DHA-paclitaxel

Docosahexaenoic acid (DHA)-paclitaxel is a taxane with a unique pharmacokinetic profile. We investigated the safety and response rate of DHA-paclitaxel weekly in patients with metastatic uveal melanoma. Chemotherapy-naive and previously treated patients were eligible for this open-label phase II study. DHA-paclitaxel (500 mg/m²/week) was administered by a 1-hour intravenous infusion for five consecutive weeks in a 6-weeks cycle. Response was assessed using the Response Evaluation Criteria in Solid Tumors every 6 weeks. Twenty-two patients were enrolled. The patients' median age was 56 years (range: 33-79 years). Nine patients had a systemic therapy for metastatic disease earlier. The median number of treatment cycles was 1 (range 1-7 cycles). One chemonaive patient with liver metastases had partial response lasting for 5 months. Seven patients (32%) had stable disease with a median duration of 3 months (range: 3-7 months). The median overall survival was 9.8 months. Neutropenia (23%) and musculoskeletal pain (10%) were the most common grade 3 and grade 4 toxicities. As a single-agent therapy, DHA-paclitaxel is safe and well-tolerated in metastatic uveal melanoma patients. Its efficacy in this disease is limited with 32% of patients achieving stable disease. Further evaluation of DHA-paclitaxel in combination with other chemotherapeutic agents and/or targeted agents may improve its antitumor activity.

To determine the maximum tolerated dose, dose-limiting toxicity (DLT), and pharmacokinetics of weekly docosahexaenoic acid-paclitaxel (DHA-paclitaxel), a taxane fatty acid conjugate.

Docosahexaenoic acid-paclitaxel was administered by 2-hour i.v. infusion weekly for three out of four weeks. DHA-paclitaxel 200 mg/m(2) was dose escalated by 100 mg/m(2) per cohort to 600 mg/m(2). Blood samples for pharmacokinetics of DHA-paclitaxel and paclitaxel derived from DHA-paclitaxel were collected.

Twenty-one patients received 42 cycles of treatment over five dose levels. Grade 3/4 neutropenia occurred in five patients but was not dose limiting. Grade 3 hyperbilirubinemia, a DLT, and grade 1 sensory neuropathy occurred at the highest dose level. PK analyses demonstrated dose proportional C (max) and AUC(0-24). Limited accumulation of DHA-paclitaxel or paclitaxel occurred with weekly treatment. Increased DHA-paclitaxel and paclitaxel AUC(0-24) were associated with increased neutropenia. Of the 19 patients evaluable for response, three patients with esophageal, melanoma and colon carcinoma had stable disease for 11, 16, and 17 weeks, respectively.

Docosahexaenoic acid-paclitaxel administered weekly to a maximum dose of 600 mg/m(2) was well-tolerated. The slow release of paclitaxel from DHA-paclitaxel and the weekly schedule approximates continuous infusion paclitaxel which may be more active than every 3 week or weekly taxanes.