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(-1). The starting dose was 6 mg DXR equivalent m(-2), 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(-2). 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(-2) (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(-2) every 3 weeks.

Figure 1

Schematic structure of NK911. A polymeric micelle carrier of NK911 consists of a block copolymer of PEG (molecular weight of about 5000) and poly(aspartic acid) (about 30 units). Polyethyleneglycol is believed to be the outer shell of the micelle. NK911 has a highly hydrophobic inner core, and therefore can entrap sufficient amounts of DXR.

Figure 2

Mean plasma levels of doxorubicin following the intravenous administration of NK911 at dosages of 6, 12, 24, 36, 50, and 67 mg m⁻² in 23 patients.

Figure 3

Correlations between dosage and AUC_0–inf (A) and C_5 min (B) after a single intravenous administration of NK911.

Figure 4

Serial CT scans of a 69-year-old male with pancreatic cancer who was treated with NK911 at an initial dosage level of 67 mg m⁻² during the first course and at 50 mg m⁻² after the second course. Changes in tumour marker levels are also shown. (A) Baseline scan showing a metastasis in the left lateral lobe. (B) Partial response, characterised by a more than 50% decrease in the size of the liver metastasis compared with the baseline scan. (C) Tumour markers, CA19-9 and CEA, decreased remarkably after treatment.