Phase I clinical trial and pharmacokinetic evaluation of NK911, a micelle-encapsulated doxorubicin

Abstract

NK911 is a novel supramolecular nanocarrier designed for the enhanced delivery of doxorubicin (DXR) and is one of the successful polymer micelle systems to exhibit an efficient accumulation in solid tumours in mice. The purpose of this study was to define the maximum-tolerated dose (MTD) and dose-limiting toxicities (DLTs) of NK911 and to evaluate its pharmacokinetic profile in man. NK911 was given intravenously to patients with solid tumours every 3 weeks using an infusion pump at a rate of 10 mg DXR equivalent min À1 . The starting dose was 6 mg DXR equivalent m À2 , and the dose was escalated according to the accelerated titration method. A total of 23 patients participated in this study. Neutropenia was the predominant haematological toxicity, and grade 3 or 4 neutropenia was observed at doses of 50 and 67 mg m À2 . Common nonhaematological toxicities were mild alopecia, stomatitis, and anorexia. In the dose identification part of the study, DLTs were observed at a dose of 67 mg m À2 (grade 4 neutropenia lasting more than 5 days). Thus, this dosage level was determined to be the MTD. Infusion-related reactions were not observed in any cases. The C 5 min and area under the concentration curve parameters of NK911 exhibited dose-dependent characteristics. Among the 23 patients, a partial response was obtained in one patient with metastatic pancreatic cancer. NK911 was well tolerated and produced only moderate nausea and vomiting at myelosuppressive dosages. The recommended phase II dose was determined to be 50 mg m À2 every 3 weeks.

Cisplatin-incorporating polymeric micelles (NC-6004) can reduce nephrotoxicity and neurotoxicity of cisplatin in rats

“…We have recently been conducting research dedicated to the development of polymeric micelles capable of incorporating anticancer drugs (Yokoyama et al, 1990(Yokoyama et al, , 1991. The Phase I clinical trial of adriamycin-incorporating polymeric micelles has been completed (Matsumura et al, 2004). Furthermore, in an animal model, the plasma and tumour area under the curve (AUC) values for taxol-incorporating polymeric micelle (NK105) showed 85-and 25-fold increases, respectively, as compared with those for taxol.…”

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).…”

“…Notably, several nanoscale drugs ("nanomedicines"), such as liposomal Doxorubicin, Doxil (Gabizon et al 2006) or albumin-bound Paclitaxel, Abraxane (Gradishar 2006) have been used in clinic already for treatment of cancer and other diseases. Others, such as Doxorubicin incorporated in polymer micelles, SP1049C (Danson et al 2004;Armstrong et al 2006) and NK911 (Matsumura et al 2004), are in clinical trials. Most importantly, such studies have demonstrated that nano-materials can be safely administered in the human body.…”

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].…”