Phase I dose escalation and pharmacokinetic study on the nanoparticle formulation of polymeric micellar paclitaxel for injection in patients with advanced solid malignancies
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Background Polymeric micellar paclitaxel (PM-paclitaxel) is a novel Cremophor EL-free, nanoparticle-encapsulated paclitaxel formulation administered through intravenous injection. The primary objective of this phase I trial was to determine the first cycle dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of PM-paclitaxel. Secondary objectives included the evaluation of the safety, antitumor activity, and pharmacokinetic (PK) profile of PM-paclitaxel in patients with advanced malignancies. Methods The PM-paclitaxel dose was escalated from 175 mg/m2 (level 1) to 435 mg/m2 (level 5). PM-paclitaxel was intravenously administered to patients for 3 h without premedication on day 1 of a 21-day cycle. Results Eighteen patients with confirmed advanced malignancies received PM-paclitaxel. DLT included grade 4 neutropenia (four patients) and grade 3 numbness (one patient), which occurred in one of the six patients who received 300 mg/m2 (level 3) PM-paclitaxel and all three patients who were treated with 435 mg/m2 PM-paclitaxel. Thus, the MTD of PM-paclitaxel was determined as 390 mg/m2 (level 4). Acute hypersensitive reactions were not observed. Partial response was observed in six of 18 patients (33.3%), three of whom had prior exposure to paclitaxel chemotherapy. The peak concentration and area under the curve values of paclitaxel increased with increasing dosage, indicating that PM-paclitaxel exhibits linear PKs. Conclusions PM-paclitaxel showed high MTD without additional toxicity, and exhibited desirable antitumor activity. The recommended dose of PM paclitaxel for phase II study is 300 mg/m2.
KeywordsPhase I Paclitaxel Nanoparticle Polymeric micelle Solid malignancies
The authors thank the patients who participated in this study and express appreciation of the assistance and understanding of their families. The authors also thank the study-site staff for their support.
The work was also supported by trial funding provided by Ministry of Science and Technology of the People’s Republic of China (grant number 14C26213100947) and science and Technology Commission of Shanghai Municipality (grant number 14431908600).
Compliance with ethical standards
Conflict of interest
All authors received research funding from Shanghai Yizhong Biotechnical Co., Ltd., China for conducting the study and preparing this report. No potential conflicts of interest were disclosed.
The study was approved by the institutional review board of the Jiangsu Cancer Hospital, Nanjing, China. The study was conducted in compliance with the ethical principles originating in the Declaration of Helsinki.
Written informed consent was obtained from all individual patients included in the study.
- 6.Sparreboom A, van Zuylen L, Brouwer E, Loos WJ, de Bruijn P, Gelderblom H et al (1999) Cremophor EL-mediated alteration of paclitaxel distribution in human blood: clinical pharmacokinetic implications. Cancer Res 59:1457–1467Google Scholar
- 13.Socinski MA, Bondarenko I, Karaseva NA, Makhson AM, Vynnychenko I, Okamoto I et al (2012) Weekly nab-paclitaxel in combination with carboplatin versus solvent-based paclitaxel plus carboplatin as first-line therapy in patients with advanced non-small-cell lung cancer: final results of a phase III trial. J Clin Oncol 30:2055–2062CrossRefPubMedGoogle Scholar
- 17.Kim TY, Kim DW, Chung JY, Shin SG, Kim SC, Heo DS et al (2004) Phase I and pharmacokinetic study of Genexol-PM, a Cremophor-free, polymeric micelle-formulated paclitaxel, in patients with advanced malignancies. Clin Cancer Res 10:3706–3716Google Scholar
- 20.Zhou GL, Han B, Song YS, Sun J, Zhou JS, Jiang XG et al (2014) Anti-tumor effects of paclitaxel micelle for injection in vivo. Chin J of New Drugs Clin Rem 33:582–587Google Scholar
- 21.Han B, Liu X, Sun J, Zhou GL, Zhang LL, You ZQ et al (2011) Tissue distribution of paclitaxel micelle and paclitaxel injection in tumor-bearing mice. Chin J of New Drugs Clin Rem 30:603–608Google Scholar
- 22.Mao XY, Zhang MX, Zhou QY, Dong CX, Shen WW, Liu GY, Jia JY et al (2015) A pharmacokinetic study of paclitaxel- loaded micelle in patients with advanced solid carcinoma by LC-MS/MS. Chin J of New Drugs Clin Rem 34:869–873Google Scholar
- 24.Ohtsu T, Sasaki Y, Tamura T, Miyata Y, Nakanomyo H, Nishiwaki Y et al (1995) Clinical pharmacokinetics and pharmacodynamics of paclitaxel: a 3-hour infusion versus a 24-hour infusion. Clin Cancer Res 6:599–606Google Scholar