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

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.