Abstract 371: Comparison of toxicity and study design issues of nanoparticle and small molecule anticancer agents in preclinical models and phase I clinical trials

Abstract

Abstract Background: Carrier-mediated agents (CMA) are classified as nanoparticles, nanosomes (nanoparticle sized liposomes) and conjugates. Anticancer CMA offer many unique advantages over their traditional small molecule (SM) counterparts, including improved solubility, longer duration of exposure, tumor-selective delivery, increased antitumor response and reduced toxicity. The interpatient variability in pharmacokinetics (PK) and pharmacodynamics (PD) associated with nanoparticles are greater than that observed with SM. The starting dose for phase I studies of SM and CMA anticancer agents is based on the toxicity profile of the most sensitive species (e.g. rat or canine). However, the optimal animal model for toxicologic and pharmacologic studies of CMA is unclear. Our preliminary data suggests that dogs are highly sensitive to nanoparticles and thus may not be an appropriate animal model in determining the starting dose of CMA for phase I clinical trials. We evaluated preclinical toxicology data and how this affected the design and progression of phase I studies of CMA compared to SM anticancer agents. Methods: In preclinical studies, the maximum tolerated dose (MTD) in rats and dogs was evaluated for CMA and their respective SM. In phase I clinical trials of CMA and their respective SM in patients with advanced solid tumors, the basis for starting dose, the number of dose escalations, number of patients and the ratio of MTD to starting dose was determined. Results: Starting dose in phase I studies of CMA was based on dogs. Conclusions: The degree of dose escalation from starting dose to MTD was significantly greater for CMA compared to SM drugs. This was also associated with a significantly greater number of dose levels, patients, and time required to complete phase I studies of CMA compared to SM. These findings necessitate the need to identify the most appropriate preclinical animal model to use to evaluate CMA toxicity in phase I studies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 371. doi:10.1158/1538-7445.AM2011-371