- Email: [email protected]
Phase II study of exatecan mesylate (DX-8951f) as first line therapy for advanced non-small cell lung cancer
Lung Cancer (2003) 41, 215 /219
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Phase II study of exatecan mesylate (DX-8951f) as first line therapy for advanced non-small cell lung cancer J.P. Braybrookea, M. Ransonb, C. Manegoldc, K. Mattsond, N. Thatcherb, P. Chevertone, M. Sekiguchif, M. Suzukif, R. Oyamae, D.C. Talbota,* a
Cancer Research UK Medical Oncology Unit, Churchill Hospital, Oxford OX3 7LJ, UK Christie Hospital NHS Trust, Manchester M20 4BX, UK c Thorax Klinik, Amalienstrasse 5, D-69126 Heidelberg, Germany d Department of Internal Medicine, University Hospital, Haartmaninkatu, 00290 Helsinki 29, Finland e Daiichi Pharmaceuticals UK Ltd., London ECA 3JB, UK f Daiichi Pharmaceutical Co., Ltd., Tokyo, Japan b
Received 10 February 2003; received in revised form 27 March 2003; accepted 1 April 2003
KEYWORDS Exatecan; Non-small cell lung cancer; Topoisomerase I; DX-8951f; Phase II
Summary Background: Exatecan mesylate (DX-8951f) is a water soluble analogue of camptothecin that inhibits topoisomerase I. This multi-centre phase II study evaluated the activity of single agent exatecan in previously untreated patients with advanced non-small cell lung cancer (NSCLC). Patients and methods: Patients with histologically or cytologically proven stage IIIb or IV NSCLC were treated with exatecan 0.5 mg/m2 per day by 30 min intra-venous (i.v.) infusion for 5 days every 3 weeks to a maximum of six cycles. Measurable disease was documented prior to study entry and patients were re-staged every two cycles. Pharmacokinetic (PK) sampling was performed during cycle one. Results: 39 patients (32 patients ECOG performance status 0 or 1; 29 male and ten female; mean age 63 years) were entered into the study. Thirty-three completed at least two cycles of exatecan and 11 completed six cycles. Two patients (5.1%, 95% C.I. 0.3 /21.3%) had a partial response, 7 (18.0%) minor response and 8 (20.5%) stable disease. Median time to tumour progression (TTP) was 88 days and median overall survival 262 days. The main toxicity was reversible neutropenia. PK analysis of exatecan demonstrated a mean clearance of 2.28 l/h per m2, volume of distribution 18.2 l/m2 and mean elimination half-life of 7.9 h. Conclusions: Exatecan mesylate has limited activity in advanced NSCLC and is not recommended for further evaluation as a single agent in this tumour type. PK data from this trial supports results established in phase I studies. – 2003 Elsevier Science Ireland Ltd. All rights reserved.
1. Introduction *Corresponding author. Tel.: /44-1865-22-6183; fax: /441865-22-6179. E-mail address: [email protected] (D.C. Talbot).
Lung cancer is the leading cause of cancer deaths in Europe and North America with non-small cell lung cancer (NSCLC) accounting for 75 /80% of
0169-5002/03/$ - see front matter – 2003 Elsevier Science Ireland Ltd. All rights reserved. doi:10.1016/S0169-5002(03)00190-9
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primary lung tumours. Untreated advanced NSCLC has a median survival of less than 6 months with a 10 /15% 1 year survival rate [1]. In recent years, there has been growing interest in the role of cytotoxic chemotherapy to improve survival and quality of life. Many drugs have been studied with randomised trials confirming a survival advantage for platinum or paclitaxel containing schedules compared with best supportive care [2,3]. Exatecan mesylate (DX-8951f, [1S , 9S]-1-amino9-ethyl-5-fluoro-1, 2, 3, 9, 12, 15-hexahydro-9hydroxy-4-methyl-10H , 13H -benzo [de ]-pyrano[3?, 4?: 6, 7]-indolizino [1, 2-b ] quinoline-10, 13-dione monomethanesulfonate (salt), dihydrate; Daiichi Pharmaceutical Co., Ltd., Tokyo, Japan) is a water-soluble hexa-cyclic analogue of camptothecin that does not require enzymatic activation [4]. In phase one studies, exatecan has been evaluated in a range of schedules including daily times five intra-venous (i.v.) infusion every 3 weeks, 30 min i.v. infusion every 3 weeks, 24 h i.v. infusion every 3 weeks and as a 30 min i.v. infusion weekly for 3 out of 4 weeks [5 /8]. In each study, dose-limiting toxicity was reversible neutropenia and thrombocytopenia. In contrast to irinotecan, only mild gastro-intestinal disturbance was seen. Partial responses were documented in several tumour types, including lung cancer, leading to further evaluation of exatecan in phase II studies. The aim of this trial was to determine response rates for previously untreated patients with locally advanced or metastatic NSCLC. The decision to select a daily times five schedule was based on phase I data indicating greater anti-tumour activity with a fractionated schedule and less nausea and vomiting. The trial was designed as a multi-centre, single arm, open label study forming part of the global development of exatecan.
2. Patients and methods Patients with histologically or cytologically proven stage IIIb or IV NSCLC, not suitable for radical chemo-irradiation, were treated at four European centres. Eligibility criteria included: no previous chemotherapy or radiotherapy (except to 5/25% of the bone marrow), measurable disease, ECOG performance status 5/2, age ]/18 years, predicted survival ]/12 weeks, absolute neutrophil count (ANC) ]/1.5 /109 per l, platelet count ]/ 100 /109 per l, adequate liver and renal function (bilirubin 5/1.5 mg/dl, SGOT 5/2 / upper limit of normal or 5/ 5 / upper limit in presence of liver metastases, serum creatinine 5/2.0 mg/dl) no known brain metastases, no previous malignancy,
J.P. Braybrooke et al.
no serious concurrent medical illness and, where applicable, approved methods of birth control. All patients gave written informed consent and the trial was conducted in accordance with the ‘Declaration of Helsinki’ and with the approval of the local research ethics committee at each participating institution. Exatecan was administered at a dose of 0.5 mg/ m2 per day by daily i.v. infusion over 30 min for 5 consecutive days. Treatment was repeated every 21 days. The dose of exatecan was reduced to 0.4 mg/m2 per day for all subsequent cycles if ANC B/ 0.5 /109 per l for ]/7 days, neutropenic fever with ANC B/1.0 /109 per l, platelet count B/25 / 109 per l, grade III non-haematological toxicity, grade II neurotoxicity or treatment delays. Patients who could not tolerate 0.4 mg/m2 per day were withdrawn from the study. Full supportive care was permitted. Patients did not receive prophylactic anti-emetics prior to commencing cycle one although anti-emetics could subsequently be prescribed if required. Within 7 days prior to entry into the study, all patients had a full clinical history and examination, baseline haematology and biochemistry, chest Xray and, if appropriate, additional imaging studies to determine measurable disease (within 28 days). Toxicity was assessed after every cycle and graded according to NCI common toxicity criteria (version 2)[9]. Tumour response was determined every two cycles. Patients with stable or responding disease (according to modified SWOG criteria [10]) could continue to a maximum of six cycles. Responses were confirmed by independent review of imaging studies. Venous blood was taken during cycle one (days 1 and 5 pre infusion, at 30 min, 0.5 /2, 4 /8 h and, on day 1 only, at 24 h) for pharmacokinetic (PK) studies. The total concentrations of exatecan were evaluated by HPLC as described previously [11]. A linear two-compartment population PK model was used for analysis utilising IT2S† software. Following completion of the trial patients were assessed every 6 weeks until progression. The study was designed to determine anti-tumour activity of exatecan and the sample size was calculated using Simon’s optimal two-stage design. In this, 12 evaluable patients were enrolled. If no patients responded, the trial was terminated. If one or more patients responded, then a further 25 evaluable patients were recruited. This design yields a ]/0.9 probability of a positive result if the true response rate is ]/20% and a ]/0.9 probability of a negative result if the true response rate is 5/5% with ]/0.54 probability of early negative stopping [12].
217
Table 1 Patients’ characteristics Demographics
Number
Patients enrolled Patients treated
40 39
Gender Male Female Mean age (range), years
29 10 63 (43 /79)
Histology NSCLC unspecified Squamous cell Adenocarcinoma Large cell
7 14 14 4
Performance status 0 1 2
7 25 7
Stage of disease a IIIb IV
14 25
Tumour sites Lung Lymph node Liver Bone
39 19 5 2
a
At study entry.
3. Results 40 patients were entered into the study (Table 1). One patient did not receive any study medication and was excluded from analysis. Thirty-three patients (84.6%) completed at least two cycles of treatment, 20 (51.3%) completed four cycles and 11 (28.2%) completed six cycles. Patients who did not complete six cycles were withdrawn from the study as follows: 17 (43.6%) disease progression, six (15.4%) adverse events, three (7.7%) died during the study, one (2.6%) because of non-compliance on day 1 and one (2.6%) because of protocol violation on day 1.
4. Response Two patients (5.1%, 95% C.I. 0.3 /21.3%) had a partial response, seven patients (18.0%) minor response, eight patients (20.5%) stable disease and 22 (56.4%) progressive disease. The responding patients were a 79-year-old woman with stage IIIb disease who had a 90% reduction in the size of her primary tumour and a complete response in med-
iastinal lymph nodes and a 73-year-old man with a 55% reduction in his primary lung cancer. Both patients completed six cycles of chemotherapy. The time to tumour progression (TTP) for these two patients was 252 and 155 days, respectively. The median TTP for all patients was 88 days (95% C.I. 50 /129 days) and the median survival 262 days (95% C.I. 125 /291 days). Performance status at the end of treatment was unchanged for 21 patients, improved for three and deteriorated for 15.
5. Toxicity Toxicity is described in Table 2. Neutropenia was the most frequently reported significant adverse event (17.9% grade II, 23.1% grade III, 20.5% grade IV; all cycles) with a mean time to maximal neutropenia of 12.5 days. Other haematological toxicity included anaemia (35.9% grade II, 2.6% grade III; all cycles) and thrombocytopenia (7.7% grade II, 5.1% grade III; all cycles). Nausea, vomiting, constipation, fatigue and alopecia were the most common non-haematological toxicities (Table 2). Diarrhoea was not a significant side effect for most patients (15.4% grade I, 10.3% grade II). There was no evidence for cumulative toxicity with successive cycles. Ten different patients had at least one treatment delay or omission (mostly due to neutropenia). Eleven patients required a dose reduction during the study, eight of whom were dose reduced after cycle 1 because of haematological changes. Three patients died whilst on treatment (two with progressive disease and one with neutropenic sepsis 8 days after their third cycle of exatecan).
6. Pharmacokinetics The PKs of exatecan were linear in this study. The mean clearance was 2.28 l/h per m2 (Percent coefficient of variation (CV%) 50.7%) and volume of distribution 18.2 l/m2 (CV% 26.2%). The mean elimination half-life was 7.9 h (CV% 33.4%). There was no auto-inhibition or induction of exatecan clearance over the first 5-day cycle of administration.
7. Discussion NSCLC is frequently responsive to cytotoxic chemotherapy. In randomised trials, cisplatin containing schedules and single agent paclitaxel have demonstrated proven survival advantages com-
218
J.P. Braybrooke et al.
Table 2 Toxicity, worst grade (NCI-CTC) Adverse event
Number of patients (N/39) Grade 1
Grade 2
Grade 3
Grade 4
Total
(5.1%) (20.5%) (7.7%) (12.8%)
7 14 1 3
(17.9%) (35.9%) (2.6%) (7.7%)
9 1 6 2
(23.1%) (2.6%) (15.4%) (5.1%)
8a (20.5%) 0 2 (5.1%) 0
26 23 12 10
(66.7%) (59.0%) (30.8%) (25.6%)
Non-haematological toxicity Nausea 13 (33.3%) Vomiting 13 (33.3%) Constipation 10 (25.6%) Alopecia 7 (17.9%) Fatigue 3 (7.7%) Dyspnoea 1 (2.6%) Chest pain 2 (5.1%) Diarrhoea 6 (15.4%) Anorexia 1 (2.6%)
13 6 5 9 7 3 7 4 7
(33.3%) (15.4%) (12.8%) (23.1%) (17.9%) (7.7%) (17.9%) (10.3%) (17.9%)
1 2 1 0 5 6 1 0 0
(2.6%) (5.1%) (2.6%)
0 0 0 0 0 1 (2.6%) 0 0 0
27 21 16 16 15 11 10 10 8
(69.2%) (53.8%) (41.0%) (41.0%) (38.5%) (28.2%) (25.6%) (25.6%) (20.5%)
Haematological toxicity Neutropenia Anaemia Leucopenia Thrombocytopenia
a
2 8 3 5
(12.8%) (15.4%) (2.6%)
One patient died secondary to neutropenic sepsis (Grade 5 toxicity).
pared with best supportive care [2,3]. However, the prognosis remains poor with few randomised studies reporting a median survival of more than 8 months [2,13]. In this phase II trial of exatecan mesylate, as first line single agent treatment for advanced NSCLC, response rates were low using a daily times five schedule every 3 weeks. Five percent of patients had a documented partial response, 18% of patients minor response and 21% of patients stable disease. The median survival for all patients treated in this study was 262 days (95% C.I. 125 /291). Whilst poor response rates suggest limited activity, the median survival in this trial is encouraging and comparable to phase II trials with single agent vinorelbine, gemcitabine and topotecan [14 /18]. The relatively good median survival, in comparison to the low response rates, may indicate that stabilisation of disease achieved with exatecan is important biologically and is influencing survival. This is comparable to data from studies with another topoisomerase I inhibitor, topotecan, in which modest response rates were seen in NSCLC (0 /18%) but survival was significantly longer than expected for this group of patients [18]. Alternatively, survival may have been influenced by a proportion of patients going on to receive radiotherapy or second line chemotherapy with platinum containing schedules. Improved response rates with combination schedules must be balanced against increased toxicity. Single agent exatecan was well tolerated in this trial with observed side-effects as predicted from
phase I trials. Reversible grade III or IV neutropenia was documented in 44% of patients and 5% patients experienced grade III thrombocytopenia. One patient death during study was attributed to myelosuppression secondary to chemotherapy. Nonhaematological toxicity was generally mild (Table 2). Nausea was well controlled with standard antiemetics and there was no evidence of significant gastro-intestinal disturbance. Significant levels of fatigue (grade II or III, 31% patients) were observed. This may have reflected advanced disease as well as being treatment related. Limited PK sampling was performed. The mean clearance of exatecan was 2.28 l/h per m2 which is comparable to previously reported phase I data. In this study, the mean elimination half-life of 7.9 h was significantly less than previous observations for this schedule [5] and may have been due to the limited sampling strategy adopted. Further PK data from pooled phase II studies will be reported separately. In conclusion, exatecan cannot be recommended as single agent first line therapy for NSCLC due to limited activity in this setting. Trials with platinum are indicated, both because of the activity of platinum in NSCLC and because of the potential synergy between cisplatin and topoisomerase I inhibitors [19,20]. This study has found that single agent exatecan was well tolerated and, despite low response rates, median survival was comparable to other single agent cytotoxics used to treat patients with advanced NSCLC. Activity from phase II trials with other tumour types is awaited.
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References [1] Rapp E, Pater JL, Willan A, et al. Chemotherapy can prolong survival in patients with advanced non-small-cell lung cancer */report of a Canadian multicenter randomized trial. J Clin Oncol 1988;6:633 /41. [2] Non-Small Cell Lung Cancer Collaborative Group. Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials. Br Med J 1995;311:899 /909. [3] Ranson M, Davidson N, Nicolson M, et al. Randomized trial of paclitaxel plus supportive care versus supportive care for patients with advanced non-small-cell lung cancer. J Natl Cancer Inst 2000;92:1074 /80. [4] Mitsui I, Kumazawa E, Hirota Y, et al. A new water-soluble camptothecin derivative, DX-8951f, exhibits potent antitumor activity against human tumors in vitro and in vivo. Jpn J Cancer Res 1995;86:776 /82. [5] Rowinsky EK, Johnson TR, Geyer CE, et al. DX-8951f, a hexacyclic camptothecin analog, on a daily-times-five schedule: a phase I and pharmacokinetic study in patients with advanced solid malignancies. J Clin Oncol 2000;18:3151 /63. [6] Boige V, Raymond E, Faivre S, et al. Phase I and pharmacokinetic study of the camptothecin analog DX-8951f administered as a 30-min infusion every 3 weeks in patients with advanced cancer. J Clin Oncol 2000;18:3986 /92. [7] Royce ME, Hoff PM, Dumas P, et al. Phase I and pharmacokinetic study of exatecan mesylate (DX-8951f): a novel camptothecin analog. J Clin Oncol 2001;19:1493 /500. [8] Braybrooke JP, Boven E, Bates NP, et al. Phase I and pharmacokinetic study of the topoisomerase I inhibitor, exatecan mesylate (DX-8951f) using a weekly 30-min intravenous infusion, in patients with advanced solid malignancies, Ann Oncol 2003, in press. [9] National Cancer Institute guidelines for the reporting of adverse drug reactions. Bethesda, MD: Division of Cancer Treatment, National Cancer Institute, 1988.
.
[10] Green S, Weiss G. Southwest Oncology Group standard response criteria, endpoint definitions and toxicity criteria. Invest New Drugs 1992;10:239 /53. [11] Oguma T, Ohshima Y, Nakaoka M. Sensitive high-performance liquid chromatographic method for the determination of the lactone form and the lactone plus hydroxy-acid forms of the new camptothecin derivative DX-8951 in human plasma using fluorescence detection. J Chromatogr B Biomed Sci Appl 2000;740:237 /45. [12] Simon R. Optimal two-stage designs for phase II clinical trials. Control Clin Trials 1989;10:1 /10. [13] Schiller JH, Harrington D, Belani CP, et al. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. New Engl J Med 2002;346:92 /8. [14] Anderson H, Lund B, Bach F, Thatcher N, et al. Single-agent activity of weekly gemcitabine in advanced non-small-cell lung cancer: a phase II study. J Clin Oncol 1994;12:1821 /6. [15] Vokes EE, Rosenberg RK, Jahanzeb M, et al. Multicenter phase II study of weekly oral vinorelbine for stage IV nonsmall-cell lung cancer. J Clin Oncol 1995;13:637 /44. [16] Perez-Soler R, Fossella FV, Glisson BS, et al. Phase II study of topotecan in patients with advanced non-small-cell lung cancer previously untreated with chemotherapy. J Clin Oncol 1996;14:503 /13. [17] The Elderly Lung Cancer Vinorelbine Italian Study Group. Effects of vinorelbine on quality of life and survival of elderly patients with advanced non-small-cell lung cancer. J Natl Cancer Inst 1999;91:66 /72. [18] White S, Cheeseman S, Thatcher N, et al. Phase II study of oral topotecan in advanced non-small cell lung cancer. Clin Cancer Res 2000;6:868 /73. [19] Kano Y, Suzuki K, Akutsu M, et al. Effects of CPT-11 in combination with other anti-cancer agents in culture. Int J Cancer 1992;50:604 /10. [20] Kudoh S, Takada M, Masuda N, et al. Enhanced antitumor efficacy of a combination of CPT-11, a new derivative of camptothecin, and cisplatin against human lung tumor xenografts. Jpn J Cancer Res 1993;84:203 /7.
www.elsevier.com/locate/lungcan
Phase II study of exatecan mesylate (DX-8951f) as first line therapy for advanced non-small cell lung cancer J.P. Braybrookea, M. Ransonb, C. Manegoldc, K. Mattsond, N. Thatcherb, P. Chevertone, M. Sekiguchif, M. Suzukif, R. Oyamae, D.C. Talbota,* a
Cancer Research UK Medical Oncology Unit, Churchill Hospital, Oxford OX3 7LJ, UK Christie Hospital NHS Trust, Manchester M20 4BX, UK c Thorax Klinik, Amalienstrasse 5, D-69126 Heidelberg, Germany d Department of Internal Medicine, University Hospital, Haartmaninkatu, 00290 Helsinki 29, Finland e Daiichi Pharmaceuticals UK Ltd., London ECA 3JB, UK f Daiichi Pharmaceutical Co., Ltd., Tokyo, Japan b
Received 10 February 2003; received in revised form 27 March 2003; accepted 1 April 2003
KEYWORDS Exatecan; Non-small cell lung cancer; Topoisomerase I; DX-8951f; Phase II
Summary Background: Exatecan mesylate (DX-8951f) is a water soluble analogue of camptothecin that inhibits topoisomerase I. This multi-centre phase II study evaluated the activity of single agent exatecan in previously untreated patients with advanced non-small cell lung cancer (NSCLC). Patients and methods: Patients with histologically or cytologically proven stage IIIb or IV NSCLC were treated with exatecan 0.5 mg/m2 per day by 30 min intra-venous (i.v.) infusion for 5 days every 3 weeks to a maximum of six cycles. Measurable disease was documented prior to study entry and patients were re-staged every two cycles. Pharmacokinetic (PK) sampling was performed during cycle one. Results: 39 patients (32 patients ECOG performance status 0 or 1; 29 male and ten female; mean age 63 years) were entered into the study. Thirty-three completed at least two cycles of exatecan and 11 completed six cycles. Two patients (5.1%, 95% C.I. 0.3 /21.3%) had a partial response, 7 (18.0%) minor response and 8 (20.5%) stable disease. Median time to tumour progression (TTP) was 88 days and median overall survival 262 days. The main toxicity was reversible neutropenia. PK analysis of exatecan demonstrated a mean clearance of 2.28 l/h per m2, volume of distribution 18.2 l/m2 and mean elimination half-life of 7.9 h. Conclusions: Exatecan mesylate has limited activity in advanced NSCLC and is not recommended for further evaluation as a single agent in this tumour type. PK data from this trial supports results established in phase I studies. – 2003 Elsevier Science Ireland Ltd. All rights reserved.
1. Introduction *Corresponding author. Tel.: /44-1865-22-6183; fax: /441865-22-6179. E-mail address: [email protected] (D.C. Talbot).
Lung cancer is the leading cause of cancer deaths in Europe and North America with non-small cell lung cancer (NSCLC) accounting for 75 /80% of
0169-5002/03/$ - see front matter – 2003 Elsevier Science Ireland Ltd. All rights reserved. doi:10.1016/S0169-5002(03)00190-9
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primary lung tumours. Untreated advanced NSCLC has a median survival of less than 6 months with a 10 /15% 1 year survival rate [1]. In recent years, there has been growing interest in the role of cytotoxic chemotherapy to improve survival and quality of life. Many drugs have been studied with randomised trials confirming a survival advantage for platinum or paclitaxel containing schedules compared with best supportive care [2,3]. Exatecan mesylate (DX-8951f, [1S , 9S]-1-amino9-ethyl-5-fluoro-1, 2, 3, 9, 12, 15-hexahydro-9hydroxy-4-methyl-10H , 13H -benzo [de ]-pyrano[3?, 4?: 6, 7]-indolizino [1, 2-b ] quinoline-10, 13-dione monomethanesulfonate (salt), dihydrate; Daiichi Pharmaceutical Co., Ltd., Tokyo, Japan) is a water-soluble hexa-cyclic analogue of camptothecin that does not require enzymatic activation [4]. In phase one studies, exatecan has been evaluated in a range of schedules including daily times five intra-venous (i.v.) infusion every 3 weeks, 30 min i.v. infusion every 3 weeks, 24 h i.v. infusion every 3 weeks and as a 30 min i.v. infusion weekly for 3 out of 4 weeks [5 /8]. In each study, dose-limiting toxicity was reversible neutropenia and thrombocytopenia. In contrast to irinotecan, only mild gastro-intestinal disturbance was seen. Partial responses were documented in several tumour types, including lung cancer, leading to further evaluation of exatecan in phase II studies. The aim of this trial was to determine response rates for previously untreated patients with locally advanced or metastatic NSCLC. The decision to select a daily times five schedule was based on phase I data indicating greater anti-tumour activity with a fractionated schedule and less nausea and vomiting. The trial was designed as a multi-centre, single arm, open label study forming part of the global development of exatecan.
2. Patients and methods Patients with histologically or cytologically proven stage IIIb or IV NSCLC, not suitable for radical chemo-irradiation, were treated at four European centres. Eligibility criteria included: no previous chemotherapy or radiotherapy (except to 5/25% of the bone marrow), measurable disease, ECOG performance status 5/2, age ]/18 years, predicted survival ]/12 weeks, absolute neutrophil count (ANC) ]/1.5 /109 per l, platelet count ]/ 100 /109 per l, adequate liver and renal function (bilirubin 5/1.5 mg/dl, SGOT 5/2 / upper limit of normal or 5/ 5 / upper limit in presence of liver metastases, serum creatinine 5/2.0 mg/dl) no known brain metastases, no previous malignancy,
J.P. Braybrooke et al.
no serious concurrent medical illness and, where applicable, approved methods of birth control. All patients gave written informed consent and the trial was conducted in accordance with the ‘Declaration of Helsinki’ and with the approval of the local research ethics committee at each participating institution. Exatecan was administered at a dose of 0.5 mg/ m2 per day by daily i.v. infusion over 30 min for 5 consecutive days. Treatment was repeated every 21 days. The dose of exatecan was reduced to 0.4 mg/m2 per day for all subsequent cycles if ANC B/ 0.5 /109 per l for ]/7 days, neutropenic fever with ANC B/1.0 /109 per l, platelet count B/25 / 109 per l, grade III non-haematological toxicity, grade II neurotoxicity or treatment delays. Patients who could not tolerate 0.4 mg/m2 per day were withdrawn from the study. Full supportive care was permitted. Patients did not receive prophylactic anti-emetics prior to commencing cycle one although anti-emetics could subsequently be prescribed if required. Within 7 days prior to entry into the study, all patients had a full clinical history and examination, baseline haematology and biochemistry, chest Xray and, if appropriate, additional imaging studies to determine measurable disease (within 28 days). Toxicity was assessed after every cycle and graded according to NCI common toxicity criteria (version 2)[9]. Tumour response was determined every two cycles. Patients with stable or responding disease (according to modified SWOG criteria [10]) could continue to a maximum of six cycles. Responses were confirmed by independent review of imaging studies. Venous blood was taken during cycle one (days 1 and 5 pre infusion, at 30 min, 0.5 /2, 4 /8 h and, on day 1 only, at 24 h) for pharmacokinetic (PK) studies. The total concentrations of exatecan were evaluated by HPLC as described previously [11]. A linear two-compartment population PK model was used for analysis utilising IT2S† software. Following completion of the trial patients were assessed every 6 weeks until progression. The study was designed to determine anti-tumour activity of exatecan and the sample size was calculated using Simon’s optimal two-stage design. In this, 12 evaluable patients were enrolled. If no patients responded, the trial was terminated. If one or more patients responded, then a further 25 evaluable patients were recruited. This design yields a ]/0.9 probability of a positive result if the true response rate is ]/20% and a ]/0.9 probability of a negative result if the true response rate is 5/5% with ]/0.54 probability of early negative stopping [12].
217
Table 1 Patients’ characteristics Demographics
Number
Patients enrolled Patients treated
40 39
Gender Male Female Mean age (range), years
29 10 63 (43 /79)
Histology NSCLC unspecified Squamous cell Adenocarcinoma Large cell
7 14 14 4
Performance status 0 1 2
7 25 7
Stage of disease a IIIb IV
14 25
Tumour sites Lung Lymph node Liver Bone
39 19 5 2
a
At study entry.
3. Results 40 patients were entered into the study (Table 1). One patient did not receive any study medication and was excluded from analysis. Thirty-three patients (84.6%) completed at least two cycles of treatment, 20 (51.3%) completed four cycles and 11 (28.2%) completed six cycles. Patients who did not complete six cycles were withdrawn from the study as follows: 17 (43.6%) disease progression, six (15.4%) adverse events, three (7.7%) died during the study, one (2.6%) because of non-compliance on day 1 and one (2.6%) because of protocol violation on day 1.
4. Response Two patients (5.1%, 95% C.I. 0.3 /21.3%) had a partial response, seven patients (18.0%) minor response, eight patients (20.5%) stable disease and 22 (56.4%) progressive disease. The responding patients were a 79-year-old woman with stage IIIb disease who had a 90% reduction in the size of her primary tumour and a complete response in med-
iastinal lymph nodes and a 73-year-old man with a 55% reduction in his primary lung cancer. Both patients completed six cycles of chemotherapy. The time to tumour progression (TTP) for these two patients was 252 and 155 days, respectively. The median TTP for all patients was 88 days (95% C.I. 50 /129 days) and the median survival 262 days (95% C.I. 125 /291 days). Performance status at the end of treatment was unchanged for 21 patients, improved for three and deteriorated for 15.
5. Toxicity Toxicity is described in Table 2. Neutropenia was the most frequently reported significant adverse event (17.9% grade II, 23.1% grade III, 20.5% grade IV; all cycles) with a mean time to maximal neutropenia of 12.5 days. Other haematological toxicity included anaemia (35.9% grade II, 2.6% grade III; all cycles) and thrombocytopenia (7.7% grade II, 5.1% grade III; all cycles). Nausea, vomiting, constipation, fatigue and alopecia were the most common non-haematological toxicities (Table 2). Diarrhoea was not a significant side effect for most patients (15.4% grade I, 10.3% grade II). There was no evidence for cumulative toxicity with successive cycles. Ten different patients had at least one treatment delay or omission (mostly due to neutropenia). Eleven patients required a dose reduction during the study, eight of whom were dose reduced after cycle 1 because of haematological changes. Three patients died whilst on treatment (two with progressive disease and one with neutropenic sepsis 8 days after their third cycle of exatecan).
6. Pharmacokinetics The PKs of exatecan were linear in this study. The mean clearance was 2.28 l/h per m2 (Percent coefficient of variation (CV%) 50.7%) and volume of distribution 18.2 l/m2 (CV% 26.2%). The mean elimination half-life was 7.9 h (CV% 33.4%). There was no auto-inhibition or induction of exatecan clearance over the first 5-day cycle of administration.
7. Discussion NSCLC is frequently responsive to cytotoxic chemotherapy. In randomised trials, cisplatin containing schedules and single agent paclitaxel have demonstrated proven survival advantages com-
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Table 2 Toxicity, worst grade (NCI-CTC) Adverse event
Number of patients (N/39) Grade 1
Grade 2
Grade 3
Grade 4
Total
(5.1%) (20.5%) (7.7%) (12.8%)
7 14 1 3
(17.9%) (35.9%) (2.6%) (7.7%)
9 1 6 2
(23.1%) (2.6%) (15.4%) (5.1%)
8a (20.5%) 0 2 (5.1%) 0
26 23 12 10
(66.7%) (59.0%) (30.8%) (25.6%)
Non-haematological toxicity Nausea 13 (33.3%) Vomiting 13 (33.3%) Constipation 10 (25.6%) Alopecia 7 (17.9%) Fatigue 3 (7.7%) Dyspnoea 1 (2.6%) Chest pain 2 (5.1%) Diarrhoea 6 (15.4%) Anorexia 1 (2.6%)
13 6 5 9 7 3 7 4 7
(33.3%) (15.4%) (12.8%) (23.1%) (17.9%) (7.7%) (17.9%) (10.3%) (17.9%)
1 2 1 0 5 6 1 0 0
(2.6%) (5.1%) (2.6%)
0 0 0 0 0 1 (2.6%) 0 0 0
27 21 16 16 15 11 10 10 8
(69.2%) (53.8%) (41.0%) (41.0%) (38.5%) (28.2%) (25.6%) (25.6%) (20.5%)
Haematological toxicity Neutropenia Anaemia Leucopenia Thrombocytopenia
a
2 8 3 5
(12.8%) (15.4%) (2.6%)
One patient died secondary to neutropenic sepsis (Grade 5 toxicity).
pared with best supportive care [2,3]. However, the prognosis remains poor with few randomised studies reporting a median survival of more than 8 months [2,13]. In this phase II trial of exatecan mesylate, as first line single agent treatment for advanced NSCLC, response rates were low using a daily times five schedule every 3 weeks. Five percent of patients had a documented partial response, 18% of patients minor response and 21% of patients stable disease. The median survival for all patients treated in this study was 262 days (95% C.I. 125 /291). Whilst poor response rates suggest limited activity, the median survival in this trial is encouraging and comparable to phase II trials with single agent vinorelbine, gemcitabine and topotecan [14 /18]. The relatively good median survival, in comparison to the low response rates, may indicate that stabilisation of disease achieved with exatecan is important biologically and is influencing survival. This is comparable to data from studies with another topoisomerase I inhibitor, topotecan, in which modest response rates were seen in NSCLC (0 /18%) but survival was significantly longer than expected for this group of patients [18]. Alternatively, survival may have been influenced by a proportion of patients going on to receive radiotherapy or second line chemotherapy with platinum containing schedules. Improved response rates with combination schedules must be balanced against increased toxicity. Single agent exatecan was well tolerated in this trial with observed side-effects as predicted from
phase I trials. Reversible grade III or IV neutropenia was documented in 44% of patients and 5% patients experienced grade III thrombocytopenia. One patient death during study was attributed to myelosuppression secondary to chemotherapy. Nonhaematological toxicity was generally mild (Table 2). Nausea was well controlled with standard antiemetics and there was no evidence of significant gastro-intestinal disturbance. Significant levels of fatigue (grade II or III, 31% patients) were observed. This may have reflected advanced disease as well as being treatment related. Limited PK sampling was performed. The mean clearance of exatecan was 2.28 l/h per m2 which is comparable to previously reported phase I data. In this study, the mean elimination half-life of 7.9 h was significantly less than previous observations for this schedule [5] and may have been due to the limited sampling strategy adopted. Further PK data from pooled phase II studies will be reported separately. In conclusion, exatecan cannot be recommended as single agent first line therapy for NSCLC due to limited activity in this setting. Trials with platinum are indicated, both because of the activity of platinum in NSCLC and because of the potential synergy between cisplatin and topoisomerase I inhibitors [19,20]. This study has found that single agent exatecan was well tolerated and, despite low response rates, median survival was comparable to other single agent cytotoxics used to treat patients with advanced NSCLC. Activity from phase II trials with other tumour types is awaited.
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References [1] Rapp E, Pater JL, Willan A, et al. Chemotherapy can prolong survival in patients with advanced non-small-cell lung cancer */report of a Canadian multicenter randomized trial. J Clin Oncol 1988;6:633 /41. [2] Non-Small Cell Lung Cancer Collaborative Group. Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials. Br Med J 1995;311:899 /909. [3] Ranson M, Davidson N, Nicolson M, et al. Randomized trial of paclitaxel plus supportive care versus supportive care for patients with advanced non-small-cell lung cancer. J Natl Cancer Inst 2000;92:1074 /80. [4] Mitsui I, Kumazawa E, Hirota Y, et al. A new water-soluble camptothecin derivative, DX-8951f, exhibits potent antitumor activity against human tumors in vitro and in vivo. Jpn J Cancer Res 1995;86:776 /82. [5] Rowinsky EK, Johnson TR, Geyer CE, et al. DX-8951f, a hexacyclic camptothecin analog, on a daily-times-five schedule: a phase I and pharmacokinetic study in patients with advanced solid malignancies. J Clin Oncol 2000;18:3151 /63. [6] Boige V, Raymond E, Faivre S, et al. Phase I and pharmacokinetic study of the camptothecin analog DX-8951f administered as a 30-min infusion every 3 weeks in patients with advanced cancer. J Clin Oncol 2000;18:3986 /92. [7] Royce ME, Hoff PM, Dumas P, et al. Phase I and pharmacokinetic study of exatecan mesylate (DX-8951f): a novel camptothecin analog. J Clin Oncol 2001;19:1493 /500. [8] Braybrooke JP, Boven E, Bates NP, et al. Phase I and pharmacokinetic study of the topoisomerase I inhibitor, exatecan mesylate (DX-8951f) using a weekly 30-min intravenous infusion, in patients with advanced solid malignancies, Ann Oncol 2003, in press. [9] National Cancer Institute guidelines for the reporting of adverse drug reactions. Bethesda, MD: Division of Cancer Treatment, National Cancer Institute, 1988.
.
[10] Green S, Weiss G. Southwest Oncology Group standard response criteria, endpoint definitions and toxicity criteria. Invest New Drugs 1992;10:239 /53. [11] Oguma T, Ohshima Y, Nakaoka M. Sensitive high-performance liquid chromatographic method for the determination of the lactone form and the lactone plus hydroxy-acid forms of the new camptothecin derivative DX-8951 in human plasma using fluorescence detection. J Chromatogr B Biomed Sci Appl 2000;740:237 /45. [12] Simon R. Optimal two-stage designs for phase II clinical trials. Control Clin Trials 1989;10:1 /10. [13] Schiller JH, Harrington D, Belani CP, et al. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. New Engl J Med 2002;346:92 /8. [14] Anderson H, Lund B, Bach F, Thatcher N, et al. Single-agent activity of weekly gemcitabine in advanced non-small-cell lung cancer: a phase II study. J Clin Oncol 1994;12:1821 /6. [15] Vokes EE, Rosenberg RK, Jahanzeb M, et al. Multicenter phase II study of weekly oral vinorelbine for stage IV nonsmall-cell lung cancer. J Clin Oncol 1995;13:637 /44. [16] Perez-Soler R, Fossella FV, Glisson BS, et al. Phase II study of topotecan in patients with advanced non-small-cell lung cancer previously untreated with chemotherapy. J Clin Oncol 1996;14:503 /13. [17] The Elderly Lung Cancer Vinorelbine Italian Study Group. Effects of vinorelbine on quality of life and survival of elderly patients with advanced non-small-cell lung cancer. J Natl Cancer Inst 1999;91:66 /72. [18] White S, Cheeseman S, Thatcher N, et al. Phase II study of oral topotecan in advanced non-small cell lung cancer. Clin Cancer Res 2000;6:868 /73. [19] Kano Y, Suzuki K, Akutsu M, et al. Effects of CPT-11 in combination with other anti-cancer agents in culture. Int J Cancer 1992;50:604 /10. [20] Kudoh S, Takada M, Masuda N, et al. Enhanced antitumor efficacy of a combination of CPT-11, a new derivative of camptothecin, and cisplatin against human lung tumor xenografts. Jpn J Cancer Res 1993;84:203 /7.