Phase I and Pharmacokinetic Study of Genexol-PM, a Cremophor-Free, Polymeric Micelle-Formulated Paclitaxel, in Patients with Advanced Malignancies

Abstract

Purpose:The rationale for developing an alternative paclitaxel formulation concerns Cremophor EL-related side effects, and a novel paclitaxel delivery system might augment its therapeutic efficacy. Genexol-PM is a polymeric micelle formulated paclitaxel free of Cremophor EL. A phase I study was performed to determine the maximum tolerated dosage, dose-limiting toxicities, and the pharmacokinetic profile of Genexol-PM in patients with advanced, refractory malignancies.Experimental Design: Twenty-one patients were entered into the study. Genexol-PM was i.v. administered over 3 h every 3 weeks without premedication. The Genexol-PM dose was escalated from 135 mg/m 2 to 390 mg/m 2 . Results: All of the patients were evaluable for toxicity and response. Acute hypersensitivity reactions were not observed. Neuropathy and myalgia were the most common toxicities. During cycle 1, grade 3 myalgia occurred in 1 patient at 230 and 300 mg/m 2 , respectively. At 390 mg/m 2 , 2 of 3 patients developed grade 4 neutropenia or grade 3 polyneuropathy. Therefore, the maximum tolerated dosage was determined to be 390 mg/m 2 . There were 3 partial responses (14%) among the 21 patients. Of the 3 responders, 2 were refractory to prior taxane therapy. The paclitaxel area under the curve from time 0 to infinity and peak or maximum paclitaxel concentration seemed to increase with escalating dose, except at 230 mg/m 2 , which suggests that Genexol-PM has linear pharmacokinetics. Conclusion:The main dose-limiting toxicities were neuropathy, myalgia, and neutropenia, and the recommended dosage for a phase II study is 300 mg/m 2 . Genexol-PM is believed to be superior to conventional paclitaxel in terms of the obviation of premedication and the delivery of higher paclitaxel doses without additional toxicity.

Intracellularly Degradable, Self‐Assembled Amphiphilic Block Copolycurcumin Nanoparticles for Efficient In Vivo Cancer Chemotherapy

“…[3] Despite significant research achievements, most of the current NDDSs, especially those in clinical trials or usage, e.g. drug encapsulated lipids vesicles or polymer micelles, [4] polymerdrug conjugates, and albumin-based nanoparticles, [5] mostly rely on passive targeting and generally lack the ability of active targeting. Moreover, drugs are mostly physically encapsulated or entrapped into the NDDSs, where drug release is mainly achieved via passive diffusion, making it difficult to achieve controlled release, a vital property for high therapeutic 2 efficacy.…”

Novel Nanomaterials for Clinical Neuroscience

“…After reaching target cells, the drug is released from the micelle via diffusion. Several clinical trials are completed or are underway to evaluate polymeric micelles for delivery of anti-cancer drugs (Danson et al 2004;Kim et al 2004;Matsumura et al 2004;Armstrong et al 2006;Matsumura 2006).…”

Nanomedicine in the diagnosis and therapy of neurodegenerative disorders

“…Examples include polymeric micelles [118,[123][124][125][126], DNA/polycation complexes ("polyplexes") [127][128][129][130][131][132][133][134][135], block ionomer complexes [116,[136][137][138][139], nanogels [140][141][142][143][144] and others. Of these materials, polymeric micelles have been evaluated in human trials for the delivery of anti-cancer agents [145][146][147][148][149]. The promising results of these trials suggest that polymeric micelles are likely to find practical use in medicine.…”

“…After reaching target cells drug is released from the micelle via diffusion. Several clinical trials are completed or underway to evaluate polymeric micelles for delivery of anti-cancer drugs [145][146][147][148][149].…”