A phase I and pharmacokinetic study of NK105, a paclitaxel-incorporating micellar nanoparticle formulation

Abstract

This phase I study was designed to examine the maximum tolerated dose (MTD), the dose-limiting toxicities (DLTs), the recommended dose (RD) for phase II, and the pharmacokinetics of NK105, a new polymeric micelle carrier system for paclitaxel (PTX). NK105 was administered as a 1-h intravenous infusion every 3 weeks, without antiallergic premedication. The starting dose was 10 mg m(-2), and the dose was escalated according to the accelerated titration method. Nineteen patients were recruited. The tumour types treated included pancreatic (n=11), bile duct (n=5), gastric (n=2), and colonic (n=1) cancers. Neutropenia was the most common haematological toxicity. A grade 3 fever developed in one patient given 180 mg m(-2). No other grades 3 or 4 nonhaematological toxicities, including neuropathy, was observed during the entire study period. DLTs occurred in two patients given 180 mg m(-2) (grade 4 neutropenia lasting for more than 5 days). Thus, this dose was designated as the MTD. Grade 2 hypersensitivity reactions developed in only one patient given 180 mg m(-2). A partial response was observed in one patient with pancreatic cancer. The maximum concentration (C(max)) and area under the concentration (AUC) of NK105 were dose dependent. The plasma AUC of NK105 at 150 mg m(-2) was approximately 15-fold higher than that of the conventional PTX formulation. NK105 was well tolerated, and the RD for the phase II study was determined to be 150 mg m(-2) every 3 weeks. The results of this phase I study warrant further clinical evaluation.

Figure 1

Schematic structure of NK105. A polymeric micelle carrier of NK105 consists of a block copolymer of PEG (molecular weight of about 12 000) and modified polyaspartate. PEG is believed to be the outer shell of the micelle. PEG is believed to form the outer shell of the micelle. NK105 has a highly hydrophobic inner core, and therefore can entrap a sufficient amount of PTX.

Figure 2

(A) Individual plasma concentrations of PTX in seven patients following 1-h intravenous infusion of NK105 at a dose of 150 mg m⁻². (B) Relationships between dose and C_max, and (C) between dose and AUC_0−inf. of PTX in patients following 1-h intravenous infusion of NK105. Regression analysis for dose vs C_max was applied using all points except one patient at 80 mg m⁻² whose medication time became 11 min longer and one patient at 180 mg m⁻² who had medication discontinuation and steroid medication. (Plots were shown as open circle). Regression analysis for dose vs AUC_0−inf. was applied using all points except one patient who had medication discontinuation and steroid medication. (Plot was shown as open circle.) Relationships between dose and C_max, and AUC_0−inf. in patients following conventional PTX administration were plotted (closed square, see Tamura et al, 1995).

Figure 3

Serial CT scans. (A) A 60-year-old male with pancreatic cancer who was treated with NK105 at a dose level of 150 mg m⁻². Baseline scan (upper panels) showing multiple metastasis in the liver. Partial response, characterized by a more than 90% decrease in the size of the liver metastasis (lower panels) compared with the baseline scan. The antitumour response was maintained for nearly 1 year. (B) A 64-year-old male with stomach cancer who was treated with NK105 at a dose level of 150 mg m⁻². Baseline scan (left panel) showing a peritoneal metastasis and liver metastasis. About 40% reduction (right panel) was observed in peritoneal metastasis, but not in the liver metastasis after fifth course.