Multicenter Phase II Trial of Genexol-PM
Multicenter Phase II Trial of Genexol-PM
Background: Genexol-PM is a novel Cremophor EL (CrEL)-free polymericmicelle formulation of paclitaxel (Taxol). This multicenterphase 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 peripheralsensory 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.
Primary lung cancer is the leading cause of cancer death in Korea as well as in the United States. 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. 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). Paclitaxel (Taxol) is a one ofthe most commonly used agents in combination with platinum forthe treatment of advanced NSCLC. However, its use islimited 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 themicelle-forming vehicle CrEL to enhance drug solubility. However, the addition of CrEL has been shown to cause hypersensitivity reactions and neuropathy. In addition, CrEL significantlyalters the pharmacokinetics of paclitaxel. Moreover, paclitaxel must be prepared either in a glass bottle or in non-polyvinylchloride infusion systems with in-line filtration to prevent precipitation from CrEL and solvent.
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 andconjugates are currently under investigation. For example, ABI-007, CrEL-free, albumin-bound, nanoparticle paclitaxel has shown significant antitumor activity in patients with metastatic breastcancer without premedication needed for hypersensitivity reactions. For the treatment of advanced NSCLC, ABI-007 has shown modest antitumor activity (objective response rate was 16%)as a single agent.
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 higherlevels 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).
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, andneutropenia. No hypersensitivity reactions were observed without premedication. The recommended dosage for phase II study was 300 mg/m².
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.
Background: Genexol-PM is a novel Cremophor EL (CrEL)-free polymericmicelle formulation of paclitaxel (Taxol). This multicenterphase 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 peripheralsensory 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.
Primary lung cancer is the leading cause of cancer death in Korea as well as in the United States. 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. 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). Paclitaxel (Taxol) is a one ofthe most commonly used agents in combination with platinum forthe treatment of advanced NSCLC. However, its use islimited 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 themicelle-forming vehicle CrEL to enhance drug solubility. However, the addition of CrEL has been shown to cause hypersensitivity reactions and neuropathy. In addition, CrEL significantlyalters the pharmacokinetics of paclitaxel. Moreover, paclitaxel must be prepared either in a glass bottle or in non-polyvinylchloride infusion systems with in-line filtration to prevent precipitation from CrEL and solvent.
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 andconjugates are currently under investigation. For example, ABI-007, CrEL-free, albumin-bound, nanoparticle paclitaxel has shown significant antitumor activity in patients with metastatic breastcancer without premedication needed for hypersensitivity reactions. For the treatment of advanced NSCLC, ABI-007 has shown modest antitumor activity (objective response rate was 16%)as a single agent.
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 higherlevels 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).
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, andneutropenia. No hypersensitivity reactions were observed without premedication. The recommended dosage for phase II study was 300 mg/m².
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.
