Phase 1 and pharmacokinetic study of AI-850, a novel microparticle hydrophobic drug delivery system (HDDS) for paclitaxel

Abstract

2048 Background: AI-850 is a novel, rapidly dissolving, cremophor-free microparticle formulation of the hydrophobic drug paclitaxel (PCTX). Preclinical studies demonstrated that AI-850 can be administered quickly and safely at higher doses with improved efficacy in xenograft models as compared to cremophor paclitaxel formulations. The principle study objectives were to define the dose-limiting toxicity (DLT) and maximally tolerated dose (MTD) of AI-850 and to study the pharmacokinetics (PK) of PCTX. Methods: AI-850 was administered by rapid intravenous infusion (<30 minutes), without corticosteroid pretreatment, every 3 weeks to patients (pts) with solid tumors in cohorts of 3–6. Total and free plasma PCTX concentrations were measured by LC/MS/MS, up to 168h post dose. Results: 22 pts (13M:9F) median age 58 yrs (range 38–76) have been enrolled at doses of 36–250 mg/m2. Tumor types; 8 colorectal, 3 melanoma, 2 each of pancreatic, head & neck, gynecological cancers and 5 other. At the current dose of 250mg/m2, 3/6 pts had grade IV neutropenia, one of these pts had a DLT with grade 3 mucositis and neutropenic sepsis. Total and free PCTX PK parameters (mean ± SD) are shown in the table. The PK data suggest some degree of saturable elimination. One head & neck cancer patient (non-measurable disease) had durable radiographic resolution of pleural disease after 4 cycles at 205 mg/m2. Conclusions: Administration of AI-850 by short infusion was generally well tolerated and the study is ongoing. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Acusphere, Inc. Acusphere, Inc. Acusphere, Inc. Accusphere Pharmaceutical Company