Phase I study of docosahexaenoic acid-paclitaxel: A taxane-fatty acid conjugate with a unique pharmacology and toxicity profile

Purpose: Docosahexaenoic acid (DHA)-paclitaxel, a novel conjugate formed by covalently linking the natural fatty acid DHA to paclitaxel, was designed as a prodrug targeting intratumoral activation. This Phase I trial examined its toxicity and pharmacokinetics (PKs). Experimental Design: Patients with advanced refractory solid tumors received a 2-h i.v. infusion of DHA-paclitaxel every 3 weeks. Plasma and urine samples were obtained to characterize the pharmacological profile of DHA-paclitaxel and paclitaxel. Results: Twenty-four patients received 78 cycles of DHA-paclitaxel over five dose levels (200-1100 mg/m²). Median number of cycles was 2 (range, 1-8). Myelosuppression was the principal toxicity observed (grade 3/4 neutropenia in 21%/53% of courses at 1100 mg/m²); during cycle 1, febrile neutropenia occurred in 1 of 9 patients treated at 1100 mg/m². Other grade 3 toxicities were infrequent. No patients developed alopecia, peripheral neuropathy > grade 1, or musculoskeletal toxicity > grade 1. At 1100 mg/m², DHA-paclitaxel had a mean (CV%) volume of distribution of 7.5 (64) liters, β half-life of 112 (56) h, and clearance of 0.11 (30) liters/h. Paclitaxel PK parameters at 1100 mg/m² were: C_max, 282 (46) ng/ml; AUC, 10,705 (60) ng/ml × h; and terminal half-life, 85 (101) h. Paclitaxel plasma exposure represented ≤0.06% of DHA-paclitaxel exposure. Paclitaxel AUC was correlated with neutropenia. One partial response was observed. Conclusions: The starting dose recommended for subsequent studies is 1100 mg/m². DHA-paclitaxel dramatically alters the PK profile of derived paclitaxel compared with values observed after a 3-h infusion of paclitaxel (175 mg/ m²). In addition, its favorable toxicity profile offers potential advantages over existing taxanes.