control is essential for use of amrubicin. In conclusion, the present phase I trial demonstrated that the DLTs of amrubicin in combination with carboplatin for patients with ED-SCLC were neutropenia, leukopenia, thrombocytopenia, febrile neutropenia, liver dysfunction, and mucositis. The RD for this regimen is 35 mg/m2 for amrubicin and AUC 5 for carboplatin. Based on the present results, a phase II trial is now ongoing for ED-SCLC.
Phase I of Amrubicin and Carboplatin in SCLC
12.
13. 14. 15.
16.
17.
18.
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Copyright © 2009 by the International Association for the Study of Lung Cancer
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A Phase I Study of Amrubicin and Carboplatin for Previously Untreated Patients with Extensive-Disease Small Cell Lung Cancer Minoru Fukuda, MD, PhD,* Yoichi Nakamura, MD, PhD,† Takashi Kasai, MD, PhD,‡ Seiji Nagashima, MD, PhD,§ Katsumi Nakatomi, MD, PhD,† Seiji Doi, MD, PhD,† Hirofumi Nakano, MD, PhD,† Hiroshi Takatani, MD, PhD,‡ Masaaki Fukuda, MD, PhD,‡ Akitoshi Kinoshita, MD, PhD,储 Hiroshi Soda, MD, PhD,§ Kazuhiro Tsukamoto, MD, PhD,¶ Mikio Oka, MD, PhD,# and Shigeru Kohno, MD, PhD†; Nagasaki Thoracic Oncology Group
Background: Amrubicin and cisplatin are active in the treatment of small cell lung cancer (SCLC), and carboplatin is an analogue of cisplatin with less nonhematological toxicity. The appropriate dose of amrubicin and carboplatin combination chemotherapy for previously untreated patients with extensive-disease (ED) SCLC has not been established. Purpose: To determine the maximum-tolerated dose and doselimiting toxicity (DLT) of amrubicin and carboplatin in ED-SCLC. Patients and methods: Eligibility criteria were chemotherapy-naive ED-SCLC patients, performance status 0 –1, age ⱕ75, and adequate hematological, hepatic, and renal function. Patients received escalating amrubicin doses under a fixed target area under the curve (AUC) 5 of carboplatin (Chatelut formula). Amrubicin and carboplatin were administered by intravenous (IV) infusion on days 1, 2, and 3, and day 1, respectively. The initial dose of amrubicin was 30 mg/m2, and the dose was escalated to 35 and 40 mg/m2. Results: Sixteen patients were enrolled and 15 eligible patients were evaluated. One of six patients in level 1, one of six in level 2, and three of three in level 3 experienced DLTs. The presentation of DLTs included neutropenia, leukopenia, thrombocytopenia, febrile neutropenia, and liver dysfunction. Evaluation of responses were two complete response, nine partial response, three stable disease, and one progressive disease (response rate 73%), and the median survival time was 13.6 months. The maximum-tolerated doses of amrubicin and carboplatin were determined as 40 mg/m2 and AUC 5.
*Department of Medicine, Nagasaki Municipal Hospital; †Second Department of Internal Medicine, Nagasaki University School of Medicine; ‡Japanese Red Cross Nagasaki Atomic Bomb Hospital; §Sasebo General Hospital; 储National Hospital Organization Nagasaki Medical Center; ¶Nagasaki University School of Pharmaceutical Science, Nagasaki; and #Division of Respiratory Diseases, Department of Medicine, Kawasaki Medical School, Kurashiki, Japan. Disclosure: The authors declare no potential conflicts of interest. Address for correspondence: Minoru Fukuda, MD, PhD, Department of Medicine, Nagasaki Municipal Hospital, 6-39 Shinchi, Nagasaki 8508555, Japan. E-mail: [email protected] Copyright © 2009 by the International Association for the Study of Lung Cancer ISSN: 1556-0864/09/0406-0741
Journal of Thoracic Oncology • Volume 4, Number 6, June 2009
A dose of 35 mg/m2 amrubicin and carboplatin AUC 5 was recommended in this regimen. Conclusions: This regimen is associated with an acceptable tolerability profile, and warrants evaluation in the phase II setting. Key Words: Amrubicin, Carboplatin, Small cell lung cancer, Phase I study. (J Thorac Oncol. 2009;4: 741–745)
L
ung cancer is the leading cause of cancer death worldwide. It is also the leading cause of death in Japan with 63,255 deaths (19.2% of all cancer deaths) in 2006.1 Of all lung cancer cases, approximately 20% is small cell lung cancer (SCLC).2 Despite this cancer being highly responsive to chemotherapy initially, most of patients will ultimately relapse and die of recurrent disease within 2 years.3 Recently, combination chemotherapy with irinotecan and cisplatin for extensive-disease (ED) SCLC produced equal or better survival with increased toxicities compared with etoposide and cisplatin, the worldwide standard regimen since 1981.4 – 6 As the therapy provided 2-year survival rates of only 8.0 to 19.5%, with a median survival time (MST) of 9.3 to 12.8 months, new and more effective agents are clearly needed against SCLC. Amrubicin is a completely synthetic anthracycline derivative characterized by a 9-amino group and a simple sugar moiety. The chemical structure and acute toxicity of amrubicin are similar to that of doxorubicin7,8; however, amrubicin shows almost no cardiotoxicity.9,10 Amrubicin alone and combination chemotherapy with cisplatin exhibited high response rates of 75.8% and 87.8% and MSTs of 11.7 and 13.6 months in previously untreated ED-SCLC, respectively.11,12 Carboplatin is a platinum derivative with less renal toxicity and less nausea and vomiting than cisplatin,13 and which has been combined with other newer agents in chemotherapy for SCLC.14 Pharmacodynamic studies have been performed to predict clearance (CL) and administer the appropriate dose of carboplatin in individual patients.15–17 The preceding study evaluated the Chatelut formula, and reported that
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predicted carboplatin CL was closely correlated with the actual CL, and the actual area under the curves (AUCs) of carboplatin nearly reached the target AUC of 5.18 Based on these results, a phase I study of amrubicin and carboplatin was conducted for SCLC. The main objective of this study was to determine the maximum-tolerated dose (MTD) of this combination chemotherapy.
PATIENTS AND METHODS The study protocol was reviewed and approved by the Ethics Committee of each institution, and written informed consent was obtained from all study participants. This study is an independent collaborative (not sponsored) group study.
Patients and Evaluation Eligibility criteria for patients in this study included the following: a histologically and/or cytologically confirmed diagnosis of SCLC; extensive stage disease19; no prior chemotherapy or radiotherapy; age ⱕ75 years; Eastern Cooperative Oncology Group performance status ⱕ1; life expectancy greater than 12 weeks; adequate bone marrow function (leukocyte count ⱖ4000/l, platelet count ⱖ10.0 ⫻ 104/l, and hemoglobin level ⱖ10.0 g/dl); serum bilirubin level ⱕ1.5 mg/dl; alanine aminotransferase (ALT) and aspartate transaminase (AST) levels ⱕ2 times the normal upper limit; serum creatinine level less than the normal upper limit; and no medical problems severe enough to prevent compliance with the protocol.
Treatment and Dose Escalation Under a fixed-target AUC of 5 mg/min/ml for carboplatin on day 1, the starting dose of amrubicin was 30 mg/m2 administered on days 1 to 3. The dose of carboplatin was determined by multiplying the target AUC of 5 by the carboplatin CL, which was predicted with the Chatelut formula17 using the Jaffe´ method to measure serum creatinine.20 The values of serum creatinine obtained using the enzymatic method (X) were converted by the Jaffe´ method (Y) using the formula Y ⫽ 0.97X ⫹ 0.27. Then, the estimated CL (ml/min) was calculated as follows: CL ⫽ 0.134 ⫻ weight ⫹ (218 ⫻ weight ⫻ (1 ⫺ 0.00457 ⫻ age) ⫻ (1 ⫺ 0.314 ⫻ sex)) ⫻ 116.4 ⫻ 10⫺4/(sCr ⫹ 0.28) (with weight in kg, age in years, and sex ⫽ 0 if male and sex ⫽ 1 if female). In Japanese institutions, the measurement method of serum creatinine was changed to the enzymatic method. The dose of amrubicin was increased by 5 mg/m2 as shown in Table 1. Carboplatin was administered during a 60-minute intravenous (IV) infusion of 250 ml of 5% dextrose. Amrubicin was diluted in 20 ml of normal saline and administered as an IV injection during a drip infusion of normal saline. Intrapatient dose escalation was not allowed.
TABLE 1. Dose Escalation Schedule Dose Level 1 2 3
No. of Patients
Amrubicin (mg/m2)
Carboplatin Target AUC (mg/min/ml)
6 6 3
30 35 40
5 5 5
AUC, area under the concentration-time curve.
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Granulocyte colony-stimulating factor was administrated when the neutrophil count reached ⬍1000/l and discontinued when the count recovered to ⬎5000/l. The next cycle at each level commenced after leukocyte and platelet counts reached at least 3000/l and 100,000/l, respectively. In patients showing a response, this chemotherapy was repeated every 3 weeks for four cycles. The dose-limiting toxicity (DLT) was evaluated at the first cycle and defined as follows: grade 4 leukopenia or neutropenia lasting 4 days or more; grade 3 febrile neutropenia; platelets ⬍20,000/l; grade 3 or worse nonhematological toxicity except for nausea, vomiting, anorexia, fatigue, hyponatremia, and infection. For dose escalation, three patients were enrolled at each dose level, and the dose was escalated to the next level when none of patients experienced DLT. When two or more patients experienced DLT, the dose level was defined as the MTD. When one of three patients experienced DLT, an additional three patients were treated at the same level. When none of the additional patients experienced DLT, the dose was escalated to the next level. When one or more of the additional patients experienced DLT, the dose level was also defined as the MTD. The recommended dose (RD) of this regimen for a phase II study was defined as the previous level below the MTD. Dose escalation was determined based only on the data from the first course of chemotherapy. Leukocytes ⱖ3000/l and platelets ⱖ10 ⫻ 104/l were mandatory to commence the second cycle of treatment, and if levels fell below these limits, the second cycle was postponed until the counts recovered. Doses of amrubicin and carboplatin were reduced to 80% when DLT occurred during the first treatment cycle.
Toxicity and Response Evaluation Eligibility, assessability, and tumor responses were determined by external reviewers. Drug toxicity was graded according to the National Cancer Institute Common Toxicity Criteria, Version 2.0.21 Before the first cycle, a blood cell count, urinalysis, and biochemistry tests were performed to assess renal and hepatic function, and electrolytes. This monitoring was repeated during treatment, whereas other investigations were repeated as necessary, to evaluate marker lesions. After the completion of treatment, each disease was assessed and tumors restaged. Tumor response was classified according to Response Evaluation Criteria in Solid Tumors (RECIST) and tumor markers were excluded from the criteria.22 Complete response was defined as the complete disappearance of all clinically detectable tumors for at least 4 weeks and no new lesions. Partial response was defined as at least a 30% decrease in the sum of the longest diameters of target lesion, taking as reference the baseline sum of the longest diameters, the required nonprogression in nontarget lesions, and no new lesions for at least 4 weeks. Stable disease included regression of target lesions insufficient to meet the criteria for partial response, a ⬍20% increase in the sum of the longest diameters of target lesion, taking as reference the smallest sum of the longest diameters recorded since the start of treatment, the required nonprogression in nontarget lesions, and no new lesions for at least 6 weeks. Progressive disease indicated a ⬎20% increase in the sum of the longest diame-
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ters of the target lesion, taking as reference the smallest sum of the longest diameter recorded since the start treatment and/or unequivocal progression of existing nontarget lesions and/or appearance of new lesions. The evaluation of objective tumor response for all patients was performed by external reviewers.
Sixteen patients were enrolled and 15 patients treated in this trial, between July 2003 and August 2007. One patient did not receive the protocol therapy because radiotherapy was needed after enrollment. All patients who received the planned therapy were evaluated for toxicity, response, and survival. The baseline patient characteristics are shown in Table 2.
Treatment Administration A total of 49 cycles of this therapy were administered with a median of 4 cycles per patient: 1 cycle in 2 patients (13%), 2 cycles in 2 (13%), 3 cycles in 3 (20%), 4 cycles in 6 (40%), and 5 cycles in 2 (13%). Six patients were treated at dose levels 1 and 2, and 3 patients were treated at dose level 3.
Dose Escalation At level 1, one of the three original patients experienced DLTs (grade 4 neutropenia lasting 10 days, grade 4 leukopenia lasting 7 days, and grade 4 AST/ALT elevation), but none of the three additional patients experienced DLT. At level 2, one of the three original patients experienced DLT (thrombocytopenia ⬍20,000/ml), but none of three additional patients experienced DLT. At level 3, all three patients experienced DLTs as follows: three patients experienced TABLE 2. Patient Characteristics Gender Male Female Age (yr) Median Range Performance status (ECOG) 0 1 Stage IIIB IV No. of metastasis sites ⱕ1 ⬎1 LDH Normal Increased Weight loss ⱖ5% ⬍5%
grade 4 neutropenia lasting ⱖ4 days, one patient experienced grade 4 leukopenia ⱖ4 days, thrombocytopenia ⬍20,000/ml, febrile neutropenia, and grade 3 mucositis. Level 3 was considered to be too toxic and determined to be the MTD. Therefore, level 2 (amrubicin 35 mg/m2 and carboplatin AUC 5) was regarded as the RD of this regimen for the phase II study.
Hematological Toxicity
RESULTS
Characteristics
Phase I of Amrubicin and Carboplatin in SCLC
No. of Patients 15 0 67 49–75 2 13 6 9 10 5 8 7 2 13
ECOG, Eastern Cooperative Oncology Group; LDH, lactate dehydrogenase.
The worst grades of hematological toxicities experienced by each patient are listed Table 3. Leukopenia, neutropenia, thrombocytopenia, and febrile neutropenia were the principal toxicities. Of the 15 patients, 6 (40%) experienced grade 4 hematological toxicities and 5 (33%) experienced hematological DLTs. At dose level 1, 1 patient (17%) experienced grade 4 hematological toxicity as a DLT. At dose level 2, 2 patients (33%) experienced grade 4 hematological toxicity including 1 (17%) hematological DLT. At dose level 3, all 3 patients experienced grade 4 hematological toxicities as DLTs, and one patient required platelet transfusion. Anemia requiring blood transfusion was observed one patient each at levels 1 and 2. There was one treatment-related death due to severe hematological toxicity. In the third cycle of dose level 3, a patient treated with 32 mg/m2 amrubicin and carboplatin with a target AUC of 4 mg/min/ml because of 20% dose reduction experienced grade 4 leukopenia, neutropenia, and thrombocytopenia and grade 3 febrile neutropenia on day 16. Despite intensive care, the patient developed sepsis due to methicillin-resistant Staphylococcus aureus, and died on day 23.
Nonhematological Toxicity The worst grades of nonhematological toxicity experienced by each patient are listed Table 4. Frequent nonhematological adverse events included nausea, liver dysfunction (AST and ALT elevation), and mucositis of the oral cavity. In total, 2 patients (13%) experienced nonhematological DLTs. At dose level 1, 1 patient experienced grade 4 liver dysfunction. At dose level 3, 1 patient experienced grade 3 mucositis of the oral cavity.
Efficacy All 15 patients were assessable for response. Objective tumor response was observed in 11 patients, with an overall response rate of 73% (95% confidence interval, 45–92%) (Table 5). Two patients (13%) had complete response. At the survival assessment in July 2008, 3 patients were still alive and the other 12 patients had died. The overall survival of 15 patients is shown in Figure 1. MST was 13.6 months and the 1-year survival rate was 50.3%.
DISCUSSION Amrubicin has shown excellent activity for the treatment of previously untreated patients with ED-SCLC. In a single agent phase II study with 45 mg/m2 amrubicin on days 1–3, the overall response rate, MST, and 1-year and 2-year survival rates were 75.8%, 11.7 months, 48.5%, and 20.2%, respectively.11 Because recent randomized trials of cisplatin/ etoposide have demonstrated MSTs of 9.1 to 10.2 months,4 – 6 this single agent might be comparable with standard combi-
Copyright © 2009 by the International Association for the Study of Lung Cancer
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TABLE 3. Hematological Toxicities Anemia Dose Level
Leukopenia
Neutropenia
Plt
No. of Patients
Gr 2
3
2
3
4
2
3
4
3
4
FN 3
6 (1) 6 (1) 3 (3)a
1 2 3
0 0 0
2 3 0
1 2 1
1 (1) 0 2 (1)
1 0 0
4 4 0
1 (1) 2 3 (3)
1 2 1
0 1 (1) 1 (1)
1 (1) 0 1 (1)
1 2 3
The numbers in parentheses are the number of patients who experienced dose-limiting toxicities. a One patient experienced grade 4 leukopenia, neutropenia, thrombocytopenia, and febrile neutropenia. Plt, thrombocytopenia; FN, febrile neutropenia.
TABLE 4. Nonhematological Toxicities Nausea Dose Level
No. of Patients
1 2 3
>2
Gr 1
6 (1) 6 (1) 3 (3)
s-AST
2 2 1
>2
1
2 0 0
s-ALT
1 0 1
1 (1) 0 0
1 a
0 0 2
s-Cr
>2 1 (1) 0 0
a
Mucositis
1
>2
1
>2
1 0 0
0 0 1
0 0 0
0 0 1 (1)b
The numbers in parentheses are the number of patients who experienced dose-limiting toxicities. a Grade 4 toxicity. b Grade 3 toxicity.
TABLE 5. Tumor Response Dose Level
CR
PR
SD
PD
1 2 3 Rate (%)
0 1 1 13
4 5 0 60
2 0 1 27
0 0 1 7
Overall response 73% (95% confidence interval, 45–92%). CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease.
100
MST: 13.6 months 1-year survival rate: 50.3%
Overall survival rate (%)
90 80 70 60 50 40 30 20 10 0
0
3
6
9 12 15 18 Survival time (months)
21
24
27
FIGURE 1. Overall survival curves of the 15 patients enrolled in the present study.
nation chemotherapy. In combination with cisplatin, amrubicin demonstrated promising overall response, MST, and 1-year survival rate of 87.8%, 13.6 months, and 56.1%, respectively.12 Carboplatin is a platinum derivative with similar activity and less nonhematologic toxicity than cisplatin. Thus, taken together with carboplatin and the most active single agent amrubicin, the present combination chemotherapy for SCLC was considered to be worthwhile.
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In vivo comparison between single day therapy and repeated 5-consective-day therapy on several cell lines revealed superior antitumor effects for the 5-day administration of amrubicin.23 As for clinical, phase I trials, both day 1 therapy and 5-consecutive-day therapy every 3 weeks were performed in patients with various types of malignant tumors that had been treated previously.24,25 However, a clear tumor shrinking effect was not seen. Finally, because another anthracycline reported higher response26 and in consideration of its convenience for practical use, 3-consecutive-day administration every 3 weeks came to be recommended for amrubicin. In a phase I/II trial of previously untreated patients with non-small cell lung cancer, the RD of single agent amrubicin was determined as 45 mg/m2.27 This dose was also used in SCLC.11 In combination with cisplatin, the RD of amrubicin was decreased to 40 mg/m2.12 In present study of amrubicin 40 mg/m2 and carboplatin AUC 5 level, all three patients experienced severe hematological toxicities, and it was considered that this dose level was too toxic. The RD of amrubicin in combination with carboplatin was determined as 35 mg/m2. In combination chemotherapy with irinotecan, which is also a topoisomerase inhibitor, the RD of carboplatin (50 mg/m2) is lower than cisplatin (60 mg/m2).28,18 Considering the hematological toxicity of carboplatin, it is reasonable to lower RD level compared with cisplatin. The principal toxicity in the present study was myelotoxicity. In the toxicity profile of amrubicin, neutropenia was most severe toxicity for determining of the RD for amrubicin. Grade 4 leukopenia, neutropenia, and thrombocytopenia occurred in 12, 42, and 18% of patients treated with amrubicin alone,11 17, 78, and 0% at the RD of amrubicin/cisplatin,12 and 0, 33, and 17% at the RD in the present study, respectively. Although the numbers were small for the comparisons, the rate of grade 4 neutropenia in amrubicin/cisplatin seems too high. Recently, a phase I trial of amrubicin/carboplatin for elderly
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Journal of Thoracic Oncology • Volume 4, Number 6, June 2009
patients was reported.29 The RD of amrubicin was 35 mg/m2 (but with carboplatin AUC 4), which is same as the present study. Grade 4 neutropenia in this study at the RD29 also occurred at high rate of 78%. Unfortunately, one patient died due to severe hematological toxicities during the third cycle of dose level 3. This was discussed at an investigator’s meeting, and it was determined to decrease the dose modification of 80 to 75% for next cycle in the phase II trial. Based on these data, careful hematological toxicity control is essential for use of amrubicin. In conclusion, the present phase I trial demonstrated that the DLTs of amrubicin in combination with carboplatin for patients with ED-SCLC were neutropenia, leukopenia, thrombocytopenia, febrile neutropenia, liver dysfunction, and mucositis. The RD for this regimen is 35 mg/m2 for amrubicin and AUC 5 for carboplatin. Based on the present results, a phase II trial is now ongoing for ED-SCLC.
Phase I of Amrubicin and Carboplatin in SCLC
12.
13. 14. 15.
16.
17.
18.
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