Weekly paclitaxel combined with pegylated liposomal doxorubicin (Caelyx™) given every 4 weeks:: dose-finding and pharmacokinetic study in patients with advanced solid tumors

Background: We aimed to define the maximum tolerated dose (MTD) and characterize the toxicity of the combination of pegylated liposomal doxorubicin (PLD; Caelyx(TM)) and weekly paclitaxel (wPTX), and to investigate pharmacokinetics of PLD in this combination. Methods: A phase I study was performed with an initial dose of 50 mg/m(2) wPTX and 30 mg/m(2) PLD. The paclitaxel dose was escalated in increments of 10 mg/m(2) and PLD in increments of 5 mg/m(2) until the MTD was reached. The pharmacokinetics of PLD were studied at the highest achieved dose levels. Results: Forty-four cancer patients were enrolled. The MTD was 30/90 and 35/80 mg/m(2) for PLD/wPTX. Dose-limiting toxicities included treatment delay for neutropenia grade 3, febrile neutropenia, palmar-plantar erythrodysesthesia and deep venous thrombosis. Toxicity below the MTD was mild: skin toxicity grade 1-2 developed at high cumulative doses and vascular thrombotic events occurred in two patients with predisposing factors. No cardiotoxicity or clinically relevant peripheral neuropathy was seen. Nausea/vomiting and alopecia were negligible. Three complete responses and nine partial responses were documented among 34 evaluable cases. PLD plasma concentrations were evaluated in seven patients treated at subMTD. Paclitaxel produced a median 53.5% increase of PLD area under the concentration curve (range 4.4%-219%). Conclusions: The combination of PLD/wPTX constitutes an active chemotherapy regimen with mild toxicity that merits investigation in phase II at 30/80 or 35/70 mg/m(2). Patients should be monitored for a potentially increased risk of thromboembolic events.