Phase I and Pharmacokinetic Study of Genexol-PM, a Cremophor-Free, Polymeric Micelle-Formulated Paclitaxel, in Patients with Advanced Malignancies

• Published in: Clinical cancer research Vol. 10; no. 11; pp. 3708 - 3716
• Main Authors: Kim, Tae-You, Kim, Dong-Wan, Chung, Jae-Yong, Shin, Sang Goo, Kim, Sung-Chul, Heo, Dae Seog, Kim, Noe Kyeong, Bang, Yung-Jue
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.06.2004
• Subjects: Adult; Antineoplastic agents; Antineoplastic Agents - therapeutic use; Antineoplastic Agents, Phytogenic - adverse effects; Antineoplastic Agents, Phytogenic - therapeutic use; Area Under Curve; Biological and medical sciences; Dose-Response Relationship, Drug; Female; Humans; Male; Medical sciences; Micelles; Middle Aged; Neoplasms - drug therapy; Paclitaxel - adverse effects; Paclitaxel - analogs & derivatives; Paclitaxel - therapeutic use; Pharmacology. Drug treatments; Polyethylene Glycols - chemistry; Polymers - chemistry; Time Factors; Tumors; Antineoplastic agent; Human; Taxane derivatives; Paclitaxel; Phase I trial; Micelle; Advanced stage; Pharmacokinetics; Antimitotic
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-03-0655

Purpose: The rationale for developing an alternative paclitaxel formulation concerns Cremophor EL-related side effects, and a novel paclitaxel delivery system might augment its therapeutic efficacy. Genexol-PM is a polymeric micelle formulated paclitaxel free of Cremophor EL. A phase I study was performed to determine the maximum tolerated dosage, dose-limiting toxicities, and the pharmacokinetic profile of Genexol-PM in patients with advanced, refractory malignancies. Experimental Design: Twenty-one patients were entered into the study. Genexol-PM was i.v. administered over 3 h every 3 weeks without premedication. The Genexol-PM dose was escalated from 135 mg/m 2 to 390 mg/m 2 . Results: All of the patients were evaluable for toxicity and response. Acute hypersensitivity reactions were not observed. Neuropathy and myalgia were the most common toxicities. During cycle 1, grade 3 myalgia occurred in 1 patient at 230 and 300 mg/m 2 , respectively. At 390 mg/m 2 , 2 of 3 patients developed grade 4 neutropenia or grade 3 polyneuropathy. Therefore, the maximum tolerated dosage was determined to be 390 mg/m 2 . There were 3 partial responses (14%) among the 21 patients. Of the 3 responders, 2 were refractory to prior taxane therapy. The paclitaxel area under the curve from time 0 to infinity and peak or maximum paclitaxel concentration seemed to increase with escalating dose, except at 230 mg/m 2 , which suggests that Genexol-PM has linear pharmacokinetics. Conclusion: The main dose-limiting toxicities were neuropathy, myalgia, and neutropenia, and the recommended dosage for a phase II study is 300 mg/m 2 . Genexol-PM is believed to be superior to conventional paclitaxel in terms of the obviation of premedication and the delivery of higher paclitaxel doses without additional toxicity.