Phase I and Pharmacokinetic Study of AI-850, A Novel Microparticle Hydrophobic Drug Delivery System for Paclitaxel

• Published in: Clinical cancer research Vol. 13; no. 11; pp. 3293 - 3301
• Main Authors: Mita, Alain C, Olszanski, Anthony J, Walovitch, Richard C, Perez, Raymond P, MacKay, Kathleen, Tuck, David P, Simmons, Cecilia, Hammond, Susan, Mita, Monica M, Beeram, Muralidhar, Stone, Anne J, Rowinsky, Eric K, Lewis, Lionel D
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research 01-06-2007
• Subjects: Adult; Aged; AI-850; Antineoplastic Agents, Phytogenic - administration & dosage; Capsules - chemistry; Castor; Chromatography, Liquid - methods; clinical pharmacology; Drug Delivery Systems; Female; Humans; Hydrophobic and Hydrophilic Interactions; hydrophobic drug delivery system; Male; Mass Spectrometry - methods; Maximum Tolerated Dose; microparticle; Middle Aged; Neoplasms - drug therapy; novel drug delivery systems; paclitaxel; Paclitaxel - administration & dosage; Paclitaxel - pharmacokinetics; phase I-III clinical trials; Treatment Outcome
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-06-2496

Purpose: AI-850, paclitaxel in a novel polyoxyethylated castor oil-free hydrophobic microparticle delivery system, is being developed
based on its favorable preclinical safety and antitumor activity profiles. The objectives of the study were to assess the
feasibility and safety of administering AI-850 as a <30-min i.v. infusion without premedication every 3 weeks, determine the
maximum tolerated dose and the phase II recommended dose of AI-850, study the pharmacokinetics of paclitaxel in this new formulation,
and seek evidence of anticancer activity.
Experimental Design: This was an open-label phase I dose escalation study of AI-850 in patients with advanced solid malignancies. AI-850 doses
were escalated according to a modified Fibonacci scheme. Clinical and laboratory toxicity was monitored, and paclitaxel plasma
concentrations were measured by liquid chromatography-tandem mass spectrometry.
Results: Twenty-two patients received 56 courses of AI-850 at five dose cohorts ranging from 36 to 250 mg/m 2 . Grade 4 neutropenia, either exceeding 5 days or complicated by fever, was dose limiting in two of six patients at 250 mg/m 2 AI-850. Three patients experienced grade 2 to 4 infusion-related adverse reactions. Toxicities, including fatigue, alopecia,
nausea and vomiting, neuropathy, anorexia, and myalgia, were mild to moderate, reversible, and not dose related. Pharmacokinetics
of free and total paclitaxel showed biexponential plasma decay and dose proportionality for maximum plasma paclitaxel concentration
and area under the concentration versus time curve. Antitumor activity was documented in two patients with endometrial and
tongue carcinomas.
Conclusions: The administration of AI-850 as a brief infusion once every 3 weeks was feasible at doses up to 205 mg/m 2 . The potential of AI-850 as an alternative to other approved paclitaxel formulations requires further clinical evaluation.