Phase I dose escalation study of a polymeric micellar formulation of paclitaxel in patients (pts) with refractory non-hematologic cancer

Abstract

2088 Background: Genexol-PM (G-PM) utilizes a low molecular weight, biodegradable, amphiphilic diblock copolymer, methoxy-poly(ethylene glycol)-block-poly(D,L-lactide) to form polymeric micelles of paclitaxel. G-PM does not contain Cremephor EL, thus has the potential for lower toxicities and administration of higher doses. Methods: G-PM was administered as a 3 hr intravenous infusion on day 1 of 21-day cycle. Dose cohorts were 85 mg/m2, 175 mg/m2, 290 mg/m2 and 435 mg/m2. Results: 23 pts were treated with doses of 85 mg/m2 to 435 mg/m2. 19 pts are fully evaluable, 6 male and 13 female, with a mean age of 54 years (33 to 78 years). Two pts experienced dose-limiting toxicities (DLTs), one pt with grade 3 diarrhea (290 mg/m2) and one with grade 3 febrile neutropenia (435 mg/m2). No cohort had 2 or more pts with DLTs thus the maximum tolerated dose (MTD) was not exceeded. The most common non-hematolgoic toxicities were fatigue (58%), constipation (47%), decreased appetite (42%), nausea (42%), dyspnea (37%), peripheral /sensory neuropathy (37%) and diarrhea (32%). Myelosuppression was uncommon and mild (anemia 21%, neutropenia and thrombocytopenia 5% each). The mean Cmax ranged from 713.67 (85 mg/m2) to 4510 ng/mL (435 mg/m2), mean half-life 11.06 to 17.20 hr, and mean total area under the curve (AUC0-∞) 2956.35 to 24812.78 ng · hr /mL. G-PM appeared to follow a three-compartment model, suggesting a slow flux of paclitaxel into the plasma from the peripheral tissues or “deep” compartment. Three pts had partial responses (PR). Two pts with refractory pancreatic cancer had decreases in CA 19–9, one of which had radiologic PR (96+ months). Conclusion: G-PM was well tolerated in doses up to 435 mg/m2 every 21 days. The MTD was not reached, however, due to a trend towards increased toxicities at the 435 mg/m2 the presumptive MTD and recommended dose for phase 2 is 435 mg/m2. No significant financial relationships to disclose.