Annals of Oncology Advance Access originally published online on September 4, 2007
Annals of Oncology 2007 18(12):2009-2014; doi:10.1093/annonc/mdm374
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© 2007 European Society for Medical Oncology
lung cancer |
Multicenter phase II trial of Genexol-PM, a novel Cremophor-free, polymeric micelle formulation of paclitaxel, with cisplatin in patients with advanced non-small-cell lung cancer
1 Department of Internal Medicine, Seoul National University Hospital, Seoul
2 Cancer Research Institute, Seoul National University College of Medicine, Seoul
3 Department of Internal Medicine, Kyung Hee University Hospital, Seoul
4 Department of Internal Medicine, St Vincent's Hospital, Suwon
5 Department of Internal Medicine, Asan Medical Center, Seoul
6 Department of Internal Medicine, Korea University Anam Hospital, Seoul
7 Department of Internal Medicine, Korea University Guro Hospital, Seoul
8 Department of Medicine, Samsung Medical Center, Seoul
9 Samyang Corporation, Seoul, Korea
* Correspondence to: Prof. D. S. Heo, Department of Internal Medicine, Seoul National University Hospital, 28 Yongon-Dong, Chongro-Gu, Seoul 110-744, Korea. Tel: +82-2-2072-2857; Fax: +82-2-747-2199; E-mail: heo1013{at}plaza.snu.ac.kr
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Abstract |
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Background: Genexol-PM is a novel Cremophor EL (CrEL)-free polymeric micelle formulation of paclitaxel (Taxol). This multicenter phase II study was designed to evaluate the efficacy and safety of the combination of Genexol-PM and cisplatin for the treatment of advanced non-small-cell lung cancer (NSCLC).
Patients and methods: Patients with advanced NSCLC received Genexol-PM 230 mg/m2 and cisplatin 60 mg/m2 on day 1 of a 3-week cycle as first-line therapy. Intrapatient dose escalation of Genexol-PM to 300 mg/m2 was carried out from the second cycle if the prespecified toxic effects were not observed after the first cycle.
Results: Sixty-nine patients were enrolled in this study. Overall response rate was 37.7%. The median time to progression was 5.8 months and the median survival period was 21.7 months. The major non-hematologic toxic effects included grade 3 peripheral sensory neuropathy (13.0%) and grade 3/4 arthralgia (7.3%). Four patients (5.8%) experienced grade 3/4 hypersensitivity reactions. The major hematological toxic effects were grade 3/4 neutropenia (29.0% and 17.4%, respectively).
Conclusion: Genexol-PM plus cisplatin combination chemotherapy showed significant antitumor activity. The use of CrEL-free, polymeric micelle formulation of paclitaxel allowed administration of higher doses of paclitaxel compared with the CrEL-based formulation without significant increased toxicity.
Key words: chemotherapy, Genexol-PM, non-small-cell lung cancer, phase II
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introduction |
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TopAbstractintroductionpatients and methodsresultsdiscussionfundingAcknowledgementsReferences |
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Primary lung cancer is the leading cause of cancer death in Korea as well as in the United States [1, 2]. Two-thirds of patients with newly diagnosed non-small-cell lung cancer (NSCLC) have inoperable disease at the time of diagnosis and many of the patients who undergo curative surgery suffer from recurrent NSCLC [3]. Platinum-based chemotherapy is a well-established first-line therapy in the palliative setting for patients with advanced disease, as it improves the quality of life and prolongs overall survival (OS) [4, 5]. Paclitaxel (Taxol) is a one of the most commonly used agents in combination with platinum for the treatment of advanced NSCLC [6, 7]. However, its use is limited by the toxic effects associated with Cremophor EL (CrEL), the lipid-based solvent used as a vehicle for paclitaxel. Because of its water insolubility, paclitaxel is formulated with the micelle-forming vehicle CrEL to enhance drug solubility [8]. However, the addition of CrEL has been shown to cause hypersensitivity reactions and neuropathy [8, 9]. In addition, CrEL significantly alters the pharmacokinetics of paclitaxel [10, 11]. Moreover, paclitaxel must be prepared either in a glass bottle or in non-polyvinyl chloride infusion systems with in-line filtration to prevent precipitation from CrEL and solvent [12].
To circumvent these drawbacks resulting from the use of CrEL, new CrEL-free formulations of paclitaxel are of great interest for development in the clinical setting. Several drug delivery systems using emulsion, micelles, water-soluble prodrugs and conjugates are currently under investigation. For example, ABI-007, CrEL-free, albumin-bound, nanoparticle paclitaxel has shown significant antitumor activity in patients with metastatic breast cancer without premedication needed for hypersensitivity reactions [13]. For the treatment of advanced NSCLC, ABI-007 has shown modest antitumor activity (objective response rate was 16%) as a single agent [14].
Genexol-PM (Samyang Co., Seoul, Korea) is a novel formulation of paclitaxel, a sterile lyophilized polymeric micellar formulation without CrEL. Genexol-PM was found to have a three-fold higher maximum tolerated dose (MTD) in nude mice. In addition, the biodistribution of Genexol-PM showed two- to three-fold higher levels in a variety of tissues including liver, spleen, kidney, and lung and more importantly in tumors. Moreover, the in vivo antitumor efficacy has been shown to be greater than that of Taxol (Bristol-Myers Squibb, Wallingford, CT) [15].
A phase I study of Genexol-PM, administered i.v. for 3 h every 3 weeks, established 390 mg/m2 as the MTD, which is higher than the MTD for paclitaxel with the 3-week regimen (175 mg/m2). Dose-limiting toxic effects included neuropathy, myalgia, and neutropenia. No hypersensitivity reactions were observed without premedication. The recommended dosage for phase II study was 300 mg/m2 [16].
We conducted a multicenter, phase II trial to explore the efficacy and safety of the combination of Genexol-PM and cisplatin for the treatment of advanced NSCLC. The primary goal of this study was to evaluate objective tumor response rate. Secondary objectives were the evaluation of toxic effects, time to progression (TtP), and OS.
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patients and methods |
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TopAbstractintroductionpatients and methodsresultsdiscussionfundingAcknowledgementsReferences |
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This multicenter, phase II, single arm trial was conducted at the seven major hospitals in the Republic of Korea. The protocol and all related materials were approved by the local institutional review boards. The study was conducted in compliance with Good Clinical Practice, guidelines of the International Conference on Harmonisation, and the Declaration of Helsinki. Written informed consent was required from all patients before participation.
patient population
Patients were eligible if they had histological or cytological evidence of locally advanced, metastatic or recurrent NSCLC. In recurrent cases, prior curative surgical or radiation treatment was allowed, but only if it was carried out at least 4 weeks before enrollment into the study. No prior chemotherapy or immunotherapy for the treatment of NSCLC was allowed. Patients were required to have measurable lesions according to the Response Criteria in Solid Tumors (RECIST) [17].
The patient ages ranged from 19 to 70 years. Patients were required to have an Eastern Cooperative Oncology Group performance status of zero to two, a life expectancy of 3 months or longer and adequate hematologic [absolute neutrophil count (ANC) 
1.5 x 109/l, platelet count 100 x 109/l], hepatic [serum bilirubin 
1.25 times the upper limit of normal (ULN), transaminases 2.0 times the ULN, and alkaline phosphatase 3.0 times the ULN], and renal (serum creatinine ULN) function.
Exclusion criteria included central nervous system metastasis, uncontrolled infection, medically uncontrollable heart disease, active infection, other serious medical illness or prior malignancies other than nonmelanoma skin cancer or in situ cervical cancer within the previous 5 years. Pregnant or lactating women were excluded.
treatment
Genexol-PM at a dose of 230 mg/m2 was diluted in 500 ml of 5% dextrose solution or normal saline and infused i.v. for 3 h on day 1. Specialized i.v. infusion sets or in-line filtration was not used. Following completion of the Genexol-PM infusion, cisplatin 60 mg/m2 was infused i.v. with adequate hydration and 5-HT3 antagonist antiemetic prophylaxis. Treatment was repeated every 3 weeks until either disease progression or intolerance. A maximum of six cycles was recommended.
Toxic effects were assessed at baseline and at the conclusion of each cycle of treatment using the National Cancer Institute—Common Toxicity Criteria version 2.0 [18]. Dose modification was carried out according to the grade of hematological and non-hematologic toxic effects except for nausea, vomiting, and alopecia. Intrapatient dose escalation of Genexol-PM to 300 mg/m2 was carried out from the second cycle when the prespecified criteria for dose escalation (ANC nadir 1.0 x 109/l, platelet count nadir 100 x 109/l, and no grade 2–4 non-hematologic toxic effects during first cycle of treatment) were fulfilled. Dose reductions of 20% of the Genexol-PM dose were required in case with grade 4 hematologic toxicity, any grade of neutropenic fever, grade 2 hepatic or neurological toxicity or grade 3 non-hematologic toxic effects other than hepatic or neurological toxicity. If grade 3/4 hepatic or neurological toxicity or grade 4 non-hematologic toxic effects occurred, the patient was excluded from the study. If any of these adverse events recurred after initial resolution, further dose reduction of 20% was recommended. Cisplatin dose reduction was carried out according to the grade of renal toxic effects. Dose reductions were permanent with no reescalation permitted. A maximum of two dose reductions were allowed. Any patient who experienced treatment-related toxicity that would require a third dose reduction was excluded from the study.
Premedication for prevention of hypersensitivity was not initially recommended. However, prophylaxis for hypersensitivity including hydrocortisone 100 mg i.v. (or equivalent corticosteroid), pheniramine maleate 45.5 mg i.v. (or equivalent antihistamine), and cimetidine 300 mg or ranitidine 50 mg i.v. (or equivalent H2 blocker) at 30 min before Genexol-PM administration was routinely recommended after enrollment of the fifteenth patient; this was due to unexpected grade 3/4 hypersensitivity reactions in two of the initial 15 patients.
assessments
Measurable disease was assessed by imaging using the RECIST criteria [17]. Patients underwent baseline imaging within 3 weeks of enrollment, and were scanned with the imaging method used for a given tumor at baseline before every other cycle. All partial and complete responses were confirmed at least 4 weeks later with repeat imaging.
statistical methods
The primary efficacy end point was objective tumor response rate in the treated population. The response rate was calculated as the percentage of patients who achieved complete or partial responses. All patients who received at least one dose of Genexol-PM were included in the response and toxicity analyses. TtP and survival were determined by the Kaplan–Meier method [19].
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results |
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From August 2003 to November 2005, 71 patients signed the informed consent form and were screened. One patient withdrew consent before treatment, and the other patient was excluded from the study because of not fulfilling the inclusion criteria. A total of 69 patients who received at least one cycle of treatment were included in the analysis of efficacy and safety. The patients received a median of four cycles (range, 1–7 cycles) with a total of 282 cycles of treatment. Baseline characteristics of patients are presented in Table 1.
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The dose intensity (the actual dose delivered as a proportion of the planned dose) was 97% at the first cycle (planned dose, 76.7 mg/m2/week) and 84% at subsequent cycles (planned dose, 100 mg/m2/week) for Genexol-PM and 98% for cisplatin (planned dose, 20 mg/m2/week) (Table 2). Dose escalation of the Genexol-PM to 300 mg/m2 at the second cycle in the patients that fulfilled the prespecified criteria was carried out in 46% of patients.
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efficacy
The objective response rate was 37.7% (95% confidence interval, 26.3% to 49.1%); all responses were partial responses. Twenty patients (29.0%) achieved a stable disease status (Table 3). The median response duration of 26 responders was 19.8 weeks (range, 15.4–22.3). Response could not be evaluated in seven patients because of discontinuation of the study before evaluation due to withdrawal of consent (three patients), treatment unrelated death (two patients), and hypersensitivity reactions (two patients, grade 2 and grade 4, respectively). The median TtP for all patients was 5.8 months (range, 5.2–6.4) and the median OS was 21.7 months (range, 12.6 –) with a median follow-up of 9.6 months (Figure 1). The probability of surviving 1 year was 60%.
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safety
The most severe grade of hematological and non-hematologic toxic effects for each patient are listed in Tables 4 and 5. The most common hematological toxicity was neutropenia. Grade 3/4 neutropenia occurred in 46.4% of patients. Neutropenia was generally transient and asymptomatic. Only two patients experienced febrile neutropenia. Other hematological toxic effects were not significant. Grade 3 anemia occurred in 2.9% of patients and there were no patients with grade 3/4 thrombocytopenia.
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The most common non-hematologic toxicity was peripheral sensory neuropathy (PSN). Nine (13.0%) patients experienced grade 3 PSN. However, no episode of grade 4 PSN was observed. The incidence of PSN increased with repeated treatment cycles. Other observed grade 3/4 toxic effects in >5% of patients were myalgia (5.8%) and arthralgia (7.3%). Grade 3/4 hypersensitivity reactions occurred in two (13.3%) of the initial 15 patients who did not receive premedication. After routine premedication, grade 3/4 hypersensitivity reactions were observed in only two (3.7%) of 54 patients. Eight patients (11.6%) lost >5% of their baseline body weight after completion of study treatment.
Nine patients (13%) discontinued study participation prematurely because of treatment-related adverse events including four with grade 2–4 hypersensitivity, two with grade 3 PSN, one with grade 4 neutropenia, one with grade 3 abdominal pain, and one with multiple grade 1–2 adverse events. Dose reduction was required in seven patients (10%) for toxic effects. Toxic effects resulting in a dose reduction included neutropenia, neutropenic fever, anorexia, dyspnea, hepatic toxicity, syndrome of inappropriate antidiuretic hormone, and bone pain.
Of the 282 treatment cycles administered, 23 (8%) cycles were delayed. One patient died as a result of pneumonia unrelated to the study treatment, and one patient died suddenly on 10th day of the first cycle of treatment which was unlikely related to the study treatment.
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discussion |
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TopAbstractintroductionpatients and methodsresultsdiscussionfundingAcknowledgementsReferences |
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This is the first reported phase II clinical trial using a polymeric micelle formulation of paclitaxel combined with cisplatin for the treatment of malignancies. This study confirmed that Genexol-PM has significant antitumor activity in patients with NSCLC. The use of CrEL-free, polymeric micelle formulation of paclitaxel allowed administration of higher doses of paclitaxel than achieved with CrEL-based formulations without a significant increase in toxicity. Specialized i.v. infusion sets or in-line filtration was not required for the administration of the Genexol-PM.
The overall response rate of Genexol-PM at 230–300 mg/m2 for a 3-h infusion combined with cisplatin at 60 mg/m2 every 3 weeks was 37.7%. The median TtP was 5.8 months and the median OS was 21.7 months. It is well known that the response rates and survival data reported in phase II studies are influenced by patient selection and subsequent treatment. However, our data are more favorable in terms of response rate and survival duration than most phase II or phase III clinical trials using Taxol 175–200 mg/m2 (3-h infusion) combined with higher dose (75–80 mg/m2) of cisplatin [20–23]. In preclinical models, Genexol-PM produced a higher paclitaxel tumor concentration than Taxol [15] and this may have contributed to the higher response rate observed in this study.
In spite of the higher paclitaxel dose, the Genexol-PM and cisplatin combination regimen-associated adverse events were comparable with conventional paclitaxel and cisplatin combination regimens. The incidence of grade 3/4 neutropenia in this study was 46.4%. This incidence is comparable with that of other phase III studies using relatively low doses of paclitaxel (175–200 mg/m2 with 3-h infusion) combined with cisplatin 75–80 mg/m2 [21–24]. Moreover, the incidence was significantly lower than that of the 24-h infusion paclitaxel/cisplatin combination regimen [4]. PSN was the most common non-hematologic toxicity observed with the Genexol-PM and cisplatin combination. Nine patients (13%) experienced grade 3 PSN. This rate is a little higher than that of conventional paclitaxel/cisplatin regimens (ranged 4%–9%) [21–24]. We found that the PSN was generally manageable and the incidence increased with repeated treatment cycles. PSN would not interfere with the clinical usefulness of this combination regimen because the usual recommended number of treatment cycles for advanced NSCLC is four cycles.
Because no hypersensitivity reactions were observed in any patients in the phase I study of Genexol-PM, prophylactic medications were not routinely recommended in original protocol. However, two of the 15 initial patients unexpectedly experienced grade 3/4 hypersensitivity reactions without premedication. The incidence of grade 3/4 hypersensitivity reactions decreased after implementation of routine prophylaxis; however, a few patients experienced hypersensitivity even with premedication. The occurrence of hypersensitivity reactions with Genexol-PM, a CrEL-free formulation of paclitaxel, indicates that paclitaxel itself causes hypersensitivity. Histamine release was observed with paclitaxel alone and no histamine release was detected with CrEL alone [25], which indicates that paclitaxel is the probable cause of hypersensitivity. In addition, combination with cisplatin or the relatively high doses of Genexol-PM administered in this study might have contributed to the occurrence of the hypersensitivity reactions.
In conclusion, Genexol-PM, a CrEL-free, polymeric micelle formulation of paclitaxel plus cisplatin combination chemotherapy showed significant antitumor activity with relatively low incidence and severity of toxicity in spite of a high paclitaxel dose in patients with advanced NSCLC. Future studies with different dosing schedules, in combination with other drugs or comparisons with standard regimens for advanced NSCLC are warranted.
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funding |
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TopAbstractintroductionpatients and methodsresultsdiscussionfundingAcknowledgementsReferences |
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Korean Health 21 Research and Development Project, Ministry of Health and Welfare, Republic of Korea (#0412-CR01-0704-0001); Samyang Co. Seoul, Korea.
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Acknowledgements |
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TopAbstractintroductionpatients and methodsresultsdiscussionfundingAcknowledgementsReferences |
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Co-author M.Y.L. is an employee of Samyang Corporation.
Received for publication January 12, 2007. Revision received June 22, 2007. Accepted for publication July 2, 2007.
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References |
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